Trigeminal cold receptors and airflow perception are altered in chronic rhinosinusitis.

BACKGROUND: In chronic rhinosinusitis (CRS), nasal obstruction can often be explained by anatomical deformities, polyps, or congested nasal mucosa. However, in cases with little deformity or inflammation, perceived nasal obstruction may result from reduced airflow perception caused by an alteration of the intranasal trigeminal system. The aim of this study was to assess this association. METHODOLOGY: We performed a prospective case-control study of 15 CRS patients, 18 patients with a deviated nasal septum (DNS) and 16 healthy controls. We assessed olfactory function using the Sniffin' Sticks test and Visual Analog Scales (VAS). We used the Trigeminal Lateralization Task (TLT) with eucalyptol and cinnamaldehyde to examine intranasal trigeminal function. Further, we assessed nasal patency with Peak Nasal Inspiratory Flow and VAS. Finally, we measured protein levels of trigeminal receptors (TRPM8, TRPA1 and TRPV1) and inflammatory markers (IL-13, INF-y and eosinophils) in CRS and DNS patients' mucosal biopsies using Western Blots. RESULTS: CRS patients had significantly lower olfactory function than DNS and healthy controls. They also had significantly lower TLT scores for eucalyptol than both other groups. CRS patients had significantly lower nasal patency than controls; for DNS patients this was limited to subjective measures of nasal patency. In line with this, CRS patients exhibited significantly higher levels of sTRPM8-18 than DNS patients. CONCLUSIONS: Intranasal trigeminal function is decreased in CRS patients, possibly due to the overexpression of short isoforms of TRPM8 receptors.

Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative.

STATEMENT OF PROBLEM: Evaluating the effectiveness of the management of Olfactory Dysfunction (OD) has been limited by a paucity of high-quality randomised and/or controlled trials. A major barrier is heterogeneity of outcomes in such studies. Core outcome sets (COS) - standardized sets of outcomes that should be measured/reported as determined by consensus-would help overcome this problem and facilitate future meta-analyses and/or systematic reviews (SRs). We set out to develop a COS for interventions for patients with OD. METHODS: A long-list of potential outcomes was identified by a steering group utilising a literature review, thematic analysis of a wide range of stakeholders' views and systematic analysis of currently available Patient Reported Outcome Measures (PROMs). A subsequent e-Delphi process allowed patients and healthcare practitioners to individually rate the outcomes in terms of importance on a 9-point Likert scale. RESULTS: After 2 rounds of the iterative eDelphi process, the initial outcomes were distilled down to a final COS including subjective questions (visual analogue scores, quantitative and qualitative), quality of life measures, psychophysical testing of smell, baseline psychophysical testing of taste, and presence of side effects along with the investigational medicine/device and patient's symptom log. CONCLUSIONS: Inclusion of these core outcomes in future trials will increase the value of research on clinical interventions for OD. We include recommendations regarding the outcomes that should be measured, although future work will be required to further develop and revalidate existing outcome measures.

Position paper on olfactory dysfunction: 2023

BACKGROUND: Since publication of the original Position Paper on Olfactory Dysfunction in 2017 (PPOD-17), the personal and societal burden of olfactory disorders has come sharply into focus through the lens of the COVID-19 pandemic. Clinicians, scientists and the public are now more aware of the importance of olfaction, and the impact of its dysfunction on quality of life, nutrition, social relationships and mental health. Accordingly, new basic, translational and clinical research has resulted in significant progress since the PPOD-17. In this updated document, we present and discuss currently available evidence for the diagnosis and management of olfactory dysfunction. Major updates to the current version include, amongst others: new recommendations on olfactory related terminology; new imaging recommendations; new sections on qualitative OD and COVID-19 OD; updated management section. Recommendations were agreed by all co-authors using a modified Delphi process. CONCLUSIONS: We have provided an overview of current evidence and expert-agreed recommendations for the definition, investigation, and management of OD. As for our original Position Paper, we hope that this updated document will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency, and generalisability of work in this field.

Trigeminal impairment in treatment-refractory chronic nasal obstruction.

BACKGROUND: Patients with anatomically unexplained, chronic nasal obstruction (CNO) that is refractory to medical treatment pose a challenge for clinicians. A surgical solution, addressing mechanical obstacles, is unsuited for these patients. CNO may result from disrupted airflow perception due to activation of the intranasal trigeminal system; therefore, aim of this study is to evaluate if intranasal trigeminal function of these CNO patients is decreased. METHODS: In this retrospective cross-sectional study, we compared 143 CNO patients and 58 healthy volunteers, between 18 to 80 years old. We assessed nasal patency by means of rhinomanometry (RM) and measured susceptibility of intranasal trigeminal system by the trigeminal lateralization task (TLT). RESULTS: TLT scores were significantly lower in CNO patients compared to controls (p less than 0.001), but RM scores were not different between groups. Accordingly, TLT allowed to identify CNO patients with an accuracy of the area under the curve (AUC) of 0.78, while the value for RM was at chance (AUC=0.47). CNO patients showed normal reaction to vasoconstrictive agents with significantly lower RM values after Xylomethazoline application. CONCLUSION: Results suggest that reported nasal obstruction in CNO patients without any obvious anatomical obstacle and resistant to medical treatment may be linked to decreased perception of nasal airflow rather than physical obstruction. In this sub-set of CNO patients, trigeminal testing more adequately reflects the reported obstruction than nasal resistance assessment does. In future studies, the relation of the trigeminal status and the subjective sensation of nasal obstruction needs to be addressed with validated patient rated outcome measures (PROMs).

Position paper on olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Olfactory and executive dysfunctions following orbito-basal lesions in traumatic brain injury.

OBJECTIVE: To study the acute relationship between olfactory function and traumatic brain injury (TBI), cognitive functions and outcome. METHODS: Sixty-two patients with TBI were evaluated within the first 2 weeks following TBI. The Sniffin'Sticks identification test was used to assess olfaction. A neuropsychological evaluation was carried out to assess attention, verbal fluency, naming, memory, problem-solving and mental flexibility. The extended Glasgow Outcome Scale (GOSE) and the Disability Rating Scale (DRS) were rated at discharge from acute care. RESULTS: Traumatic lesions located in the basal frontal area resulted in odour identification scores that were significantly lower than when lesions were elsewhere (p < 0.001). A significant positive correlation was shown between odour identification scores and mental flexibility scores (p = 0.004) and patients with hyposmia had worse performances on executive tests measuring problem-solving, verbal fluency and mental flexibility (p < 0.01). Moreover, the odour identification score and the DRS total score were related (p = 0.019). CONCLUSIONS: These findings add information regarding acute olfactory status following TBI and provide evidence on the importance of assessing olfaction very early post-TBI in order to plan intervention and determine what accident prevention advice will be required for home or work re-integration.

[How we smell and what it means to us: basic principles of the sense of smell]. / Wie wir riechen und was es für uns bedeutet : Grundlagen des Geruchssinns.

The origins of the sense of smell lie in the perception of environmental molecules and go back to unicellular organisms such as bacteria. Odors transmit a multitude of information about the chemical composition of our environment. The sense of smell helps people and animals with orientation in space, warns of potential threats, influences the choice of sexual partners, regulates food intake and influences feelings and social behavior in general. The perception of odors begins in sensory neurons residing in the olfactory epithelium that express G protein-coupled receptors, the so-called olfactory receptors. The binding of odor molecules to olfactory receptors initiates a signal transduction cascade that converts olfactory stimuli into electrical signals. These signals are then transmitted to the olfactory bulb, the first relay center in the olfactory pathway, via the axons of the sensory neurons. The olfactory information is processed in the bulb and then transferred to higher olfactory centers via axons of mitral cells, the bulbar projection neurons. This review describes the mechanisms involved in peripheral detection of odorants, outlines the further processing of olfactory information in higher olfactory centers and finally gives an overview of the overall significance of the ability to smell.

Intranasal localizability of odorants: influence of stimulus volume.

When an odorant is presented to one side of the nose and air to the other, the ability to localize which side received the odorant depends upon trigeminal nerve stimulation. It has been shown that performance on this lateralization task increases as stimulus concentration increases. In this study, we determined the influences of stimulus volume and sex on the ability to localize each of 8 odorants presented at neat concentrations: anethole, geraniol, limonene, linalool, menthol, methyl salicylate, phenyl ethanol, and vanillin. At a low stimulus volume (11 mL), only menthol was localized at an above-chance level. At a high stimulus volume (21 mL), above-chance localization occurred for all odorants except vanillin. Women were significantly better than men in localizing menthol. Stimuli rated as most intense were those that were most readily localized. The detection performance measures, as well as rated intensity values, significantly correlated with earlier findings of the trigeminal detectability of odorants presented to anosmic and normosmic subjects. This study suggests that differences in stimulus volume may explain some discrepant findings within the trigeminal chemosensory literature and supports the concept that vanillin may be a "relatively pure" olfactory stimulus.

Cross-modal integration of intranasal stimuli: a functional magnetic resonance imaging study.

Most odorants, in addition to the olfactory system, also activate the intranasal trigeminal system. Recent studies have shown that pure trigeminal stimulation activates somatosensory regions as well as regions traditionally thought of as primary olfactory areas. As a main aim of this study we wished to a) ascertain which brain regions are responsive to an "artificially" bimodal odor composed of a trigeminal (CO(2)) and an olfactory stimulant (phenyl ethyl alcohol, PEA) and b) determine if presenting CO(2) and PEA simultaneously activates different brain regions than when presenting them individually. Fifteen men were scanned using functional magnetic resonance imaging while smelling PEA, CO(2), and a mixture of both stimuli (CO(2)PEA) presented simultaneously. Odors were presented monorhinally to the right nostril in a block design. The contrast between CO(2)PEA and baseline revealed areas implicated in the processing of both olfactory and trigeminal stimuli. When the mixture was contrasted with the sum of its single components (CO(2)PEA-{CO(2)+PEA}), activations in integration centers (left superior temporal and right intraparietal sulcus) and in orbitofrontal areas (left medial and lateral orbitofrontal cortex) were detected. The opposite contrast ({CO(2)+PEA}-CO(2)PEA) did not reveal any significant activation. In contrast to studies which have used natural mixed olfactory/trigeminal stimuli, we have shown that the perception of an artificial mixed olfactory/trigeminal stimulus activates, as opposed to inhibiting the olfactory cortex. Further, we also conclude that a mixed olfactory/trigeminal stimulus appears to lead to higher cortical activations than the sum of its parts.

Cerebral processing of gustatory stimuli in patients with taste loss.

Aim was to investigate differences in the central-nervous processing of gustatory stimuli between normogeusic subjects and patients with taste disorders. Twelve subjects with normal gustatory function and eight patients suffering from hypo- to ageusia underwent one fMRI run each in a 1.5 T scanner where they received liquid gustatory stimuli. fMRI analyses were performed by means of SPM2. Across all participants clusters of activated voxels were mainly found in orbitofrontal and insular regions of interest. Even those patients who did not perceive any stimuli showed some activation of gustatory centers. Group comparisons revealed higher activation of the insular and orbitofrontal cortices in patients compared to the group of healthy subjects. While further studies are needed, this finding may be interpreted in terms of enhanced neuronal recruitment due to functional impairment in patients with gustatory loss. It may ultimately prove useful in terms of the prognostic evaluation of individual patients.

Intranasal trigeminal function in subjects with and without an intact sense of smell.

The intranasal trigeminal system is involved in the perception of odors. To investigate the cerebral processing of sensory information from the trigeminal nerve in detail we studied subjects with and without olfactory function using functional magnetic resonance imaging. A normosmic group (n=12) was compared with a group of anosmic subjects (n=11). For trigeminal stimulation gaseous CO(2) was used. Following right-sided stimulation with CO(2) controls exhibited a stronger right-sided cerebral activation than anosmic subjects. Stronger activation was found in controls compared to anosmic subjects for the right prefrontal cortex, the right somatosensory cortex (SI), and the left parietal insula. In contrast, relatively higher activation was found in anosmic subjects for the left supplementary motor area in the frontal lobe, the right superior and middle temporal lobe, the left parahippocampal gyrus in the limbic lobe, and the sub-lobar region of the left putamen and right insula which was mostly due to a decreased BOLD signal of controls in these areas. Additional conjunction analysis revealed that activated areas common to the two groups were the cerebellum and the right premotor frontal cortex. These data suggest that the processing of the trigeminally mediated information is different in the presence or absence of an intact sense of smell, pointing towards the intimate connection between the two chemosensory systems.

The neural representation of odor is modulated by the presence of a trigeminal stimulus during odor encoding.

OBJECTIVES: Odor perception does not simply consist in hierarchical processing from transduction to a single "true" cerebral representation. Odor sensation may be modulated by available sensory information during encoding. The present study set out to examine whether the presence of a pure trigeminal stimulus during odor encoding may modulate odor perception at both behavioral and cortical levels. METHODS: Participants were tested in a 2-session within-subject design: first, an odor encoding session included a delay conditioning procedure in which relatively selective olfactory stimulants (phenyl ethyl alcohol or vanillin, Conditioned Stimulus+, CS+) were presented either with a pulse of CO(2) (Unconditioned Stimulus, US), or alone (Conditioned Stimulus-, CS-); then, in the second session, both pure odorants (CS+ and CS-) were presented alone. During this second session, olfactory event-related potentials were simultaneously recorded and analyzed at different electrode sites including Cz and Pz (sites known to have maximal amplitudes for trigeminal and olfactory stimuli, respectively). After each trial, subjects were asked to rate odor intensity and hedonics. RESULTS: The results showed that CS+ intensity ratings increased in 8 subjects and decreased in 6. Cortically, a group effect was observed for P2 amplitude, which increased in the "CS+ intensity increase" group vs. the "CS+ intensity decrease" group at Cz (p<0.05) but not at Pz (p>0.05). CONCLUSIONS: This result suggests that the presence of a pure trigeminal stimulus (CO(2)) during odor encoding alters the neural representation of a pure odor. SIGNIFICANCE: The neural representation of odors comprises not only the odor itself but also contextual information (trigeminal in the present case) presented during encoding.

Interactions between the chemical senses: trigeminal function in patients with olfactory loss.

The intranasal trigeminal and the olfactory system are intimately connected. There is evidence showing that acquired olfactory loss leads to reduced trigeminal sensitivity due to the lack of a central-nervous interaction. Both, the orbitofrontal cortex and the rostral insula appear to be of significance in the amplification of trigeminal input which is missing in patients with olfactory loss. On peripheral levels, however, adaptive mechanisms seem to produce an increase in the trigeminal responsiveness of patients with hyposmia or anosmia.

Position paper on olfactory dysfunction.

Background: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: • Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. • Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. • Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. • Comprehensive chemosensory assessment should include gustatory screening. • Smell training can be helpful in patients with olfactory loss of several aetiologies. Conclusions: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Chemosensory specific reduction of trigeminal sensitivity in subjects with olfactory dysfunction.

Humans with olfactory loss have been found to exhibit a decreased sensitivity of the chemosensory trigeminal system. It is not clear, whether the reduced trigeminal sensitivity is restricted to the chemosensitive properties of the trigeminal nerve, or whether it reflects a general decrease of trigeminal sensitivity which is also found for cutaneous afferents. To investigate the relationship between cutaneous somatosensory and intranasal chemosensory trigeminal sensitivity, 91 subjects were investigated. Forty-five of them were considered healthy controls, whereas 46 subjects had olfactory dysfunction. Subjects with olfactory dysfunction were found to have higher thresholds for CO2 than controls indicating lower trigeminal chemosensory sensitivity in subjects with olfactory dysfunction. Both etiology and degree of olfactory dysfunction appeared to have an impact on CO2 thresholds. In contrast, no such differences were found with regard to detection thresholds for electrical cutaneous stimulation. These results indicate that the decrease of trigeminal sensitivity in subjects with olfactory dysfunction is specific for chemosensory sensations.

Euosmia: a rare form of parosmia.

The nature of qualitative olfactory disorders such as phantosmia and parosmia is a matter of debate. Parosmia and phantosmia mainly occur in combination with post-traumatic or post-infectious olfactory loss. Rare causes of these disorders such as brain tumors, side-effects of drugs, paraneoplastic syndromes, psychiatric disorders or intracerebral haemorrhage have been reported. Parosmias are distorted sensations of smell elicited by an odor, whereas phantosmias persist permanently or occur without the presence of an odor source. Phantosmias differ widely in terms of their nature. In contrast, parosmias always seem to be unpleasant. We report the case of a female with post-infectious hyposmia who reported a pleasant parosmia to selected odorants. We have called this rare clinical presentation euosmia.

Post-infectious olfactory dysfunction exhibits a seasonal pattern.

HYPOTHESIS: We investigated whether olfactory dysfunction following infections of the upper respiratory tract (post-URTI) has an incidence matching the seasonality of URTIs. STUDY DESIGN: Retrospective study. METHODS: In total, 457 patients (126 male, 331 female) with post-URTI olfactory loss were examined during a 6-year-period (1999-2004). Their records were assessed for age, sex, and time of onset of the disease. The severity of olfactory dysfunction was assessed using the "Sniffin' Sticks" (odour threshold, odour discrimination, and odour identification). RESULTS: Incidence of post-URTI olfactory dysfunction exhibited seasonal fluctuations with deviations from the winter seasonality of URTIs. The overall incidence of the disease differed significantly between months. March (12.7%) and May (12.6%) were the months with the highest incidence of the disease throughout the year. The lowest incidence was observed in September (5.6%). Significant differences were found between these months and months with a high incidence of URTIs. DISCUSSION: The peak incidence of post-URTI olfactory loss in March may be explained by the high incidence of influenza at this time. However, it is unclear why the incidence of the disease presents a second peak in May, when the incidence of respiratory viruses is relatively low. Climate conditions at this time might play a role in the susceptibility of the nasal epithelia towards certain viral infections, e.g. parainfluenza type III. CONCLUSION: Post-URTI olfactory dysfunction exhibits spring seasonality with peaks in March and May and possible causative factors being influenza and parainfluenza viruses (type III), respectively.

Olfactory function in acute traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) represents a significant public health problem and is associated with a high rate of mortality and morbidity. Although TBI is amongst the most common causes of olfactory dysfunction the relationship between injury severity and olfactory problems has not yet been investigated with validated and standardized methods in the first days following the TBI. METHODS: We measured olfactory function in 63 patients admitted with TBI within the first 12 days following the trauma by means of the Sniffin' Sticks identification test (quantitative assessment) and a parosmia questionnaire (qualitative assessment). TBI severity was determined by means of the Glasgow Coma Scale (GCS) and by duration of post-traumatic amnesia (PTA) as measured by the Galveston Orientation and Amnesia Test. RESULTS: Poor olfactory scores correlated with a longer amnesia period, but not with GCS scores. Further, we observed higher parosmia scores in assault victims than in victims of falls or motor vehicle collisions. CONCLUSIONS: We show that PTA is intimately related to olfactory problems following a TBI. Thus, a thorough evaluation of olfaction is essential in order to detect posttraumatic olfactory dysfunction and to take appropriate actions early on to help the individual deal with this impairment.

Gustatory function in chronic inflammatory middle ear diseases.

HYPOTHESIS: Changes of gustatory function after ear surgery have been studied extensively. However, little is known on the influence of repeated/chronic inflammation within the middle ear on taste. STUDY DESIGN: Prospective study. MATERIALS AND METHODS: Forty-six patients suffering from either cholesteatoma (n = 25) or chronic otitis media mesotympanalis (n = 21) received quantitative gustatory tests. None of these patients had been operated on before these investigations. RESULTS: Side by side comparison showed a significantly lower taste function on the anterior two thirds of the tongue ipsilateral to the site of inflammation, regardless of the diagnosis. Further analyses exhibited a trend toward greater impairment in relation to the severity of the inflammatory process. CONCLUSION: These data are proof that taste function changes in relation to chronic middle ear diseases. It further shows that many of these alterations go unnoticed by the patients.

Comparison of lateralized and binasal olfactory thresholds.

We investigated whether dirhinal olfactory thresholds differ from monorhinal ones. Experiments 1 and 2 investigated butanol, Experiment 3 phenylethylalcohol. In Experiments 2 and 3 pen-like odor dispensing devices were used, in Experiment 1 odors were presented in glass bottles. Participants were in excellent health (Experiment 1: 14 female [f], 15 m [m], mean age [ma] 24 years; Experiment 2: 12 f, 19 m, ma 24 years; Experiment 3: 19 f, 19 m, ma 32 years). Thresholds were assessed for left, right, and both nostrils. No significant difference was found between dirhinal results and results for the best of two nostrils. Apart from this, thresholds were found to improve with repeated testing. In conclusion, using two odorants with different techniques of administration in studies performed at different sites, the present results indicated that there is no major difference between odor detection thresholds obtained for the best and both nostrils.