Palmitoylethanolamide and Luteolin for postinfectious olfactory disorders: How clinically meaningful is its effect?

INTRODUCTION: The prevalence of post-viral olfactory dysfunction has increased significantly during the COVID-19 pandemic, posing a major challenge for patients and practitioners. While olfactory training (OT) is a common approach to therapy, there has been increasing interest in supplementing therapy with a combination of palmitoylethanolamide (PEA) and luteolin (LUT), which are known for their anti-inflammatory properties. In this study, their efficacy in the treatment of patients with olfactory loss following upper respiratory tract infections, mainly COVID-19, was investigated in an outpatient clinic. METHODS: Fifty patients with persistent olfactory dysfunction were randomized to two groups: one receiving OT and PEA-LUT, the other OT alone. Olfactory function was evaluated before and after treatment. RESULTS: The study group showed significant improvements in odor discrimination and overall olfactory function (TDI score) after treatment with PEA-LUT and OT, while the control group did not. However, when clinically meaningful improvements were considered, there was no significant difference between the groups. CONCLUSION: The present study suggests that while PEA-LUT may have the potential to improve olfactory function in post-viral dysfunction, the additional benefit over OT alone may be limited. These results contrast with some previous studies.

Pronounced Olfactory Habituation with Age.

OBJECTIVES: Olfactory habituation is a transient decrease in olfactory sensitivity caused by prolonged odor exposure, aiding in the discernment of new olfactory stimuli against the background. We explored the impact of subclinical olfactory impairment on odor habituation using age as a proxy. METHODS: Before the actual experiment, the individual olfactory threshold for the rose-like odorant phenylethyl alcohol (PEA) was assessed separately for the left and right nostril using the "Sniffin' Sticks" test, and ratings for odor intensity and pleasantness were collected. After applying a nasal clip continuously delivering PEA odor to one nostril for 10 min and 2 h, respectively, threshold, intensity, and pleasantness were reassessed immediately after clip removal. RESULTS: In the group of 80 participants (younger adults-mean age 27.7 ± 4.5 years; older adults-mean age 61.5 ± 4.7 years), olfactory thresholds were already significantly elevated after just 10 min, and this habituation was even more pronounced after 2 h. This effect could be observed bilaterally even though significantly more distinct on the exposed side. Older participants generally exhibited a more pronounced habituation on the exposed side after 2 h compared to the younger participants. CONCLUSION: The results indicate that older people experience more notable habituation after extended exposure to odors. This is most likely due to the compromised olfactory function in age. Although older and younger subjects scored in the normosmic range when tested with standardized olfactory tests, the stress on the system after exposure to an odor clearly revealed the lower functionality of the aging sense of smell. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Comparison of Patient Characteristics and Olfactory Sensitivity for Trigger Odorants in Parosmia and Phantosmia.

OBJECTIVES: This study aimed to determine the characteristics of patients with qualitative olfactory dysfunction (qualOD) and whether individuals with parosmia exhibit increased olfactory sensitivity to previously reported odorous triggers of parosmia. METHODS: This study included individuals aged ≥18 years, divided into quantitative OD only, parosmia, and phantosmia groups. Data collected included: clinical-demographic data, "Sniffin' Sticks" scores, questionnaires (depression scale, importance of olfaction), and information about parosmia and phantosmia. A proportion of patients underwent trigger odor threshold testing for 2-Furfurylthiol [FFT] found in coffee and 2,6-nonadienal [Nonadienal] found in cucumber. RESULTS: Those with parosmia were typically younger women, with shorter OD duration due to post-viral OD (PVOD), hyposmic/normosmic, and experienced parosmia more severely. Parosmia was 3.5 times more likely in PVOD. Those with phantosmia were older, with longer OD duration due to idiopathic OD, hyposmic/anosmic, and experienced phantosmia less severely. There were no significant differences between FFT and Nonadienal threshold scores in patients with parosmia, phantosmia, or only quantitative OD, but all groups had significantly increased olfactory sensitivity for trigger odors compared to phenyl ethyl alcohol (PEA). CONCLUSION: Parosmia and phantosmia patients have distinct characteristics. This may provide clinicians with a better understanding of possible olfactory outcomes in these patients. The higher olfactory sensitivity of all groups to trigger odors compared to PEA raises interesting points about parosmia triggers and odors in the context of warning for danger, in relation to the pathophysiology of parosmia that may be worth exploring in future studies. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3277-3285, 2024.

Patients with parosmia respond faster to unpleasant odors than patients with hyposmia: Insights from olfactory event-related potentials.

BACKGROUND: Diagnosing parosmia is a challenge. The present study aimed to explore the distinctions between hyposmic patients with and without parosmia utilizing electroencephalography-derived olfactory event-related potentials (ERP). METHODS: Forty-four patients with hyposmia were enrolled and divided into a group with parosmia (n = 23, mean age ± standard deviation = 48 ± 14 years, seven men) and a group without parosmia (n = 21, age = 52 ± 12 years, seven men) based on the clinical interview. Additionally, 21 healthy controls (mean age = 45 ± 14 years, six men) were included. Various measurements were obtained, including the Sniffin' Stick test, threshold tests for the odorants furfural mercaptan and 2,6-nonadienal, a modified Sniffin' Stick parosmia test, and well-being ratings. Chemosensory ERPs were recorded separately for each nostril using high-precision, computer-controlled air-dilution olfactometry. RESULTS: Patients with parosmia had a decreased olfactory function similar to that observed in patients with hyposmia, although the odor sensitivity of patients with severe parosmia remained relatively unaffected. Patients with parosmia reported a decrease in well-being compared to controls. The severity of parosmia was positively correlated with odor sensitivity. Furthermore, patients with severe parosmia exhibited faster responses to unpleasant odors than patients without parosmia. CONCLUSION: Overall, the present findings support the idea that parosmia predominantly occurs during olfactory recovery, significantly disturbing patients and warranting the development of effective treatments. Notably, the relatively faster responses of hyposmic patients with severe parosmia suggest that the generation of distorted olfactory responses may involve early stages of the processing of olfactory information.

Odor dilution sorting as a clinical test of olfactory function: normative values and reliability data.

Clinical assessment of an individual's sense of smell has gained prominence, but its resource-intensive nature necessitates the exploration of self-administered methods. In this study, a cohort of 68 patients with olfactory loss and 55 controls were assessed using a recently introduced olfactory test. This test involves sorting 2 odorants (eugenol and phenylethyl alcohol) in 5 dilutions according to odor intensity, with an average application time of 3.5 min. The sorting task score, calculated as the mean of Kendall's Tau between the assigned and true dilution orders and normalized to [0,1], identified a cutoff for anosmia at a score ≤ 0.7. This cutoff, which marks the 90th percentile of scores obtained with randomly ordered dilutions, had a balanced accuracy of 89% (78% to 97%) for detecting anosmia, comparable to traditional odor threshold assessments. Retest evaluations suggested a score difference of ±0.15 as a cutoff for clinically significant changes in olfactory function. In conclusion, the olfactory sorting test represents a simple, self-administered approach to the detection of anosmia or preserved olfactory function. With balanced accuracy similar to existing brief olfactory tests, this method offers a practical and user-friendly alternative for screening anosmia, addressing the need for resource-efficient assessments in clinical settings.

Olfactory dysfunction after autoimmune encephalitis depending on the antibody type and limbic MRI pathologies.

Objective: Patients' olfactory function after autoimmune encephalitis (AE) involving limbic structures may be impaired. This study aimed to characterize olfactory function in patients after autoimmune encephalitides. Methods: A case-control study was performed including 11 AE patients with antibodies against NMDAR (n = 4), GAD (n = 3), VGKC (n = 3) and antibody-negative AE (n = 1) and a control group of 12 patients with pneumococcal meningo-encephalitis (PC). In subgroup analyses, AE patients with and without NMDAR-antibodies were compared. Olfactory function was assessed using the Sniffin Sticks test and the resulting TDI-score (threshold, discrimination, identification). Involvement of limbic structures was evaluated on imaging data (MRI). Statistical analyses were performed to test for correlations of TDI-score and MRI results. Results: The overall olfactory function of the AE-group and the PC-group was comparable (mean TDI 32.0 [CI 27.3-36.7], 32.3 [CI 28.5-36.0)]. The proportions of hyposmic patients were similar compared to the general population. However, AE patients of the non-NMDAR group had significantly lower TDI-scores (28.9 ± 6,8) than NMDAR patients (37.4 ± 3.5) (p = 0.046) and a significantly lower discrimination capability than the NMDAR patients (9.9 ± 2.0 vs. 14.5 ± 0.6) (p = 0.002). The non-NMDAR patients had significantly more limbic MRI pathologies (6/7) compared to the NMDAR patients (0/4) (p = 0.015). Furthermore, a correlation between limbic MRI pathologies and worse capability of smelling discrimination was found (p = 0.016, r = -0.704, n = 11). Conclusion: Our results indicate that patients with NMDAR autoimmune encephalitis have normal long term olfactory function. However, patients with non-NMDAR autoimmune encephalitis appear to have a persistently impaired olfactory function, probably mediated by encephalitic damage to limbic structures.

Olfactory Dysfunction: Etiology, Diagnosis, and Treatment.

BACKGROUND: Disorders of the sense of smell have received greater attention because of the frequency with which they occur as a symptom of SARS-CoV-2 infection. Olfactory dysfunction can lead to profound reduction in quality of life and may arise from many different causes. METHODS: A selective literature review was conducted with consideration of the current version of the guideline issued by the Association of the Scientific Medical Societies in Germany. RESULTS: The cornerstones of diagnosis are the relevant medical history and psychophysical testing of olfactory function using standardized validated tests. Modern treatment strategies are oriented on the cause of the dysfunction. While treatment of the underlying inflammation takes precedence in patients with sinunasal dysosmia, olfactory training is the primary treatment option for other forms of the disorder. The prognosis is determined not only by the cause of the olfactory dysfunction and the patient's age, but also by the olfactory performance as measured at the time of diagnosis. CONCLUSION: Options for the treatment of olfactory dysfunction are available but limited, depending on the cause. It is therefore important to carry out a detailed diagnostic work-up and keep the patient informed of the expected course and prognosis.

Assessment of postviral qualitative olfactory dysfunction using the short SSParoT in patients with and without parosmia.

PURPOSE: To examine if the short formed Sniffin Sticks Parosmia Test (SSParoT), a test for parosmia can distinguish cases with parosmia from cases without parosmia. METHODS: In this study, 63 patients with postviral olfactory dysfunction were investigated including both COVID and non-COVID cases. The age, symptom duration, degree of parosmia/phantosmia was collected. For olfactory function, the Sniffin Sticks olfactory score was obtained including scores for odor threshold, discrimination and identification. For assessment of parosmic changes, the short SSParoT was adopted and both hedonic range (HedRang) and direction (HedDir) was calculated. RESULTS: The mean HedRang of patients with parosmia (2.35, standard deviation, SD = 1.40) and without parosmia (2.78, SD = 1.09) was smaller than that in controls (4.5, SD = 2.15). However, the mean HedDir of both parosmia (- 0.32, SD = 0.98) and non-parosmia patients (0.04, SD = 1.07) was similar to controls (- 0.1, SD = 1.55). When considering that the 10th percentile of the distribution of SSParoT score should distinguish between patients with and without parosmia, the sensitivity of the HedRang was 29% and specificity was 67%. For HedDir, the sensitivity was 6% and specificity was 100%. Only the odor identification score (r = 0.34, p = 0.01) discriminated parosmia and non-parosmia while other measures including HedRang and HedDir did not. CONCLUSION: The present study showed that the short SSParoT score could not distinguish patients with parosmia from patients without parosmia. Although the SSParoT represents an innovative approach to assess parosmia, and could be useful in the tracking of parosmic changes, the development of measures to diagnose parosmia in an objective way remains a challenge.

Functional improvement in children and adolescents with primary headache after an interdisciplinary multimodal therapy program: the DreKiP study.

BACKGROUND: More than 2/3 of children and adolescents in Germany regularly suffer from headaches. Headache-related limitations in everyday life, school drop-out and educational impairment are common. Structured therapy programs for young headache patients are widely missing. METHODS: One hundred eleven patients with frequent migraine and/or tension type headache were treated in a 15 hour group program in afternoons, parallel with school, parents received 7 hours of therapy. At the beginning of the program (T0), 6 (T1) and 12 months (T2) after completion, data on headache related disability (PedMidas), headache frequency, intensity, and pediatric pain disability score (PPDI) were prospectively collected to investigate the effects of the therapy. RESULTS: Seventy-five patients (9-19 years, median = 14; 66.7% female) and their parents provided patient reported outcome measures showing at T1 (65 patients) and T2 (47 patients) reduced headache frequency (last 3 months headache days median T0: 30 days; T1: 18 days, reduction of median 12 days since T0; T2: 13 days, reduction of median 17 days since T0). Linear mixed models revealed significant reduction (T0/T1 p = 0,002; T0/T2 p = 0,001). Reduced headache disability has been reported at T1 and T2 (PedMidas median T0 = 30, T1 = 15, T2 = 7; p < 0,001, p < 0,001 respectively). Follow up data of a subgroup of patients 24 months after the treatment point to sustainable effects. CONCLUSIONS: The interdisciplinary multimodal headache therapy program DreKiP reduces headache frequency and headache related disability significantly 6-12 months following its completion. TRIAL REGISTRATION: DRKS00027523, retrospectively registered.

Acupuncture is associated with a positive effect on odour discrimination in patients with postinfectious smell loss-a controlled prospective study.

INTRODUCTION: Smell disorders are common in the general population and occur e.g., after infections, trauma or idiopathically Treatment strategies for smell loss range from surgery, medication to olfactory training, depending on the pathology, but they are limited This study examined the effect of acupuncture on olfactory function. METHODS: Sixty patients with smell loss following infections of the upper respiratory tract were included in this investigation Half of the study group were randomly assigned to verum acupuncture and the other half to sham acupuncture Olfaction was measured by means of the "Sniffin' Sticks" test battery (odour threshold, discrimination and identification). RESULTS: Compared to sham acupuncture, verum was associated with an improvement of smell function as measured by the TDI score (p = 0.039) The improvement was largely determined by improvement in odour discrimination, and was significantly better in patients with a shorter duration of the disorder. CONCLUSION: The present results suggest that acupuncture is an effective supplementary treatment option for patients with olfactory loss.

A Simple Taste Test for Clinical Assessment of Taste and Oral Somatosensory Function-The "Seven-iTT".

Taste dysfunctions may occur, for example, after viral infection, surgery, medications, or with age. In clinical practice, it is important to assess patients' taste function with rapidity and reliability. This study aimed to develop a test that assesses human gustatory sensitivity together with somatosensory functions of astringency and spiciness. A total of 154 healthy subjects and 51 patients with chemosensory dysfunction rated their gustatory sensitivity. They underwent a whole-mouth identification test of 12 filter-paper strips impregnated with low and high concentrations of sweet, sour, salty, bitter (sucrose, citric acid, NaCl, quinine), astringency (tannin), and spiciness (capsaicin). The percentage of correct identifications for high-concentrated sweet and sour, and for low-concentrated salty, bitter and spicy was lower in patients as compared with healthy participants. Interestingly, a lower identification in patients for both astringent concentrations was found. Based on the results, we proposed the Seven-iTT to assess chemo/somatosensory function, with a cut-off of 6 out of 7. The test score discriminated patients from healthy controls and showed gender differences among healthy controls. This quantitative test seems to be suitable for routine clinical assessment of gustatory and trigeminal function. It also provides new evidence on the mutual interaction between the two sensory systems.

Machine Learning Refutes Loss of Smell as a Risk Indicator of Diabetes Mellitus.

Because it is associated with central nervous changes, and olfactory dysfunction has been reported with increased prevalence among persons with diabetes, this study addressed the question of whether the risk of developing diabetes in the next 10 years is reflected in olfactory symptoms. In a cross-sectional study, in 164 individuals seeking medical consulting for possible diabetes, olfactory function was evaluated using a standardized clinical test assessing olfactory threshold, odor discrimination, and odor identification. Metabolomics parameters were assessed via blood concentrations. The individual diabetes risk was quantified according to the validated German version of the "FINDRISK" diabetes risk score. Machine learning algorithms trained with metabolomics patterns predicted low or high diabetes risk with a balanced accuracy of 63-75%. Similarly, olfactory subtest results predicted the olfactory dysfunction category with a balanced accuracy of 85-94%, occasionally reaching 100%. However, olfactory subtest results failed to improve the prediction of diabetes risk based on metabolomics data, and metabolomics data did not improve the prediction of the olfactory dysfunction category based on olfactory subtest results. Results of the present study suggest that olfactory function is not a useful predictor of diabetes.

Data-science based analysis of perceptual spaces of odors in olfactory loss.

Diminished sense of smell impairs the quality of life but olfactorily disabled people are hardly considered in measures of disability inclusion. We aimed to stratify perceptual characteristics and odors according to the extent to which they are perceived differently with reduced sense of smell, as a possible basis for creating olfactory experiences that are enjoyed in a similar way by subjects with normal or impaired olfactory function. In 146 subjects with normal or reduced olfactory function, perceptual characteristics (edibility, intensity, irritation, temperature, familiarity, hedonics, painfulness) were tested for four sets of 10 different odors each. Data were analyzed with (i) a projection based on principal component analysis and (ii) the training of a machine-learning algorithm in a 1000-fold cross-validated setting to distinguish between olfactory diagnosis based on odor property ratings. Both analytical approaches identified perceived intensity and familiarity with the odor as discriminating characteristics between olfactory diagnoses, while evoked pain sensation and perceived temperature were not discriminating, followed by edibility. Two disjoint sets of odors were identified, i.e., d = 4 "discriminating odors" with respect to olfactory diagnosis, including cis-3-hexenol, methyl salicylate, 1-butanol and cineole, and d = 7 "non-discriminating odors", including benzyl acetate, heptanal, 4-ethyl-octanoic acid, methional, isobutyric acid, 4-decanolide and p-cresol. Different weightings of the perceptual properties of odors with normal or reduced sense of smell indicate possibilities to create sensory experiences such as food, meals or scents that by emphasizing trigeminal perceptions can be enjoyed by both normosmic and hyposmic individuals.

Olfactory impairment as an early marker of Parkinson's disease in REM sleep behaviour disorder: a systematic review and meta-analysis.

Olfactory impairment and rapid eye movement sleep behaviour disorder (RBD) are prodromal symptoms of Parkinson's disease (PD) that may be associated with each other. This review aims to investigate the significance of olfaction in the diagnosis and prognosis of patients with RBD and to assess moderating factors affecting olfactory performance. We searched articles on olfaction in RBD and PD in five electronic databases. We identified 32 studies for the systematic review and used 28 of those, including 2858 participants for meta-analysis. Results revealed significant deficits in odour identification (g=-1.80; 95% CI: -2.17 to -1.43), threshold (g=-1.29; 95% CI: -1.67 to -0.91), discrimination (g=-1.08; 95% CI: -1.28 to -0.87) and overall olfactory function (g=-1.64; 95% CI: -1.94 to -1.35) in patients with RBD. Except for the Unified Parkinson's Disease Rating Scale Part III scores, none of the known moderating variables (including age, sex, disease duration and years of education) accounted for the olfactory function heterogeneity in patients with RBD. We identified similar olfactory impairments in patients with RBD and patients with PD (either with or without underlying RBD). These findings suggest that olfactory impairment may be a sensitive and stable diagnostic biomarker of RBD and appears to be useful for identifying patients with idiopathic RBD at high risk for early conversion to PD.

Brain response to odors presented inside the nose, directly in front of the nose or with ambient air.

OBJECTIVE: Functional magnetic resonance imaging (fMRI) allows the measurement of changes in blood flow in association with changes in brain activity. This technique has been used frequently to study brain activation in response to odorous stimuli. The aim of this study was to evaluate the effects of odor delivery conditions on brain responses obtained with fMRI. STUDY DESIGN: Prospective cohort study SETTING: Academic institution. METHODS: Twenty healthy volunteers (mean age = 29.5 years; 9 women, 11 men) participated. Three odor delivery methods were used: "tube" (odor presented intranasally with separate tubing for each nostril), "mask" (odor presented in a face mask covering the subject's nose) and "vacuum" (odor presented into the ambient air). Presentation of the pleasant "peach" odor was performed using a computer-controlled olfactometer. Subjects were asked to evaluate the intensity of the odors after each fMRI run. RESULTS: "Tube" showed higher self-rated odor intensity compared to "mask" and "vacuum" (F = 18.4, p < 0.001). Odor intensity had a positive correlation (r = 0.6, p < 0.05) with percent signal change extracted from the secondary olfactory cortex region in the mask condition. In the tube condition, several selected regions of interest (Amygdala, Insula, Thalamus) showed lower activations compared to the other two conditions (puncorrected < 0.001, mask > tube, vacuum > tube). CONCLUSION: Activations of region of interests (ROIs) in response to the odorous stimuli showed differences under the three conditions (mask, tube, vacuum). In this passive fMRI paradigm, this may partly reflect the differences in odor intensity, but also in attention and contextual variables related to odor perception.

Parosmia is Associated with Relevant Olfactory Recovery After Olfactory Training.

OBJECTIVE/HYPOTHESIS: This study aims to determine the association between parosmia and clinically relevant recovery of olfactory function in patients with post-infectious olfactory dysfunction (PIOD) receiving olfactory training. STUDY DESIGN: Retrospective cohort study. METHODS: This was a retrospective cohort study of patients with PIOD that received olfactory training. Adult patients with the major complaint of quantitative smell loss were recruited and treated at several ENT clinics in German between 2008 and 2018. The outcome was based on the association between smell-loss related factors (including parosmia and phantosmia) and clinically relevant changes in overall and subdimension olfactory function of threshold, discrimination, and identification using binary logistic regression analysis. RESULTS: A total of 153 participants with PIOD were included. Clinically relevant improvements in overall olfactory function were more likely in those that had lower baseline olfactory function. Relevant improvements in discrimination function were more likely in those that had lower baseline olfactory function and those that had parosmia at the initial visit. Similarly, relevant improvements in odor identification were more likely in those that had a lower baseline olfactory function and in those who had parosmia at the first visit. Clinically significant improvements in odor threshold were more likely in those who were older in age. CONCLUSIONS: This study demonstrated that the presence of parosmia is associated with clinically relevant recovery in olfactory discrimination and identification function in patients with PIOD receiving olfactory training. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:618-623, 2021.

Apparently Minor Head Trauma Can Lead to Anosmia: A Case Report.

We report the case of a 49-year-old female patient who suffered from anosmia following an apparently mild head trauma when bumping into a door at her home. She reported no other accompanying symptoms after the injury that day. Olfactory function was completely lost, which was noted the day after the trauma. Gustatory function remained normal. Magnetic resonance imaging indicated lesions/bleeding in the right frontal lobe and in the area of the olfactory sulcus/bulb. The present case indicates that in case of apparently mild head trauma with anosmia, an MRI scan of the head should be performed because of suspect brain damage. This case also points to the deeper question how to gauge severity of head trauma.

Chemosensory function is decreased in rheumatoid arthritis.

PURPOSE: Research indicates that rheumatic disorders are accompanied by decreased chemosensory function. The present study aimed to specifically evaluate this issue in patients with rheumatoid arthritis (RA). METHODS: 212 RA patients (43 men, 169 women, mean age 59 ± 13.3 years), and 30 healthy controls (10 men, 20 women, mean age 40 ± 15.3 years), were included in this study. Chemosensory measurements consisted of olfactory testing using the "Sniffin' Sticks" test battery (with odor thresholds, odor discrimination and odor identification; OT, OD, OI) and gustatory testing on a suprathreshold and a quasi-threshold level using "taste sprays" and "taste strips", respectively. In addition, inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) and RA autoantibodies (anti-cyclic citrullinated peptides, RA factors) were evaluated. RESULTS: Olfactory measurements showed 4% of the RA patients functionally anosmic and 40% hyposmic. RA patients scored significantly lower in suprathreshold olfactory tests (OD, OI) compared to controls (OI: 12.5 ± 2.5 vs. 14.1 ± 1.3; OD: 11.3 ± 2.7 vs. 12.9 ± 1.7). In addition, RA patient had decreased taste function compared to healthy individuals (10.4 ± 2.6 vs. 11.7 ± 1.7). Chemosensory function did not correlate with parameters related to the severity of disease. CONCLUSION: Chemosensory function (taste, OD and OI) appears to be decreased in RA patients. In contrast, OT was not affected. Changes in chemosensory function seem to be independent of disease parameters such as duration of disease or disease activity.