Future therapeutic strategies for olfactory disorders: electrical stimulation, stem cell therapy, and transplantation of olfactory epithelium-an overview.

Olfactory disorders may be temporary or permanent and can have various causes. Currently, many COVID-19 patients report a reduced or complete loss of olfactory function. A wide range of treatment options have been investigated in the past, such as olfactory training, acupuncture, medical therapy, transcranial magnetic stimulation, or surgical excision of olfactory epithelium, e.g., in severe qualitative smell disorders. The development of a bioelectric nose, e.g., in connection with direct electrical stimulation or transplantation of olfactory epithelium or stem cells, represent treatment options of the future. The basis of these developments and the state of knowledge is discussed in the following work.

[Future therapeutic strategies for olfactory disorders: electrical stimulation, stem cell therapy, and transplantation of olfactory epithelium-an overview]. / Zukunftsweisende Therapieansätze bei Riechstörungen: elektrische Stimulation, Stammzelltherapie und Transplantation von Riechepithel ­ eine Übersicht.

Olfactory disorders may be temporary or permanent and can have various causes. Currently, many COVID-19 patients report a reduced or complete loss of olfactory function. A wide range of treatment options have been investigated in the past, such as olfactory training, acupuncture, medical therapy, transcranial magnetic stimulation, or surgical excision of olfactory epithelium, e.g., in severe qualitative smell disorders. The development of a bioelectric nose, e.g., in connection with direct electrical stimulation or transplantation of olfactory epithelium or stem cells, represent treatment options of the future. The basis of these developments and the state of knowledge is discussed in the following work.

Association between olfactory function and quality of life in patients with olfactory disorders: a multicenter study in over 760 participants.

BACKGROUND: This cross-sectional, multi-centric study aimed to investigate the differences in quality of life among patients with olfactory dysfunction (OD) of different origin, and to identify factors associated with olfactory-related quality of life (QOL). METHODS: Seven hundred sixty-three adults were recruited from 8 Smell & Taste clinics in Germany, Switzerland, and Austria. Olfactory-related QOL was assessed by the Questionnaire of Olfactory Disorders (QOD). Olfactory function was assessed with the "Sniffin' Sticks" test; self-assessment was performed with visual analog scales. RESULTS: Patients with post-infectious and post-traumatic OD showed poorer olfactory-related QOL than patients with sinonasal and idiopathic OD. The olfactory-related QOL was positively associated with the "Sniffin' Sticks" test score, self-assessed olfactory function, disease duration, and age, with younger olfactory dysfunction patients showing lower QOL. Female patients presented with poorer olfactory-related QOL. In addition, the results showed that self-assessment of olfactory function explained more of the variance in olfactory-related QOL than olfactory function evaluated by the Sniffin’ Sticks test. CONCLUSIONS: In addition to the psychophysical testing results, several factors such as disease cause, disease duration, sex, or self- assessed olfactory dysfunction should be taken into account when assessing the individual severity of the smell loss.

Relation of anxiety and other psychometric measures, balance deficits, impaired quality of life, and perceived state of health to dizziness handicap inventory scores for patients with dizziness.

BACKGROUND: An important question influencing therapy for dizziness is whether the strengths of the relationships of emotional and functional aspects of dizziness to 1) anxiety and other mental states, 2) perceived state of health (SoH) and quality of life (QoL) are different in patients with and without normal balance control. We attempted to answer this question by examining these dimensions' regression strengths with Dizziness Handicap Inventory (DHI) scores. METHODS: We divided 40 patients receiving group cognitive behavioural therapy (CBT) and vestibular rehabilitation for dizziness, into 2 groups: dizziness only (DO) and normal balance control; dizziness and a quantified balance deficit (QBD). Group-wise, we first performed stepwise multivariate regression analysis relating total DHI scores with Brief Symptom Inventory (BSI) sub-scores obtained pre- and post-therapy. Then, regression analysis was expanded to include SoH, QoL, and balance scores. Finally, we performed regressions with DHI sub-scores. RESULTS: In both groups, the BSI phobic anxiety state score was selected first in the multivariate regression analysis. In the DO group, obsessiveness/compulsiveness was also selected. The correlation coefficient, R, was 0.74 and 0.55 for the DO and QBD groups, respectively. When QoL and SoH scores were included, R values increased to 0.86 and 0.74, explaining in total 74, and 55% of the DHI variance for DO and QBD groups, respectively. Correlations with balance scores were not significant (R ≤ 0.21). The psychometric scores selected showed the strongest correlations with emotional DHI sub-scores, and perceived QoL and SoH scores with functional DHI sub-scores. CONCLUSIONS: Our findings suggest that reducing phobic anxiety and obsessiveness/compulsiveness during CBT may improve emotional aspects of dizziness and targeting perceived SoH and QoL may improve functional aspects of dizziness for those with and without normal balance control.

[Diagnostics and treatment of olfactory dysfunction]. / Diagnostik und Therapie von Riechstörungen.

BACKGROUND: Dysosmia is one of the most common disorders in otorhinolaryngology. However, epidemiological data are lacking and treatment strategies are insufficiently standardized. OBJECTIVE: The aim of this study was to evaluate the frequency of causes of olfactory disorders and the different therapeutic approaches used in ENT departments in German-speaking countries. The results were also compared to findings of the survey in 2000. Furthermore, a systematic review of treatment strategies was conducted. MATERIALS AND METHODS: In 2010, a two-page survey addressing olfactory dysfunction was sent to all ENT departments in German-speaking countries. The literature review included sources such as PubMed, the Cochrane Library, and relevant guidelines. RESULTS: The diagnosis of dysosmia was made less frequently in ENT departments (decrease of 52%). The three most widely used therapeutic approaches were corticosteroids (topical and systemic) and systemic antibiotics. There is evidence in the literature showing a small to medium effect of topical steroids in sinonasal smell disorders. CONCLUSION: Since a 50% decrease in the prevalence of olfactory disturbances is unlikely, the lower patient numbers may relate to a more critical diagnosis. The use of olfactory training in clinics has increased significantly (from <6% to up to 23%). The use of topical steroids for sinonasal dysosmia is evidence based. Smell training is a safe and effective treatment strategy, especially in post-infectious and post-traumatic olfactory disorders.

Effects of a program of cognitive-behavioural group therapy, vestibular rehabilitation, and psychoeducational explanations on patients with dizziness and no quantified balance deficit, compared to patients with dizziness and a quantified balance deficit.

BACKGROUND: We examined whether a program combining cognitive-behavioural therapy (CBT), vestibular rehabilitation (VR) and psychoeducation is equally effective in improving psychometric measures in patients with dizziness independent of a balance deficit. Measures of patients with dizziness only (DO) were compared to those of patients also having a quantified balance deficit (QBD). METHODS: 32 patients (23 female, 9 male) with persistent dizziness were analysed as 2 groups based on stance and gait balance control: those with QBD (pathological balance) or DO (normal balance). Dizziness Handicap Inventory (DHI) and Brief Symptom Inventory (BSI) questionnaires were used pre- and post-therapy to assess psychometric measures. Patients then received the same combination therapy in a group setting. RESULTS: The QBD group mean age was 60.6, SD 8.3, and DO group mean age 44.8, SD 12.1, years. Pre-therapy, questionnaire scores were pathological but not different between groups. Balance improved significantly for the QBD group (p=0.003) but not for the DO group. DHI and BSI scores improved significantly in the DO group (0.001

Olfactory deficits decrease the time resolution for trigeminal lateralization.

OBJECTIVES: To date the temporal resolution of the detection of almost simultaneously applied intranasal trigeminal stimuli is unknown. The aim of our study was to examine this temporal resolution in an/hyposmic subjects, who are known to have reduced trigeminal sensitivity and compare it with healthy controls. METHODS: Participants were 20 posttraumatic an/hyposmic patients, and 23 healthy controls (matched with regard to sex and age). Olfactory function was tested psychophysically using the Sniffin´ Sticks test battery. Bilateral trigeminal stimulation was carried out using a birhinal high-precision olfactometer. The trigeminal stimulus used was CO2 60% v/v, the interstimulus interval ranged from 28 to 32s, stimulus duration was 200ms. Time-lags tested between right and left side of stimulation were at 40, 80, 120, 160 and 200ms. Subjects raised their left or right hand to indicate the side on which the stimulus had been perceived first. RESULTS: In both groups the accuracy in the trigeminal lateralization task increased with the time-lag but normosmic subjects significantly outperformed an/hyposmics in the 200ms time-lag condition. Normosmics significantly exceeded 50% chance level at the time-lag of 80ms, whereas an/hyposmics were only able to score above chance starting from 120ms time-lag. Lateralization scores significantly decreased with age. CONCLUSIONS: At a time lag of 200ms intranasal trigeminal stimuli can be lateralized. The reduced trigeminal sensitivity in patients with anosmia or hyposmia leads to an increased time lag required for correct perception of intranasal, almost simultaneously, applied stimuli.

[Diagnosis of olfactory disorders]. / Diagnostik bei Riechstörungen.

Alongside a structured case history, the measurement of olfactory function and diagnosis of olfactory dysfunction is of great clinical importance. Validated and established methods have been developed to this aim. The "Sniffin' Sticks" test battery is an easy-to-use tool for assessing olfactory function. Recording of olfactory event-related potentials is a more objective approach, which is particularly important in medicolegal cases. Imaging techniques such as MRI and CT provide additional information in the diagnosis of olfactory disorders. The latter techniques enable the anatomical structures of the skull and brain with the areas relevant to olfactory function to be evaluated.

Olfactory source localization in the open field using one or both nostrils.

OBJECTIVE: This study aims to examine humans ́ abilities to localize odorants within the open field. METHODOLOGY: Young participants were tested on a localization task using a relatively selective olfactory stimulus (2-phenylethyl-alcohol, PEA) and cineol, an odorant with a strong trigeminal component. Participants were blindfolded and had to localize an odorant source at 2 m distance (far-field condition) and a 0.4 m distance (near-field condition) with either two nostrils open or only one open nostril. RESULTS: For the odorant with trigeminal properties, the number of correct trials did not differ when one or both nostrils were used, while more PEA localization trials were correctly completed with both rather than one nostril. In the near-field condition, correct localization was possible in 72-80% of the trials, irrespective of the odorant and the number of nostrils used. Localization accuracy, measured as spatial deviation from the olfactory source, was significantly higher in the near-field compared to the far-field condition, but independent of the odorant being localized. CONCLUSION: Odorant localization within the open field is difficult, but possible. In contrast to the general view, humans seem to be able to exploit the two-nostril advantage with increasing task difficulty.

[Olfactory dysfunction in neurodegenerative disorders]. / Riechstörungen bei neurodegenerativen Erkrankungen.

Impairment of olfaction is a characteristic feature of many neurodegenerative diseases. This review summarizes the available information about olfactory function in distinct neurodegenerative conditions and indicates the advantageous use of olfactory testing in the diagnosis of Parkinson's disease and Alzheimer's dementia.

Olfactory function in primary open-angle glaucoma patients.

PURPOSE: The aim of this study was to assess the olfactory function of primary open-angle glaucoma patients. PATIENTS AND METHODS: We analyzed odour threshold, identification, and discrimination in 30 primary open-angle glaucoma patients and 30 age- and gender-matched healthy control subjects. The "Sniffin' Sticks" test battery was applied sequentially on both sides, scores of two nostrils were averaged and means were compared with Mann-Whitney U-test between the groups. RESULTS: Scores for odour threshold were 5.9 +/- 2.2 and 7.4 +/- 2.1 in glaucoma and control group, respectively (p = 0.01), for odour discrimination 10.5 +/- 2.0 and 10.8 +/- 1.6 (p = 0.65), and for odour identification 11.8 +/- 2.1 and 10.6 +/- 1.6 (p = 0.008). Comparing within glaucoma group between those with (n = 18) and without history (n = 12) of cold hands and feet, the former had significantly better odour threshold scores, 6.6 +/- 1.5, than the latter, 4.8 +/- 2.6 (p = 0.036); no difference in other two olfactory modalities were detected. CONCLUSION: Changes of olfactory function have been described in neurodegenerations such as Alzheimer and Parkinson diseases. Complex alterations of olfactory performance seem to be present in POAG patients as well.

Olfactory-induced brain activity in Parkinson's disease relates to the expression of event-related potentials: a functional magnetic resonance imaging study.

Olfactory disorders are common in patients with idiopathic Parkinson's disease (IPD). In IPD patients with hyposmia olfactory event-related potentials (ERPs) are typically found to be delayed or absent. Altered ERPs in IPD patients may also be consistent with reduced neuronal activity in the medial temporal lobe following olfactory stimulation, as demonstrated by functional magnetic resonance imaging (fMRI). We analyzed ERPs and fMRI scans of hyposmic IPD patients (n=18) to gain further insight about the brain regions involved in generation of olfactory ERPs. Patients were separated into two groups (n=9 per group), based on the detectability (+) or non-detectability (-) of ERPs. Central activation during olfactory stimulation was examined using fMRI. Both ERP+ and ERP- patients showed activity in brain areas relevant to olfactory processing, such as the amygdala, parahippocampal regions, and temporal regions (BA 37, 21/22). Comparison of both groups revealed higher activation in ERP+ patients, especially in the amygdala, parahippocampal cortex, inferior frontal gyrus (BA 47), insula, cingulate gyrus, striatum, and inferior temporal gyrus. The relationship between the expression of olfactory ERPs and cortical activation patterns seen during olfactory stimulation in fMRI in IPD patients supports the idea that ERPs are a sensitive marker of neurodegeneration in olfactory regions. In accordance with current neuropathological staging concepts, olfactory ERPs may be reflecting pathological changes in olfactory regions, independent of the typically observed nigro-striatal degeneration in IPD. Reduced activation of primary olfactory areas in the ERP-group may reflect a severe disruption of olfactory processing in these patients.

Ageing, neurodegeneration, and olfactory and gustatory loss.

Olfactory and gustatory disorders increase with advancing age. Moreover, olfactory disorders are common in neurodegenerative disorders, especially in idiopathic Parkinson's disease (IPD) and Alzheimer's Disease (AD). Since the decrease in olfactory function is usually gradual, it often remains undetected. Given the poor self-assessment of olfactory function, olfactory testing is mandatory in suspected cases to establish the diagnosis of hyposmia or anosmia. The high rate of anosmia over the age of 70 is suspected to be due to several factors such as changes in the olfactory epithelium (reduced mucus secretion, hormonal changes, changes in epithelial thickness, for example), and the reduced neuroregeneration rate in olfactory receptor cells themselves. There is no known adequate treatment for stopping or reversing this age-related decline in olfaction. In IPD, olfactory impairment precedes motor symptoms by years and is independent of dopaminergic loss. Using fMRI, altered neuronal activity in the amygdaloid complex and hippocampal formation during olfactory stimulation have been demonstrated, as has a link between the expression of olfactory event-related potentials and olfactory-induced brain activity. In AD--by contrast with IPD--the severity of the disease and the olfactory disorder correlate. The olfactory disorders alone, however, cannot distinguish between AD and IPD. A complete loss of gustatory function is rare, while dysgeusia is common, especially with increasing age. There are multiple possible explanations, including concomitant disease and the side-effects of medication. These need to be established on the basis of exact history and examination. Treatment remains difficult.

Functional imaging of the cerebral olfactory system in patients with Parkinson's disease.

BACKGROUND: Olfactory dysfunction is a frequent non-motor symptom in Parkinson's disease (PD) and is considered to be an early manifestation of the disease. OBJECTIVE: To establish the cortical basis of olfactory function in patients with PD. METHOD: Functional magnetic resonance imaging (fMRI) was used to investigate brain activity related to olfactory processing in patients with hyposmic PD at mild to moderate stages of the disease (n = 12, median Hoehn and Yahr stage 2.0) and in healthy, age-matched controls (n = 16) while passively perceiving a positively valenced (rose-like) odorant. RESULTS: In both patients with PD and healthy controls, olfactory stimulation activated brain regions relevant for olfactory processing (ie the amygdaloid complex, lateral orbitofrontal cortex, striatum, thalamus, midbrain and the hippocampal formation). In controls, a bilateral activation of the amygdala and hippocampus was observed, whereas patients with PD involved these structures in the left hemisphere only. Group comparison showed that regions of higher activation in patients with PD were located bilaterally in the inferior frontal gyrus (BA 44/45) and anterior cingulate gyrus (BA 24/32), and the left dorsal and right ventral striatum. CONCLUSIONS: In patients with PD, results obtained under the specific conditions used suggest that neuronal activity in the amygdala and hippocampus is reduced. Assuming an impact on olfactory-related regions early in PD, our findings support the idea that selective impairment of these brain regions contributes to olfactory dysfunction. Furthermore, neuronal activity in components of the dopaminergic, cortico-striatal loops appears to be upregulated, indicating that compensatory processes are involved. This mechanism has not yet been demonstrated during olfactory processing in PD.

[Olfactory dysfunction. Epidemiology, pathophsiological classification, diagnosis and therapy]. / Riechstörungen. Epidemiologie, pathophysiologische Klassifikation, Diagnose und Therapie.

The present manuscript is the result of a collaborative effort within the framework of the Working Group of Olfactology and Gustology of the German Society for ENT, Head and Neck Surgery. It provides a comprehensive overview about the current views on the epidemiology, terminology, diagnostics, and therapy of olfactory dysfunction, and aims to offer a framework for the standardized procedures for the diagnosis and therapy of olfactory disorders.

[Etiology, diagnostic and therapeutic management of taste disorders]. / Schmeckstörungen--Ursachen, Diagnostik und Therapie.

Taste disorders can be subdivided in ageusia, which is the inability to detect any qualitative gustatory sensation and hypogeusia, which is a decreased sensitivity to all tastants. Dysgeusia or pargeusia is a distortion or perversion in the perception of a tastant in contrast to phantosmia, which is a perception of taste that occurs in the absence of a tastant. The site of lesion can usually be determined by history and clinical examination. History taking should always include the assessment of current and former medication. Conditions that interfere with access of a tastant to the taste bud are differentiated from conditions that either injure the receptor cell or damage the gustatory afferent nerves and the central pathways. Psychophysical taste evaluation includes identification of quality using sprays or taste strips and testing of intensity perception measuring threshold using the 3-drop technique. Moreover, measurement of taste in localized areas can be performed either with conventional chemicals or using an electrogustometer. Gustatory evoked potentials are not yet routinely elicited. Therapy has to be planned according to the cause of the disorder.

[Olfactory dysfunctions. Epidemiology and therapy in Germany, Austria and Switzerland]. / Riechstörungen. Epidemiologie und Therapie in Deutschland, Osterreich und der Schweiz.

INTRODUCTION: Olfactory dysfunction has been reported to affect more than 200,000 patients a year in the USA. The aim of this survey was to obtain comparable epidemiological data and treatment information on olfactory dysfunction in German speaking countries. METHODS: Questionnaires were sent to all otorhinolaryngology departments in Germany, Austria and Switzerland; 52% of hospitals completed the survey. RESULTS: An average of 46 patients with olfactory dysfunction were treated per hospital every month. Hyp- and anosmia were most commonly caused by inflammatory diseases of the nose/paranasal sinuses (53%), respiratory dysfunction (19%), or postviral conditions (11%). Steroids were used most frequently for pharmacological treatment (topically 82%; orally 65%). Approximately one third of the clinics used B vitamins, or zinc; 80% of the hospitals performed surgery to treat underlying diseases. Acupuncture and smell training was used by approximately 20%. CONCLUSION: A total of 79,000 patients per year are treated for olfactory dysfunction in German hospitals. The vast majority of these disorders (72%) is caused by sinunasal diseases. The quality control of therapeutic strategies is urgently needed.