Olfactory Function and Olfactory Disorders

Abstract

The sense of smell is important. This became especially clear to patients with infection-related olfactory loss during the SARS-CoV-2 pandemic. We react, for example, to the body odors of other humans. The sense of smell warns us of danger, and it allows us to perceive flavors when eating and drinking. In essence, this means quality of life. Therefore, anosmia must be taken seriously. Although olfactory receptor neurons are characterized by regenerative capacity, anosmia is relatively common with about 5 % of anosmic people in the general population. Olfactory disorders are classified according to their causes (e. g., infections of the upper respiratory tract, traumatic brain injury, chronic rhinosinusitis, age) with the resulting different therapeutic options and prognoses. Thorough history taking is therefore important. A wide variety of tools are available for diagnosis, ranging from short screening tests and detailed multidimensional test procedures to electrophysiological and imaging methods. Thus, quantitative olfactory disorders are easily assessable and traceable. For qualitative olfactory disorders such as parosmia, however, no objectifying diagnostic procedures are currently available. Therapeutic options for olfactory disorders are limited. Nevertheless, there are effective options consisting of olfactory training as well as various additive drug therapies. The consultation and the competent discussion with the patients are of major importance.

Key words

smell - nose - chemosensation - anosmia

1. Introduction

Smelling is important. This became especially clear during the SARS-CoV-2 pandemic. Many people are now aware of what it is like to go through life without a sense of smell.

2. Definitions

In the context of quantitative olfactory disorders, there is a change of olfactory intensity (hyposmia or anosmia), whereas in qualitative olfactory disorders, the quality of odors is altered (parosmia) or there is odor perception in the absence of an olfactory stimulus (phantosmia) ([Table 1]). In parosmia or phantosmia typically unpleasant sensations are perceived. Qualitative changes are often found in combination with quantitative changes, but also as solitary olfactory disorders. Parosmias and phantosmias may occur together, and parosmias may also precede prolonged phantosmias. Thus, transitions and intermediate forms are possible in quantitative and qualitative olfactory disorders [1].

Table 1 Classification of olfactory disorders.

Term	Description
Normosmia	Normal olfaction
Quantitative olfactory disorders
Hyposmia (rarely also “microsmia”)	Reduced olfaction
Functional anosmia	Reduced or non-existing olfaction that is not useful in everyday life
Anosmia	Complete absence of olfaction
Specific anosmia (or “partial anosmia”)	Reduced perception of a certain odorant even if olfaction in general is present (normal physiological property without clinical relevance [445])
Hyperosmia	Increased perception of scents [188]
Qualitative olfactory disorders
Parosmia (rarely also “cacosmia”, “euosmia”, or “troposmia”)	Qualitatively distorted odor perception
Phantosmia	Perception of odors in absence of an odor source

In addition, multiple chemosensory sensitivity (MCS, also known as idiopathic environmental intolerance) can be found. MCS is a syndrome in which affected individuals react with a variety of symptoms such as heart palpitations, fainting spells, or asthmatic symptoms to exposure to a wide range of chemicals or fragrances. MCS is classified as a psychosomatic disease and treated accordingly [2] [3].

3. Epidemiology of olfactory disorders

The prevalence of olfactory impairment in the general population has been dynamic since the outbreak of SARS-CoV-2 [COVID-19] pandemic. For both COVID-19-related and non-COVID-19-related olfactory impairment, epidemiologic estimates vary widely depending on demographic samples, definition of impairment, and study method [4].

3.1 Self ratings

The 1994 National Health Interview Survey (NHIS) assessed chemosensory disorders in 42,000 randomly selected households in the United States of America [5]. It was estimated that 1.4% of the US adult population would have olfactory disorders that persisted at least three months. This prevalence increased with age, with approximately 40% of participants over 65 years reporting olfactory problems [5]. Other trials such as the Korea National Health and Nutrition Examination Survey (KNHANES) reported in 2009 that olfactory dysfunction was present in 4.5 to 6.3% of over 10,000 participants [6] [7]. The US National Health and Nutrition Examination Survey (NHANES) estimated the incidence of olfactory dysfunction to be 10.6 and 23%, respectively, in approximately 3,500 participants [8] [9]. Other studies present estimates ranging from 2.4% to 9.4% [10] [11] [12] (but see also [13]).

3.2 Psychophysical tests

The epidemiology of olfactory disorders has also been studied with psychophysical tests, almost invariably using odor identification tests. In a sample of 1,240 rhinologically healthy patients from Germany, 4.7% showed anosmia and 15% hyposmia [14], which was confirmed by a study by Vennemann et al. in 1,312 adults (aged 25 to 75 years, also from Germany) and by Brämerson et al. in Sweden (Vennemann: anosmia in 3.6%, hyposmia in 18%; Brämerson: anosmia in 5.8%, hyposmia in 15.3%) [15] [16] [17] (see also [18]). Consistently, these and other studies revealed an increased prevalence of olfactory disorders with higher age (e. g., [19] [20] [21] [22] [23] [24] [25] [26] [27]).

The OLFACAT survey of 9,348 participants examined the detection and identification of 4 self-administered microencapsulated odorants. The prevalence of olfactory impairment ranged from 19.4% to 48.8% [28]. In the Beaver Dam trial including 2,491 adults aged 53–97 years, the mean overall prevalence amounted to 24.5% and increased to 62.5% in subjects older than 80 years [29].

A recent meta-analysis summarized data from 25 studies with a total of 175,073 participants (mean age of 63 years, 56% male) [30]. The overall population-based prevalence of olfactory disorders was 22.2%. Prevalence was significantly higher when psychophysical measurement tools were used, in contrast to reports based on self-ratings (28.8% and 9.5%, respectively).

4. Anatomy and physiology of olfaction

Humans are able to perceive millions of different odors [31] [32]. In simplified terms, the recognition of odor molecules is based on interaction with specific receptors on olfactory sensory cells, circuity in the olfactory bulb (OB), and projection to central olfactory networks [33].

Traditionally, the main olfactory epithelium is thought to be confined to the olfactory cleft in the roof of the nasal cavity. However, it is not entirely clear what the extent of the olfactory epithelium is in the nasal cavity, as mature and functional olfactory receptor neurons (ORN), particularly in younger individuals [34] [35], have been found at the base of the middle turbinate [36] [37] [38] [39] [40]. These ORN have cilia that project into the mucus and are lined with olfactory receptors [33]. The olfactory receptors are transmembrane proteins that activate a specific G-coupled protein in response to binding to an odorant molecule. Upon this activation, the subunit of the G-protein activates an adenylate cyclase, thus increasing the concentration of cyclic adenosine monophosphate (cAMP) in the cell. The increase of cAMP in turn leads to an opening of cation channels, allowing calcium, among other things, to flow into the neuron. The cation flow causes depolarization of the membrane and initiation of an action potential, which is transmitted along the axons to the OB [41] [42].

Characterization of the olfactory receptor gene families has revealed approximately 400 active olfactory receptor genes in humans [43] [44] [45]. Among them, each mature ORN expresses only one olfactory receptor at a time [46] [47]. The perception of millions of odorants is enabled by complex combinatorial coding. Most odor molecules activate multiple receptors, and receptors in turn can be activated by many different odor molecules. Each odorant activates a specific combination of olfactory receptors, which in turn can act as agonists and antagonists [48] [49] [50] [51]. This combinatorial effect from the activation or inhibition of olfactory receptors allows comparatively few receptors to recognize a very large number of odor molecules. In addition, other types of chemoreceptors have been identified that are likely to be involved in human chemoreception [52] [53] [54].

The axons of the ORN run in bundles (olfactory fila) through the foramina of the lamina cribrosa to the OB. The OB is the first relay in the olfactory system and is located immediately above (dorsal) the lamina cribrosa and below (ventral) the orbitofrontal cortex. Within the OB, olfactory axons form their first synapse with bulbar glomerular cells. ORN are first-order excitatory sensory neurons that extend directly from the mucosa of the olfactory cleft into the brain. The ORN are exposed to the external environment, including pathogens and toxins, which can cause damage and even be lethal. Possibly, as a compensatory protective response to such damage, ORN possess the potential for neurogenesis. In this process, ORN are regenerated from the globose cells of the olfactory epithelium [55]. The turnover time in humans is not known but has been estimated to be 2–4 months [56] [57]. Olfactory neurogenesis is facilitated by glia-like olfactory sheath cells, which can be found in both olfactory epithelium and OB.

The second-order output neurons of the OB are the mitral and tufted cells. After signal integration, these neurons extend their axons along the lateral olfactory tract toward the structures of the primary olfactory cortex. These structures include the piriform cortex, the periamygdaloid cortex, the anterior cortical nucleus, and the entorhinal cortex. Further odor processing occurs in “secondary” and “tertiary” brain areas, including structures such as the hippocampus, parahippocampus, insula, and orbitofrontal cortex [58] [59].

Another important aspect of odor perception relates to the influence of nasal somatosensory sensations. For example, these sensations include the cooling sensation of menthol or the tingling sensation of CO₂ in carbonated beverages. These sensations are mediated in the nose by the first and second trigeminal branches [60] [61]. Trigeminal and olfactory functions are closely interconnected and interdependent [62] [63] [64] [65]. In addition, trigeminal activation is crucial for the perception of nasal airflow, which has been used, for example, to explain the sensation of a blocked nose in the absence of an anatomical correlate [66] [67] [68] [69].

5. Causes of olfactory disorders

Olfactory disorders are classified according to the site of the lesion or their cause ([Table 2]). However, the sites of lesion in olfactory disorders are not clearly assignable. For example, in olfactory disorders caused by trauma, the periphery or the CNS may be damaged (e. g., rupture of the olfactory fila, contusion of the OB or orbitofrontal cortex) [70] [71]. For this reason, the classification by cause is typically used.

Table 2 Main causes of olfactory disorders with typical characteristics.

Cause	Onset	Prognosis	Parosmias are present	Phantosmias are present
COVID-19 or other infections of the upper airways	Sudden	Often improvement	+++	++
Chronic rhinosinusitis	Gradual	Very good treatment options	−	++
Craniocerebral trauma	Sudden	Possible improvement	+	++
Neurological diseases like Parkinsons’ disease, Alzheimer’s disease, myastenia gravis	Gradual	Possible improvement	+	++
Drug-related/toxic causes	Variable	Variable, e. g., good after interruption/removal of the noxae	+	++
Congenital anosmia		No therapy available	−	−
Age	Gradual	Possible improvement	−	−
Other causes like iatrogenic damage (e. g. sinonasal and skull base surgery, laryngectomy), tumors, multiple systemic diseases	Variable	Possible improvement	+	++

5.1 COVID-19-related olfactory disorder

The estimated prevalence of COVID-19-associated olfactory disorders (COVID-19-OD) ranges from 5% to 88% [72]. One reason for this variability is the method used to assess olfactory dysfunction. Due to the infectious nature of SARS-CoV-2, the estimation of prevalence was based on subjective claims rather than psychophysical examinations, especially for acute illness. Based on subjective data, the prevalence for olfactory loss varied from 39 [73] to 53% [74]. In this context, self-assessment seems to significantly underestimate olfactory loss, because when including validated test instruments or using psychophysical testing of olfactory function, the pooled prevalence estimate of COVID-19-OD was significantly higher with 87 and 77%, respectively, than when using non-validated methods or recording subjective information [72] [74].

Compared with other postviral olfactory disorders, COVID-19 more often causes olfactory loss in younger individuals [73] [75], and women seem to be more commonly affected than men [75] [76] [77] (however, not in [73] [78]). When interpreting differences in prevalence, attention should be paid to possible selection bias, as the determination of prevalence is linked, among other things, to the assessment of olfactory function within the context of a targeted query or the spontaneous report of possible complaints, e. g., in consultation hours of specialized Smell and Taste clinics. In a meta-analysis of 3,563 patients, Borsetto et al. [79] found a higher prevalence for the development of an olfactory disorder in patients with a mild to moderate course of disease with about 67% compared to patients with a severe course with 31% (see also [73]).

In addition, there is a correlation of the prevalence of COVID-19-OD to viral variant [80] [81], which a higher likelihood of COVID-19-OD in the alpha virus variant (50%) compared to the delta variant (44%) or omicron variant (17%), with the omicron variant being the least likely to cause COVID-19-OD, probably due to mutations related to the so-called “spike” glycoprotein [82].

Olfactory loss is sometimes the only symptom of COVID-19 infection [83] [84]. In a systematic review and meta-analysis of 3,563 patients, loss of smell occurred as the first or only symptom in 20%, it followed other symptoms in the majority of the cases (54%), and appeared concurrently with other symptoms in 28% [79] (since it is a meta-analysis of multiple studies, the total does not reach 100%). Other symptoms associated with COVID-19 include cough, sore throat, dyspnea, fever, myalgia, rhinorrhea, and nasal obstruction. At the onset of the pandemic, rhinorrhea or nasal obstruction occurred less frequently compared with non-COVID-19-associated postviral olfactory disorders [85] [86].

COVID-19-OD begins suddenly, a few days after SARS-CoV-2 infection. At the onset of the COVID pandemic, a subjectively reported “sudden loss of smell” could detect disease with COVID-19 with a specificity of 97%, a sensitivity of 65%, a positive predictive value of 63%, and a negative predictive value of 97%, excluding patients with nasal obstruction [85]. In the later omicron variant, nasal obstruction and rhinorrhea were more frequently described with mostly intact olfaction [82].

At the onset of the COVID-19 pandemic, quantitative olfactory disorders in terms of hyposmia and anosmia were prominent [87]. In this context, the described olfactory disorders affect olfactory threshold, odor discrimination, and odor identification [78]. In the course of the disease, qualitative olfactory disorders have been increasingly reported [88] [89].

Based on self-ratings, a majority of COVID-19-OD show significant improvement or complete recovery within 1–2 weeks [90] [91]. Based on subjective assessments and psychophysical examinations, Boscolo-Rizzo et al. [92] reported significant improvement in COVID-19 smell disorders after 4 weeks with improvement reaching a kind of plateau after about 8 weeks. Six months after COVID-19 infection, 77% of the 110 patients rated their initial olfactory dysfunction as completely restored, while 20% described improvement, and 3% reported deterioration. In context of psychophysical testing 6 months after infection, the majority (59%) of the patients were diagnosed with hypersensitivity or anosmia by means of an olfactory identification test, despite the subjective absence of olfactory dysfunction. Over a longer observation period of 2 years, 88% reported complete recovery of their symptoms [95].

Depending on the olfactory test performed and due to the existing selection problem, different data on the course result. In psychophysical testing, reports of persistent olfactory dysfunction vary from 7% after 3 months (self-performed olfactory test) [93], to 15% after 3 months or 5% after 6 months (Sniffin’ Sticks identification test) [94], to 21% after 3 to 6 months (Sniffin’ Sticks threshold, discrimination, and identification) [78]. In psychophysical testing, 77% of the 102 patients were diagnosed with hyp- or anosmia after a mean of 7 months [96]. Tognetti et al. [97] also found persistent olfactory dysfunction 18 months after COVID-19 infection in 37% of 100 patients, 60% of whom were not subjectively aware of it. Even for a longer observation period, the proportion of patients with a psychophysically detectable olfactory disorder was significantly higher than in the subjective assessment of olfaction. This indicates that recovery after COVID-19-OD is slower than subjectively perceived.

An analysis of the diagnosis code “post-acute COVID-19 syndrome” (long-COVID) for the second quarter of 2021 was carried out by the health insurance funds in Germany to record the symptoms in a patient group and a control group referring mainly to the wild-type and alpha variant. An olfactory and/or gustatory disorder was described in 3.2% of the approximately 160,000 long-COVID patients and in 0.2% of the 320,000 control subjects [13]. Thus, although the reporting of olfactory and gustatory dysfunction is significantly higher within the long-COVID group, it should actually be significantly higher when the general prevalence of measurable olfactory dysfunction is included with 20% and 5% anosmia, respectively [15]. In summary, the problem in determining the prevalence of COVID-19-OD is that initially, due to infectivity, many patients will not be tested psychophysically. In addition, many patients are unaware of their olfactory loss during the course of the disease.

Parosmia occurred in 64% of the patients during the course of the study and started mainly within the first month after COVID-19. For the patients with parosmia, compared to self-ratings better olfactory function was found when using psychophysical testing [89]. Parosmia is therefore discussed as a possible prognostically favorable parameter for an improvement in olfactory function, as this could also be demonstrated for non-COVID-19-related postinfectious olfactory disorders [98] [99].

Despite the SARS-CoV-2 pandemic lasting more than two years, the pathogenesis of olfactory loss has not been fully elucidated. According to current knowledge, the single-stranded RNA virus SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) on human supporting cells of the olfactory mucosa, mediated by transmembrane protease serine subtype 2 (TMPRSS2). In this way, ORN are indirectly damaged, but this may result in more permanent damage if ORN are lost [100] [101]. Downregulation of ORN olfactory signaling genes is thought to be one of the mechanisms of damage [102]. Furthermore, there is an inflammatory change with an invasion of leukocytes into the olfactory mucosa [103] [104]. In addition, a central component of olfactory dysfunction is discussed [105], which is mainly explained by microvascular disturbances [106] and is not linked to viral detection in the brain as initially suspected, which was previously successful in hamsters [103], but not in humans [106].

5.2 Non-COVID-19-related postinfectious olfactory disorder (postviral olfactory disorder)

In addition to SARS-CoV-2, upper respiratory tract infections with other viruses (e. g., parainfluenza, HIV) are a common cause of olfactory disorders [107] [108]. Olfactory disorders can also be caused by bacteria, fungi, or for example microfilariae [109] [110] [111]. Women are more frequently affected than men, typically at an age beyond 50 years [112]. The latter may be due to the age-related decreased regenerative capacity of the olfactory system and accumulation of previous lesions [113]. Onset is sudden, and although many patients describe an unusually severe infection, some are unaware of the precipitating infection or the olfactory loss is not apparent until weeks after the infection. Parosmia often occurs during recovery [114]. Postinfectious olfactory loss improves more frequently than is the case with other causes [108]. Reden and colleagues showed improvement in psychophysical test scores of about one third of 262 patients with postviral olfactory impairment (duration ≥18 months) over a 14-month follow-up period [115], with higher [116] or lower estimates found in the literature [117] [118]. Important in interpreting the studies is how long the olfactory loss had been present at study entry – the longer the olfactory loss, the lower the prospect of recovery.

Pathophysiologically, either damage to the olfactory mucosa or to the central nervous processing system underlies the postinfectious olfactory disorders [119] [120]. Histological studies in patients with postinfectious olfactory disorders show neuroepithelial remodeling and replacement of olfactory cells by respiratory epithelium or occasionally metaplastic squamous epithelium [112] [121]. The number of ORN is reduced, they are inhomogeneously distributed, and their morphology may be altered (e. g., decrease in volume, reduction or shortening of dendrites) [112]. In addition, OB volumes are reduced in relation to the olfactory deficit and during the course of the disease [122].

5.3 Olfactory disorders as sequela of sinonasal disease

Rhinosinusitis is the main cause of olfactory loss, along with age [110] [123]. This can be either acute (lasting less than 12 weeks, with complete recovery) or chronic rhinosinusitis lasting 12 weeks or longer. There are a variety of phenotypic subtypes, while patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) are most affected by olfactory loss, followed by patients with chronic rhinosinusitis without nasal polyps (CRSsNP), non-allergic rhinitis, atrophic rhinitis, and allergic rhinitis [124]. According to the European Position Paper on Rhinosinusitis and Nasal Polyps and the American Academy of Otolaryngology – Head and Neck Surgery Guidelines as well as the AWMF guidelines on rhinosinusitis, olfactory dysfunction is a cardinal symptom of the disease [125] [126] [127]. The prevalence of CRS is 11% in the general European population [11].

Olfactory dysfunction due to CRS is caused by a combination of factors. These include impaired access of odorants to ORN because of nasal obstruction, mucosal edema, increased mucous secretion, and polyposis, as well as inflammation-related disruption of the binding of odorants to receptors [128] [129], structural remodeling of the olfactory epithelium [112], and finally functional and/or structural remodeling of the OB and primary and secondary olfactory cortex [130] [131] [132] [133]. Olfactory dysfunction associated with sinonasal diseases occurs gradually over months and years and varies over time [134] [135]. They can rarely improve without treatment, and parosmias tend not to be present [114] [136] [137].

5.4 Posttraumatic olfactory disorders

Traumatic brain injury is a major cause of permanent olfactory impairment. Various mechanisms are underlying, including septal fractures with mechanical obstruction of the nasal airway, direct neuroepithelial injury, edema or changes in mucus properties [138], shearing of the fila olfactoria as they are passing through the lamina cribrosa [70] [139] (but see also [140]), cerebral contusions, and intracerebral hemorrhage with subsequent gliosis [141] [142] [143].

Trauma-induced olfactory loss usually occurs suddenly but is often noticed until weeks and months after the accident, for example, upon return to the home environment after a prolonged hospital or rehab stay. This delayed onset of olfactory dysfunction could also reflect delayed central nervous damage. The more severe the traumatic brain injury, the more likely the loss of smell [142]. However, even very mild trauma can lead to olfactory loss [144]. In posttraumatic olfactory disorders, phantosmias are found comparatively often, and parosmias less frequently [114] [145] [146]. Regeneration rates in posttraumatic olfactory disorders are significantly lower than in postinfectious olfactory disorders. Nevertheless, recovery occurs over time in about 30% of the cases, depending on the severity of the injury [108] [115] [147] [148] [149] [150].

5.5 Olfactory disorders associated with neurological diseases

Olfactory disorders are an accompanying symptom of many neurological diseases, and neurodegenerative diseases in particular are associated with olfactory disorders. They are found in more than 90% of patients with idiopathic Parkinson’s syndrome (IPS) [151] and are considered as supportive diagnostic criterion in the clinical diagnosis of IPS [152]. In view of the fact that olfactory disorders sometimes precede motor symptoms by more than 10 years [153] [154], the majority of IPS patients already exhibit marked hyposmia or anosmia at the time of diagnosis. Therefore, at least in some patients with idiopathic olfactory loss and other risk factors (e. g., positive family history), an onset of IPS must be considered and neurologically evaluated [153]. To a lesser extent, olfactory disorders occur in atypical Parkinson’s disease, whereas, for example, restless legs syndrome or an essential tremor show an almost unrestricted olfactory ability [155]. Severe olfactory dysfunction is also found in Lewy body dementia, frontotemporal dementia, and Alzheimer’s disease (AD) [155]. Olfactory dysfunction in AD is also an early symptom of the disease and can already be detected in patients with mild cognitive impairment, with limitations in olfactory identification being a powerful predictor of conversion to dementia [156]. Olfactory deficits of varying severity are also observed in Huntington’s disease, heredo-ataxia, and motor neuron disease [155], and myasthenia gravis [157]. Patients with multiple sclerosis [158], many non-degenerative syndromes, such as temporal lobe epilepsy [159], acute depressive episodes [160], and schizophrenia [161] also often are associated with olfactory disorders.

In many synucleinopathies like IPS and in AD, neuropathological changes with typical protein deposits in the olfactory mucosa, OB, and olfactory tract, as well as in the primary and secondary olfactory cortex, have been described [162]. The diagnostic usefulness of these neuropathological changes is unclear so far, since, for example, in vivo biopsies of the olfactory epithelium show no significant immunohistochemical differences between IPS and patients with olfactory disorders of other origin [163].

5.6 Olfactory disorders related to age

Age-related olfactory loss is the most common cause of olfactory dysfunction. Approximately 50% of 65- to 80-year-old subjects and 62–80% of those over 80 years suffer from hyposmia [164]. Olfactory loss in higher age is considered as a positive predictor of 5-year mortality [165] [166], proving to be a stronger risk factor compared with most chronic diseases [165]. There is a clearer association with mortality for olfactory impairment than for hearing or visual impairment [166] and a pronounced association with neurodegenerative diseases [167].

The possible causes of olfactory disorders with higher age are manifold, although replacement of olfactory by respiratory epithelium with reduced regenerative capacity of the ORN, increasing fibrosis of the foramina of the lamina cribrosa, and loss of volume of the BO are considered typical and possibly causative changes [34] [168].

5.7 Idiopathic olfactory disorders

An idiopathic olfactory disorder is present when a thorough diagnosis does not reveal a clear cause. Up to 16% of patients examined in special centers fall into this category [169]. The diagnosis of “idiopathic olfactory disorder” is complex and difficult, as some of the cases could be due to, for example, asymptomatic upper respiratory tract infections, age-related olfactory dysfunction, or pre-symptomatic CRS [170] [171].

5.8 Drug- or toxin-induced olfactory disorders

Chronic exposure to toxins can cause olfactory disorders. Causes may include metals, such as cadmium and manganese, pesticides, herbicides, and solvents. Chemotherapeutic agents and other drugs can also lead to olfactory disorders, mediated by peripheral, neuroepithelial, or central lesions [172].

5.9 Congenital olfactory disorders

With an incidence of about 1:8000, congenital anosmias are found, often as isolated congenital anosmias, less frequently in the context of a genetic disorders (e. g., Kallmann syndrome – hypogonadotropic hypogonadism; Turner syndrome [173]; Bardet-Biedl syndrome [174]). Typically, the diagnosis is made between the ages of 12 and 16 years. Characteristic of congenital anosmia are hypoplastic/aplastic OB and flattened olfactory sulcus (<8 mm) [112] [175] [176] [177] [178]. However, cases of congenital anosmia in developed OB have also been reported in mutation of the CNGA2 gene [179]. On the other hand, a normal sense of smell in the absence or very much reduced OB also seems possible [180] [181]. In cases of suspected Kallmann syndrome or other syndromic constellations, patients should undergo genetic, endocrinological, and pediatric examinations.

5.10 Other causes of olfactory disorders

Olfactory dysfunction can be caused by a number of different diseases, e. g., intranasal or intracranial neoplasms, nasal surgery (for example, septoplasty [182]), endocrine diseases (for example, Addison’s disease, hypothyroidism, diabetes mellitus), hypertension, vitamin B12 deficiency, dysfunction as a complication of surgery (for example, anterior skull base surgery) [109] [183] [184], or nasal surgery and tracheostomies (e. g., during laryngectomy) that change nasal airflow [185], psychiatric disorders [186] [187], migraine [188] [189], radiation therapy [190], or alcohol abuse [191] [192].

The role of smoking/nicotine abuse in olfactory loss is controversially discussed [193] [194] [195]. Several studies have shown a dose-dependent, negative effect of smoking on olfactory function [16] [196] [197]. Increased apoptosis of ORN [198] and/or replacement of olfactory epithelium by squamous metaplasia [199] could be at the base of these changes.

6. Qualitative olfactory disorders

Parosmia and phantosmia are qualitative olfactory disorder: parosmia is the distorted perception of a smell in the presence of an odor; phantosmia is an olfactory perception without an odor being present.

6.1 Parosmia

Perception of an odor is considered a parosmia if the subjective expectations and the actual experience of an odor quality do not match. In general, parosmias are unpleasant (“burnt, fecal, putrid, musty”), although distortions that are pleasant in principle (“euosmia”) have also been described [200] [201]. Parosmia has been reported in 4–10% of the population and in 7–56% of patients with olfactory dysfunction [87] [202] [203] [204] [205]. The high degree of variance is explained by the nature of the detection of parosmia and by the differences in the study populations, and also indicates the subjectivity of the symptomatology and its presentation.

Parosmia occurs most frequently in patients with postviral olfactory disorders, but also in olfactory disorders of other causes [205] [206]. Parosmias usually present with an interval of weeks or months after the onset of the olfactory disorder [87] [88] [97] [206], in association with recovery of olfactory function. Parosmias occur in hyposmia and anosmia but also in normosmia [205]. Moreover, they are more likely to occur in younger women and may be a positive prognostic sign [98] [99] [206] (but see also [205]). The psychosocial impact of parosmia can be severe [206] [207] [208] [209].

There are several hypotheses regarding the origin of parosmia. The “miswiring” hypothesis of parosmia [210] assumes that parosmias are due to incorrect or incomplete encoding of scents, which again may be based on different mechanisms: 1) incorrect assignment of ORN axons to glomeruli in the OB; 2) changes in ORN receptor expression; and 3) incomplete ORN regeneration leading to changes or gaps in pattern generation [102] [139] [145] [146] [211] [212] [213] [214] [215]. The “central” hypothesis assumes central nervous misprocessing or misconnection based on the following observations: 1) small OB in patients with parosmia; 2) reduced volume of grey matter in the olfactory cortex; and 3) altered activation patterns in cerebral scent processing [122] [216] [217] [218] [219].

Parosmias are more likely to be triggered by certain odor groups, such as pyrazines, thiols, or furans, than by others [220]. Typically, the thresholds for perception of these odorants are low. Coffee, chocolate, meat, onion, garlic, egg, and mint/toothpaste are commonly cited as triggering fragrances [221] [222].

The diagnosis of parosmia is based on subjective statements of patients [223]. Short questionnaires help in the diagnosis [224], similarly to the classification according to the frequency and intensity of parosmic perceptions and the impairment caused by the parosmia [225]. Psychophysical instruments have been suggested (Sniffin’ Sticks Parosmia Test – “SSParoT” [226]), but probably need further modification [227].

6.2 Phantosmia

Phantosmias are odor perceptions in the absence of an odor source; they are typically described as unpleasant (“burnt/smoky, rotten, fecal, chemical”) [228] [229]. Phantosmia is experienced by approximately 1–31% of the general population [14] [202] [230] and up to 16% of patients with olfactory disorder [204] [205] [206] [229], often together with parosmia [204]. Patients with phantosmia are often functionally anosmic (43%) [205], tend to be middle-aged, and frequently have a post-traumatic olfactory disorder. However, phantosmia also occurs in patients with other causes of olfactory disorders [205] [206], and olfactory hallucinations are reported in neurological and psychiatric disorders [240], for example in temporal lobe epilepsy or as auras in migraine [231] [232].

Hypotheses for the origin of phantosmias refer to epileptiform, i. e., disordered activity, for example in the area of the BO, orbitofrontal cortex, or gyrus rectus [233] [234] [235] [236] [237] or the olfactory mucosa [139] [206] [238] [239], and they can also be elicited by irradiation of the brain.

The diagnosis of phantosmia is based on the information provided by the patients and can be supported by structured questionnaires [224]. Graduation of phantosmia based on the incidence, intensity, and degree of impairment has been proposed in analogy to the assessment of parosmia [225]. Phantosmia often improves spontaneously within 6–12 months [241] (but see also Pellegrino et al. [206]) and tends not to indicate a favorable prognosis [98] [99] [205].

7. Clinical examination

Clinical assessment of patients with olfactory disorders is important, especially with regard to diagnosis, which is the prerequisite for prognostic counseling and therapy [242] [243].

7.1 Medical history, clinical examination

The medical history should include questions like: specific impairment of orthonasal olfaction, retronasal olfaction (fine taste), or tasting (gustatory perception); presence of parosmia or phantosmia; percentage assessment of current olfaction, tasting, and nasal breathing, duration of the olfactory disorder and type of onset (gradual, sudden) as well as concomitant/preceding events (infection, trauma, medication); fluctuations in olfactory perception; previous diseases, especially sinonasal diseases or previous ENT surgery; occupational exposure (e. g., chefs/people working in professional food processing – approximately 450,000 in Germany!); history of danger due to the lack of perception of warning odors; intake of medication; smoking status; neurodegenerative diseases (e. g., IPS) in first-degree relatives.

The examination should encompass a complete ENT examination, including anterior rhinoscopy and nasal endoscopy with inspection and evaluation of the olfactory cleft, preferably after application of a decongestant nasal spray [244] [245]). A complete olfactory examination of the patient should also include screening of tasting [246].

7.2 Olfactory tests

Olfactory examinations can be divided into three groups: 1) subjective patient reports/self-ratings; 2) psychophysical tests; 3) electrophysiological measurements and imaging procedures [242].

7.3 Subjective patient reports

Subjective reports can be performed with visual analog scales, questionnaires, or with other patient-oriented measurements. For example, the SNOT-22 is a questionnaire primarily about CRS that assesses general distress, but contains only one question about olfaction [247]. In addition, there are more specific questionnaires regarding olfaction, such as the Questionnaire of Olfactory Disorders (QOD), which better distinguishes between patients with normal and reduced olfaction than simple questions like the one used in the SNOT-22 [207] [248] [249]. For a recent review of olfactory questionnaires and scales, see [171]. However, self-ratings of chemosensory function tend to be unreliable [19] [250] [251] [252] [253].

7.4 Psychophysical tests

Psychophysical tests provide a more reliable assessment of olfaction than subjective reports, but of course also depend on the cooperation and the biases and expectations of the person being tested and also on the examiner. Roughly, a distinction can be made between tests in which olfactory thresholds are measured and tests in which olfactory performance is assessed using suprathreshold odor concentrations. Orthonasal olfactory tests are most commonly used.

The olfactory threshold is the lowest concentration of an odorant that one can perceive. As an approximation of the threshold, clinically the concentration at which 50% of the stimuli are detected is often measured. Olfactory threshold does not require identification of the odor stimulus, but rather the perception of “something”, usually in comparison to an odorless stimulus. Test results from threshold studies are therefore usually less dependent on cognitive factors than, for example, results from odor identification and odor discrimination tests [254].

In suprathreshold tests, odors are offered in concentrations that are reliably recognized by people with normal olfactory abilities. Scent identification tests use odors that should be known, but this depends on the subjective experience and also on the linguistic abilities of the person being tested. For example, the scent “wintergreen” is well known in the UK, but rather unknown in Germany. This also means that odor identification tests must be regionally different or can only be used to a limited extent with people from a different cultural background. As a rule, only a few people are able to recognize odors spontaneously, which is why odors are typically offered together with a list of odors words (e. g., pineapple, rose, grass, onion) from which the one that most closely matches the scent must be selected [255]. Odor recognition tests are based on the recognition of 3 to 40 odors. The more odors are tested, the more reliable and reproducible the results are and the better the discrimination between anosmia, hyposmia, and normosmia [256].

In scent discriminations tests, 2 or 3 odors are offered. The task of the examinee is to find out the odor which is different from the other two odors (“forced choice”). The task is largely independent of verbal abilities.

Why are the tests carried out in a forced-choice procedure? Forced-choice procedures are necessary to prevent patients form choosing the option “no odor perception”. This option would probably be chosen by many patients, regardless of whether something was actually perceived or not. Only if these patients are asked to focus on the odors by forced-choice, they exploit their actual perceptual abilities – and quite often achieve results that are surprising for the patients themselves. In addition, the forced-choice procedure standardizes the conduction of the test.

Is the assessment of multiple psychophysical components of olfaction, e. g., threshold, discrimination, and identification useful or not? Doty et al. reported that different psychophysical tests measure a common source of variance implying that olfactory loss and improvement can be effectively assessed by odor identification performance alone [257]. However, this opinion is challenged – Jones-Gotman and Zatorre showed a reduction in odor identification, but not thresholds, after selective cerebral excisions [258] [259]. Whitcroft et al. revealed that the patterns of psychophysical test scores of patients with olfactory loss of different origins reflects the underlying disease etiology [114]. In this study, patients with sinonasal olfactory disorders had lower olfactory thresholds, whereas patients with Parkinson’s disease had primarily impaired odor discrimination and identification (see also [260]).

These and other trials indicate that the olfactory threshold is more indicative of peripherally related changes in olfaction, e. g., due to sinonasal disease, whereas suprathreshold tests (discrimination and identification of odors) preferentially detect central or cognitive causes of olfactory dysfunction (see also [71]).

Results from different olfactory tests are also pooled to achieve greater accuracy and reproducibility. For example, in the Connecticut Chemosensory Clinical Research Center Test (CCCRCT), olfactory threshold and odor identification are combined [261]. In the Sniffin’ Sticks Test, the TDI score is the sum of the results for olfactory threshold (T), discrimination (D), and identification (I).

There are many test procedures to examine olfaction, but by no means have all of them been thoroughly investigated in terms of their reliability and validity. For example, the University of Pennsylvania Smell Identification Test (UPSIT) is a reliable, valid odor identification test based on microencapsulation of odors released by scratching their surface. It is adapted for use in different countries [262] [263] [264] [265]. Olfactory testing with the UPSIT does not require monitoring [266] [267] [268]. Another widely used psychophysical test is the “Sniffin’ Sticks”, which is composed of three parts (see above) [269]. The test is based on felt-tip pen-like odor dispensers, is reusable, and is typically administered by an examiner, but parts can also be used by the patients alone. Reliability and validity have also been confirmed for the Sniffin’ Sticks, and minimal clinically significant difference has been investigated [270].

In addition, there are tests based on changes in breathing behavior during odor perception [271]. These techniques allow a very precise assessment of olfactory ability (e. g., [272]), but they are not widely used.

A special case of olfactory testing is the examination of children. Here, special olfactory tests have been developed that are adapted to the relatively limited verbal abilities of children and their limited experience with odors. Psychophysical olfactory testing is more or less reliable in children as of the age of 4 years [273] [274].

[Table 3] provides a list of psychophysical tests that have been used in clinical settings.

Table 3 Selection of the most frequently applied psychophysical olfactory tests.

Psychophysical test	Assessed olfactory function
Extensive orthonasal olfactory tests
“Sniffin’ Sticks” (original version) [269]	Threshold, discrimination, identification
Connecticut Chemosensory Clinical Research Center Test [261]	Threshold, identification
T & T Olfactometer [446]	Threshold, identification
University of Pennsylvania Smell Identification Test [262]	Identification
Barcelona Smell Test (BAST-24) [447]	Odor perception, identification, olfactory memory
Orthonasal short tests
Smell diskettes [448]	Identification
Pocket Smell Test [282]	Identification
“Sniffin’ Sticks” (3, 5, o 12 odor samples) [281] [283] [449]	Identification
Brief Smell Identification Test (B-SIT; 12-item Cross-Cultural Smell Identification Test) [280]	Identification
Retronasal tests
Candy Smell Test (23 samples) [290]	Identification
Taste powders (20 samples) [289]	Identification

When using psychophysical tests to define olfactory disorders and changes in olfactory function, the availability of normative values is important. Hyposmia is differentiated from normosmia based on the 10^th percentile of test scores of young healthy subjects [262] [269]. In contrast, anosmia is defined based on the empirical distribution of olfactory test scores of anosmic people [275].

In a clinical setting, psychophysical tests are usually performed birhinally without prior application of a decongestant nasal spray [250] [276]. However, several papers show that lateralized olfactory tests have both diagnostic and prognostic value [277] [278] [279].

7.5 Short psychophysical tests

In clinical routine, screening tests are often used for cursory examination of olfaction, e. g., in the preoperative assessment of olfaction ([Table 3]). Odor identification tests are typically used [280] [281], some of which are based on only 3 or 5 odors [282] [283]. They are easy to understand and require little time ([Table 3]). However, they make it difficult to document changes because of their low resolution. If abnormalities are detected during screening, they should be further elucidated with a valid, complete olfactory test.

In addition, tests that can be performed in the home environment, using domestic odors, have also been introduced in recent years [284] [285] [286] [287]. It remains to be seen whether these tests will be widely used.

7.6 Retronasal olfactory tests

Flavor perception, retronasal smelling, depends on olfactory function. Tasting, i. e. gustatory sensitivity and retronasal smelling are often not separated, i. e. many patients complain about the loss of “taste” although actually retronasal smell is affected [209]. In addition to these confusions, it is not uncommon for patients to state that orthonasal olfaction is severely impaired but retronasal olfaction is intact [288]. Such dissociations can be found in protracted olfactory loss, e. g. in sinonasal olfactory disorders or in age-related olfactory loss. Simple retronasal olfactory detection tests are available for clinical testing [289] [290] [291].

7.7 Electrophysiological examinations and functional imaging

Electrophysiological examinations encompass the measurement of odor-induced changes in the electroencephalogram (EEG), i. e. the olfactory event-correlated potentials and also the changes in the stimulus-dependent EEG [292] [293]. They are less dependent on patients’ expectations and cooperation than psychophysical measurements. Because of the need for precise stimulus presentation, computerized olfactometers are a technical prerequisite, which limits the widespread use of the method [294].

Functional imaging allows visualization of brain activity in response to olfactory stimuli and includes for example, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Both techniques are ultimately based on odor-induced changes in cerebral blood flow [295]. The use of radioactive isotopes makes PET less attractive, and olfactory fMRI has low reliability, which significantly limits its clinical value in individual diagnostics [296].

7.8 MRI examinations of the nose and the brain

MRI can be used to assess the nose and its sinuses, the BO as well as primary and secondary olfactory cortex, and to rule out intracranial space-occupying lesions. In trauma-induced olfactory disorders, the degree of olfactory loss can be predicted based on the brain lesion pattern [141]. Imaging and measurement of the OB and olfactory sulcus are significant in the diagnosis of congenital anosmia [177] [178], and OB volume provides prognostic information in patients with olfactory loss [292].

8. Treatment of quantitative olfactory disorders

Olfactory disorders are treated according to their cause. For the treatment of olfactory disorders associated with CRS, topical or systemic application of steroids is the main focus, in addition to treatment options including surgery or monoclonal antibodies [297] [298] [299]. Precise and comprehensive guidelines exist for the treatment of CRS and are referred to in these references [125] [126] [127] [300] [301] [302] [303] [304] [305] [306]. In contrast, treatment options for olfactory disorders of other origins are limited [164] [307] [308]; however, there are also several options.

8.1 Consultation for olfactory disorders

Consultation for olfactory disorders is particularly important with regard to the avoidance of hazards, e. g., regarding the handling of food or the installation of smoke detectors and gas warning devices. Detailed information is available from the Working Group on Olfaction and Gustation of the German Society of Otorhinolaryngology, Head and Neck Surgery, https://rebrand.ly/nvru0xc., or, for example, from patient support groups like https://www.abscent.org

8.2 Systemic corticosteroids

Several studies have dealt with the use of systemic corticosteroids for treatment of postviral olfactory dysfunction and have come to negative [309] [310], but also positive results (e. g. [311] [312] [313] [314] [315]). However, in some of these studies, the control group was missing, e. g. in Ikeda et al. and also in Fukazawa. Since spontaneous recovery is common, especially in patients with postviral olfactory disorders, these studies appear difficult to interpret. The investigations of Vaira et al. and Le Bon et al. were each performed on small groups (n<10 per treatment arm).

Various studies showed improvement in posttraumatic olfactory disorders with the use of systemic steroids, but without concomitant study of a control group [316] [317] [318]. Although the spontaneous recovery rate in posttraumatic olfactory loss is lower than in postviral olfactory disorders, this still limits the interpretation of the results. Jiang et al. [319] reported that oral prednisolone per se did not result in significant improvement compared with an untreated control group.

8.3 Topical corticosteroids

Topical steroids have been used to reduce inflammation in various studies, but often in groups with different causes of olfactory disorders. Often the nasal spray is used with the regular nozzle which makes it unlikely that the injected spray would reach the olfactory cleft [320] [321] [322].

A double-blind, randomized controlled trial by Blomqvist et al. showed no significant difference in olfactory threshold after 6 months of treatment with intranasal fluticasone spray, placebo spray, or no treatment (n=20, n=10, and n=10, respectively) [323]. Heilmann et al. [324] also found no effect of treatment with mometasone nasal spray in a retrospective review. In contrast, Fleiner et al. [325] found a significant improvement in a group of patients with olfactory disorders treated with topical steroids and olfactory training (see below). Similarly, Kim et al. [326] showed improvement with the combined use of systemic and topical steroids compared with the use of topical steroids alone in a relatively large group of patients (491 in total) with various causes of olfactory disorders.

Regarding COVID-19-OD, in a controlled study Hintschich and colleagues [327] showed no advantage in terms of the TDI score for the treatment of mometasone nasal spray (application to the olfactory cleft with extra-long applicator) together with olfactory training versus olfactory training alone. Kasiri and colleagues conducted a double-blind randomized controlled trial in patients with COVID-19-OD comparing intranasal mometasone furoate spray/smell training (n=39) with intranasal sodium chloride/smell training (n=38) [328]. After 4 weeks of treatment, there was no statistically significant difference in the change in odor identification test scores between the groups. Similarly, in another randomized controlled trial of 100 patients with COVID-19-OD, 50 of whom were treated with olfactory training and 50 were treated with olfactory training and an intranasal mometasone spray [329], there was no significant difference between the two groups. However, participants rated their olfactory ability using visual analog scales only. In contrast to previous studies, a randomized controlled trial [330] comparing olfactory training and intranasal irrigation with budesonide (n=66) with olfactory training and intranasal NaCl irrigation (n=67) in patients with olfactory disorders of various origins showed a greater clinical improvement in odor identification scores for patients in the budesonide group (44%) compared to the NaCl group (27%) after 6 months.

Overall, the evidence regarding positive effects with the use of corticosteroids for non-sinonasal olfactory dysfunction is low [331] – partly due to the lack of high-quality studies. Despite this situation, systemic and topical steroids are commonly used to treat non-sinonasal olfactory disorders [123] [332].

8.4 Phosphodiesterase inhibitors

Phosphodiesterase inhibitors like theophylline have been reported to improve olfactory function by preventing the breakdown of intracellular cAMO or reducing IL-10 secretion [333] [334].

A prospective trial investigating the Sniffin’ Sticks scores before and after pentoxifylline administration [130] revealed a significant improvement in olfactory thresholds. However, normosmic and hyposmic patients were included in this study. Henkin et al. used a non-blinded, controlled study design to investigate the effect of oral theophylline on olfactory function in hyposmic patients [335]. The study showed improvement in olfactory function with incremental doses of theophylline over time, but spontaneous recovery was not considered. In a non-controlled study of the effects of topical theophylline [336] in 10 patients, subjective improvement was seen in 8/10 patients after 4 weeks of treatment. In contrast, using a double-blind, placebo-controlled, randomized design in an analysis of a small group of patients with postviral olfactory dysfunction (n≤12) [337], Lee et al. showed no improvement in odor recognition (UPSIT) for the use of theophylline, but an improvement in odor-related quality of life. Overall, the efficacy of phosphodiesterase inhibitors in olfactory disorders does not seem assessable at present [338] [339] [340].

8.5 Intranasal calcium buffer

Free calcium in the nasal mucus layer, among countless significant functions, plays a role in inhibiting negative feedback in the intracellular olfactory signaling cascade [341]. Therefore, it has been suggested that the sequestration of free calcium using buffer solutions such as sodium citrate may lead to an enhancement of the olfactory signal and a consequent improvement in olfactory function.

Panagiotopoulos et al. reported significantly improved odor identification scores in hyposmic patients with a majority of postviral olfactory disorders treated with intranasal sodium citrate [342]. A series of studies also revealed short-term effects of sodium citrate on olfaction [343] [344] [345], but there was no significant improvement in olfactory test scores (Sniffin’ Sticks) on the treated side when sodium citrate was applied monorhinally for two weeks. In addition, however, there was a significant reduction (82%) in the proportion of patients reporting phantosmia.

A series of recent blinded studies by Abdelazim et al. [346] [347] [348] on sodium gluconate, sodium pyrophosphate, and sodium nitrilotriacetate showed a significant improvement in olfaction in patients with postviral olfactory dysfunction. A confirmation of these results, for example in a multicenter study, would certainly be desirable.

8.6 Vitamin A

Vitamin A comprises a family of fat-soluble retinoids, the oxidation of which leads to the production of the biologically active retinoic acid, which is significant as a transcriptional regulator in tissue development and regeneration [349] [350]. Several studies suggest the role of retinoic acid in olfactory function [351] [352]. Specifically, retinoic acid controls the differentiation of olfactory progenitor cells [353] [354] [355].

In humans, Duncan and Briggs reported that high doses (up to 150,000 IU/day) of systemic vitamin A improved olfaction in 48 of 54 patients [356]. In a non-controlled study, significant improvement in odor identification scores (Sniffin’ Sticks) was shown after administration of isoretinoin [357]. However, in a double-blind, placebo-controlled, randomized trial in patients with postviral (n=19) and posttraumatic olfactory disorders (n=33) with 10,000 IU/day of systemic vitamin A (n=26) or placebo (n=26) for 3 months, no significant effects were found [358], possibly due to an insufficient dose.

In a retrospective analysis of the treatment of patients with postviral and posttraumatic olfactory disorders, the topical application of intranasal vitamin A (10,000 IU/day; 8 weeks, 12 weeks of olfactory training; n=124) led to significant improvement (olfactory training + vitamin A vs. olfactory training alone) [359] (see also [360].

8.7 Olfactory training

Repeated exposure to odorants, e. g. to androstenone, can improve olfactory sensitivity to this odor [361]. This principle underlies olfactory training, in which patients try to improve their sense of smell over a period of about 3 months by repeated and conscious sniffing of a range of odorants [362].

The exact mechanism that might underlie an improvement in olfaction after olfactory training is unknown. It is likely that plasticity of both peripheral [363] [364] [365] [366] and central nervous olfactory systems plays a role, at the levels of the OB [367], the primary and secondary olfactory cortex [368], and intracerebral connectivity [369].

The potential benefit of such training was first investigated in a group of 40 patients with olfactory loss due to postviral, posttraumatic, and idiopathic olfactory disorders [370]. The patients performed olfactory training twice daily with 4 odorants: phenylethyl alcohol (rose), eucalyptol (eucalyptus), citronellal (lemon), and eugenol (clove). The training group (n=40) significantly improved their psychophysical test scores (Sniffin’ Sticks) after 12 weeks, while the non-training group (n=16) did not. This result has since been repeatedly confirmed, although rarely in controlled trials [371] [372].

A randomized controlled multicenter trial [373] of 144 patients showed that olfactory training with high odor concentrations resulted in greater improvement than olfactory training with very low, barely perceptible odor concentrations [373], indicating that olfactory training is actually not related to sniffing but to olfactory stimulation. Furthermore, it was shown that the therapeutic effect was greatest when initiated promptly after olfactory loss. In addition, a greater improvement in olfactory function was demonstrated after performing olfactory training over a longer period of 9 months [374] (using 3 times 4 different odors, when changing the 4 odors every 3 months – so-called “modified olfactory training"). A recent systematic review and meta-analysis of olfactory training specifically for postviral olfactory disorders showed that patients were more likely to achieve clinically relevant improvement with olfactory training than the control group [375] [376].

In relation to posttraumatic olfactory loss, the results of olfactory training are more heterogeneous. Konstantinidis and colleagues showed clinically significant improvement after the implementation of olfactory training in 33% of 38 patients versus 13% of 15 controls [377]. Langdon and colleagues [378] conducted a prospective randomized controlled trial in 42 patients with posttraumatic olfactory dysfunction. Compared with the control group, there was a significant improvement in n-butanol thresholds after 12 weeks. However, there were no statistically significant improvements on an odor identification test (BAST-24) or the participants’ self-reports. Jiang and colleagues reported on two studies that looked at the effect of olfactory training of patients with posttraumatic olfactory dysfunction. However, in both studies, patients were pretreated with prednisolone and zinc. After 6 months of olfactory training, significant effects were seen at the level of olfactory thresholds, but not on an olfactory identification test (UPSIT-TC) [379] [380].

In general, patients with postviral olfactory disorders respond better to olfactory training than patients with posttraumatic olfactory loss. This may be due to the overall relatively poor prognosis in patients with posttraumatic olfactory disorders.

A benefit of olfactory training has also been demonstrated in patients with neurodegenerative diseases [381]. However, few studies have addressed the effect of training in patients with sinonasal disorders [325] (reviews of [372] [382] [383]).

8.8 Surgical therapy options

Surgical interventions are largely reserved for the treatment of patients with CRSwNP. Similar to steroid therapy, extensive guidelines exist for the use of surgery in such patients. Several reviews of surgical therapy in patients with sinonasal olfactory disorders are available [306] [384]. A meta-analysis on changes in olfaction with functional endoscopic sinus surgery (FESS) concluded that such surgery for CRS improves “almost all” subjective and psychophysical parameters [385] (but see also [386]). In addition, changes in the volume of olfactory significant brain structures have been shown to be associated with improved olfactory function after FESS [133] [387].

The benefit of surgical treatment strategies for non-sinonasal olfactory disorders is less well established. Schriever et al. showed that septoplasty had no significant or minor effects on olfaction [388], in contrast to other studies [252] [389] [390]. Reports of positive effects of a surgical procedure can also be found for septorhinoplasty [391] [392] [393] [394] [395]. In addition, a positive effect has been reported for dilation of the olfactory cleft [396].

8.9 Platelet-rich plasma

Platelet-rich plasma (PRP) is an autologous concentrate of platelet-rich plasma protein prepared from whole blood. During hemostasis, activated platelets release a variety of growth factors and cytokines. These factors promote angiogenesis, cell proliferation, and cell differentiation, which ultimately contributes to lesion regeneration [397] [398]. Regarding olfaction, intranasal PRP showed improvement in olfactory behavioral tests in a mouse anosmia model [399]. In patients with sinonasal olfactory disorders, Mavrogeni et al. [400] reported positive results after repeated intranasal injection of PRP. Yan et al. also showed significantly improved olfactory performance (Sniffin’ Sticks) 3 months after a single intranasal PRP injection [401] (see also [450]). In treatment-resistant patients with anosmia, improvement in the olfactory test was demonstrated after treatment with PRP-soaked sponges (B-SIT) [402].

8.10 Omega-3 fatty acids

Omega-3 fatty acids comprise a group of polyunsaturated fatty acids that are key substrates of fat metabolism. Three types of omega-3 are important for humans: α-linolenic acids (ALA – an essential fatty acid available only through the diet), eicosapentaenoic acid (EPA) and docosahexaenoid acid (DHA). Thus, animals deficient in omega-3 show poorer results in odor discrimination tasks [403]. This is thought to be due to reduced levels of DHAS in the brain and particularly in the BO. Omega-3-rich diets are associated with good performance in odor discrimination tests in humans [404] [405].

In a randomized controlled trial, Yan et al. showed significantly better recovery of olfaction in patients after endoscopic sellar or parasellar tumor resections compared to a control group [406]. A non-blinded prospective study by Hernandez et al. [407] in patients with postviral olfactory dysfunction also suggested a positive effect on olfactory recovery compared to a control group.

8.11 Further treatment options

In addition to the above, numerous other treatment options have been proposed, for example, phenytoyl ethanolamide plus luteolin [408], acupuncture [409], lavender syrup [410], famotidine [411], blocking of the stellate ganglion [412], toki shakayaku san – a mixture of herbal medicines [413] [414], or B vitamins [415].

9. Treatment of qualitative olfactory disorders

9.1 Phantosmia

Phantosmia associated with neurological diseases rarely occurs. It often disappears in the course of treatment of the initial disease. Accordingly, successful use of topiramate, verapamil, nortriptyline, and gabapentin in patients with migraine has been described in case reports [416] [417]. Sodium valproate and phenytoin have also been used successfully in two cases of idiopathic phantosmia [418]. Mirrissey et al. reported successful treatment with haloperidol in patients with idiopathic phantosmia [239].

Topical application of saline solution to the olfactory mucosa can provide temporary relief [223]. Leopold and Hornung showed transient improvement in 6 patients with idiopathic or postviral phantosmia after local anesthesia of the olfactory mucosa (topical application of cocaine) [419]. Initially the treatment resulted in anosmia in all 6 patients; in 4 patients, phantosmia returned simultaneously with olfaction, and in two, there was a delayed onset of phantosmia after return of olfaction. As described above, there was a significant decrease in postviral phantosmia after application of intranasal sodium citrate for 2 weeks [345]. In addition, there was also a decrease in parosmic symptoms, although this did not reach statistical significance.

In cases of severe, prolonged phantosmia, surgical removal of the olfactory epithelium [223] [239] [420] or the OB [236] [237] has been successfully used as a last resort in a few selected patients.

9.2 Parosmia

Because of the typical association of parosmia with quantitative olfactory disorders, they are often treated together with quantitative olfactory disorder rather than separately [324] [345] [421] [422]. Parosmias are thought to resolve with the normalization of olfactory function.

Surgical treatment of long-lasting parosmia was described by Liu et al. – by formation of mucosal adhesions, airflow to the olfactory cleft is reduced, which led to improvement for at least two years in at least a single case with unilateral parosmia [423].

Problematic in the treatment of parosmia and phantosmia, however, is the poor quantifiability and objectifiability of the complaints, which ultimately makes the control of any therapeutic attempt more difficult.

10. Possible new therapy approaches

10.1 Olfaction implants

During smelling, chemical stimuli are converted into electrical signals, which are processed in the brain in complex ways to form olfactory percepts. In analogy to the cochlear implant that is used to restore hearing in congenital or acquired severe hearing loss [424], implants to restore olfactory function are currently being developed.

In humans, the first experiments on electrical stimulation in the area of the olfactory mucosa took place as early as 1886 [425]. Some authors described that olfactory impressions could be triggered by electrical stimuli [426] [427], others were not successful [428] [429]. Activation in the area of the primary olfactory cortex by electrical stimulation was demonstrated by fMRI [429]. In addition, odor sensations could be produced by electrical stimulation of the OB [233] [430]. When studied in patients with epilepsy or IPS, olfactory sensations could be triggered after electrical stimulation using depth electrodes [234] [235] [431] [432] [433] [434] [435].

These investigations show that activation of the olfactory system by electrical stimulation is possible and thus olfactory sensations can be elicited. However, the expectations on an olfactory implant are immense. A large number of odors must be detected and odor-specific electrical signals generated for transmission. Constanzo and Coelho filed a first patent back in 2016. Extensive projects are currently underway to develop an olfactory implant, such as the EU-funded ROSE project (restoring odorant detection and recognition in smell deficits) [436].

10.2 Olfactory transplantations

Transplantation of olfactory epithelium or olfactory stem cells represents a therapeutic approach to directly restore damaged olfactory epithelium. First transplantations of olfactory mucosa took place already in 1983 by Morrison and Graziadei in rats. After transplantation of olfactory mucosa into the OB, fourth ventricle, or parietal cortex of rats/mice, regeneration of the ORN was demonstrated [437] [438] [439], with a survival rate of 83–85%.

In mice, both intravenous and local transplantation of labeled bone marrow stem cells was shown to migrate into the olfactory mucosa and partially differentiate into ORN [440] [441]. Improvement in olfactory function has been demonstrated in electrophysiological studies compared to a control group [442]. Kurtenbach et al. transplanted tissue-specific stem cells from the olfactory epithelium in mouse experiments and were able to confirm the development of ORN in the olfactory epithelium with axon sprouting into the OB in histological studies. In addition, behavioral testing and electrophysiological measurements demonstrated restored olfactory function compared with the control group [443].

Transplantation of both, stem cells and olfactory epithelium represent promising therapeutic options, but studies have not yet gone beyond animal experiments. Furthermore, it should be kept in mind that stem cell transplantation is accompanied by chemotherapy and/or radiotherapy, as well as immunosuppression, which in turn is an increased risk of morbidity and mortality [444].

11. Conclusion

Although one can apparently get through life well without a sense of smell, olfaction is significant, among other things for recognizing danger, for our social life, and for eating and drinking. Without the sense of smell, the quality of life is considerably impaired in many, but not in all, people. In this respect, patients with olfactory disorders deserve attention and care. Diagnostic methods are largely standardized and commercially available for a wide variety of questions. In contrast to the detailed diagnostic possibilities, options for the therapy of olfactory disorders are limited. However, this does not mean that there are no options.

Interessenkonflikt

T Hummel: Seit 2019 arbeitete ich zusammen mit folgenden Firmen: Smell and Taste Lab, Geneva, Switzerland; Takasago, Paris, France; aspuraclip, Berlin, Germany; Baia Foods, Madrid, Spain; Burghart, Holm, Germany; Primavera, Kempten, Germany. Alle anderen Autoren geben an, dass kein Interessenkonflikt besteht.

• Literatur

• 1 Pellegrino R, Mainland JD, Kelly CE, Parker JK, Hummel T.. Prevalence and correlates of parosmia and phantosmia among smell disorders. Chemical senses 2021; 46
• 2 Zucco GM, Doty RL.. Multiple Chemical Sensitivity. Brain sciences 2022; 12: 46
• 3 Eis D, Helm D, Mühlinghaus T, Birkner N, Dietel A, Eikmann T. et al. The German Multicentre Study on Multiple Chemical Sensitivity (MCS). International journal of hygiene and environmental health 2008; 211: 658-681
• 4 Tan BKJ, Han R, Zhao JJ, Tan NKW, Quah ESH, Tan CJ-W. et al. Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves. BMJ 2022; e069503-e069503
• 5 H Hoffman HJ, Ishii EK, MacTurk RH.. Age-related changes in the prevalence of smell/taste problems among the United States adult population. Results of the 1994 disability supplement to the National Health Interview Survey (NHIS). Ann N Y Acad Sci 1998; 855: 716-722
• 6 Lee WH, Wee JH, Kim D-K, Rhee C-S, Lee CH, Ahn S. et al. Prevalence of subjective olfactory dysfunction and its risk factors: korean national health and nutrition examination survey. PLOS ONE 2013; 8: e62725
• 7 Hwang S-H, Kang J-M, Seo J-H, Han K, Joo Y-H.. Gender Difference in the Epidemiological Association between Metabolic Syndrome and Olfactory Dysfunction: The Korea National Health and Nutrition Examination Survey. PLOS ONE 2016; 11: e0148813
• 8 Bhattacharyya N, Kepnes LJ.. Contemporary assessment of the prevalence of smell and taste problems in adults. The Laryngoscope 2015; 125: 1102-1106
• 9 Rawal S, Hoffman HJ, Bainbridge KE, Huedo-Medina TB, Duffy VB.. Prevalence and Risk Factors of Self-Reported Smell and Taste Alterations: Results from the 2011-2012 US National Health and Nutrition Examination Survey (NHANES). Chemical senses 2016; 41: 69-76
• 10 Huang Z, Huang S, Cong H, Li Z, Li J, Keller KL. et al. Smell and Taste Dysfunction Is Associated with Higher Serum Total Cholesterol Concentrations in Chinese Adults. The. Journal of Nutrition 2017; 147: 1546-1551
• 11 Hastan D, Fokkens WJ, Bachert C, Newson RB, Bislimovska J, Bockelbrink A. et al. Chronic rhinosinusitis in Europe – an underestimated disease. A GA²LEN study. Allergy 2011; 66: 1216-1223
• 12 Hirsch AG, Stewart WF, Sundaresan AS, Young AJ, Kennedy TL, Scott Greene J. et al. Nasal and sinus symptoms and chronic rhinosinusitis in a population-based sample. Allergy 2017; 72: 274-281
• 13 Schulz M, Mangiapane S, Scherer M, Karagiannidis C, Czihal T.. Post-Acute Sequelae of SARS-CoV-2 Infection. Deutsches Arzteblatt international 2022; 119: 177-178
• 14 Landis BN, Konnerth CG, Hummel T.. A study on the frequency of olfactory dysfunction. The Laryngoscope 2004; 114: 1764-1769
• 15 Brämerson A, Johansson L, Ek L, Nordin S, Bende M.. Prevalence of olfactory dysfunction: the skövde population-based study. The Laryngoscope 2004; 114: 733-737
• 16 Vennemann MM, Hummel T, Berger K.. The association between smoking and smell and taste impairment in the general population. Journal of neurology 2008; 255: 1121-1126
• 17 Nordin S, Brämerson A, Bende M.. Prevalence of self-reported poor odor detection sensitivity: the Skövde population-based study. Acta oto-laryngologica 2004; 124: 1171-1173
• 18 Hinz A, Luck T, Riedel-Heller SG, Herzberg PY, Rolffs C, Wirkner K. et al. Olfactory dysfunction: properties of the Sniffin’ Sticks Screening 12 test and associations with quality of life. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2019; 276: 389-395
• 19 Seubert J, Laukka EJ, Rizzuto D, Hummel T, Fratiglioni L, Bäckman L. et al. Prevalence and Correlates of Olfactory Dysfunction in Old Age: A Population-Based Study. The journals of gerontology. Series A, Biological sciences and medical sciences 2017; 72: 1072-1079
• 20 Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K. et al. Association of olfactory dysfunction with risk for future Parkinson’s disease. Annals of neurology 2008; 63: 167-173
• 21 Boesveldt S, Lindau ST, McClintock MK, Hummel T, Lundstrom JN, Lindstrom JN.. Gustatory and olfactory dysfunction in older adults: a national probability study. Rhinology 2011; 49: 324-330
• 22 Kern DW, Wroblewski KE, Schumm LP, Pinto JM, Chen RC, McClintock MK.. Olfactory function in Wave 2 of the National Social Life, Health, and Aging Project. The journals of gerontology. Series B, Psychological sciences and social sciences 2014; 69 Suppl 2 S134-43
• 23 Pinto JM, Schumm LP, Wroblewski KE, Kern DW, McClintock MK.. Racial disparities in olfactory loss among older adults in the United States. The journals of gerontology. Series A, Biological sciences and medical sciences 2014; 69: 323-329
• 24 Devanand DP, Lee S, Manly J, Andrews H, Schupf N, Masurkar A. et al. Olfactory identification deficits and increased mortality in the community. Annals of neurology 2015; 78: 401-411
• 25 Liu G, Zong G, Doty RL, Sun Q.. Prevalence and risk factors of taste and smell impairment in a nationwide representative sample of the US population: a cross-sectional study. BMJ open 2016; 6: e013246
• 26 Karpa MJ, Gopinath B, Rochtchina E, Jie JW, Cumming RG, Sue CM. et al. Prevalence and neurodegenerative or other associations with olfactory impairment in an older community. Journal of aging and health 2010; 22: 154-168
• 27 Shu C-H, Hummel T, Lee P-L, Chiu C-H, Lin S-H, Yuan B-C.. The proportion of self-rated olfactory dysfunction does not change across the life span. American journal of rhinology & allergy 2009; 23: 413-416
• 28 Mullol J, Alobid I, Mariño-Sánchez F, Quintó L, Haro de J, Bernal-Sprekelsen M. et al. Furthering the understanding of olfaction, prevalence of loss of smell and risk factors: a population-based survey (OLFACAT study). BMJ open 2012; 2
• 29 Murphy C, Schubert CR, Cruickshanks KJ, Klein BEK, Klein R, Nondahl DM.. Prevalence of olfactory impairment in older adults. JAMA 2002; 288: 2307-2312
• 30 Desiato VM, Levy DA, Byun YJ, Nguyen SA, Soler ZM, Schlosser RJ.. The Prevalence of Olfactory Dysfunction in the General Population: A Systematic Review and Meta-analysis. American journal of rhinology & allergy 2021; 35: 195-205
• 31 Bushdid C, Magnasco MO, Vosshall LB, Keller A.. Humans can discriminate more than 1 trillion olfactory stimuli. Science 2014; 343: 1370-1372
• 32 Mayhew EJ, Arayata CJ, Gerkin RC, Lee BK, Magill JM, Snyder LL. et al. Transport features predict if a molecule is odorous. PROC. NAT. ACAD. OF SCI. (U.S.A.) 2022; 119 e2116576119
• 33 Manzini I, Schild D, Di Natale C.. Principles of odor coding in vertebrates and artificial chemosensory systems. Physiological reviews 2022; 102: 61-154
• 34 Fitzek M, Patel PK, Solomon PD, Lin B, Hummel T, Schwob JE. et al. Integrated age-related immunohistological changes occur in human olfactory epithelium and olfactory bulb. Journal of Comparative Neurology 2022; 530: 2154-2175
• 35 Holbrook EH, Wu E, Curry WT, Lin DT, Schwob JE.. Immunohistochemical characterization of human olfactory tissue. The Laryngoscope 2011; 121: 1687-1701
• 36 Féron F, Perry C, McGrath JJ, Mackay-Sim A.. New techniques for biopsy and culture of human olfactory epithelial neurons. Archives of otolaryngology – head & neck surgery 1998; 124: 861-866
• 37 Lang J.. Clinical anatomy of the nose, nasal cavity, and paranasal sinuses. Stuttgart, New York, New York: Thieme; Thieme Medical Publishers; 1989
• 38 Leopold DA, Hummel T, Schwob JE, Hong SC, Knecht M, Kobal G.. Anterior distribution of human olfactory epithelium. The Laryngoscope 2000; 110: 417-421
• 39 E. A. Read. A Contribution to the Knowledge of the Olfactory Apparatus in Dog, Cat and Man. Am. J. Anat. 8: 17-47
• 40 v. Brunn A.. Beiträge zur mikroskopischen Anatomie der menschlichen Nasenhöhle. Archiv f. mikrosk. Anatomie 1892; 39: 632-651
• 41 Buck L, Axel R.. A novel multigene family may encode odorant receptors: A molecular basis for odor recognition. Cell 1991; 65: 175-187
• 42 Dale Purves, George J Augustine, David Fitzpatrick, Lawrence C Katz, Anthony-Samuel LaMantia, James O McNamara, et al. The Transduction of Olfactory Signals. In: Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia A-S, McNamara JO, et al. (eds). Neuroscience. 2nd editionSinauer Associates; 2001
• 43 Gilad Y, Bustamante CD, Lancet D, Pääbo S.. Natural selection on the olfactory receptor gene family in humans and chimpanzees. American journal of human genetics 2003; 73: 489-501
• 44 Verbeurgt C, Wilkin F, Tarabichi M, Gregoire F, Dumont JE, Chatelain P.. Profiling of olfactory receptor gene expression in whole human olfactory mucosa. PloS one 2014; 9: e96333
• 45 Dunkel A, Steinhaus M, Kotthoff M, Nowak B, Krautwurst D, Schieberle P. et al. Nature’s chemical signatures in human olfaction: a foodborne perspective for future biotechnology. Angewandte Chemie (International ed. in English) 2014; 53: 7124-7143
• 46 Ressler KJ, Sullivan SL, Buck LB.. A zonal organization of odorant receptor gene expression in the olfactory epithelium. Cell 1993; 73: 597-609
• 47 Mombaerts P.. Odorant receptor gene choice in olfactory sensory neurons: the one receptor-one neuron hypothesis revisited. Current opinion in neurobiology 2004; 14: 31-36
• 48 Axel R.. The molecular logic of smell. Scientific American 1995; 273: 154-159
• 49 Firestein S.. How the olfactory system makes sense of scents. Nature 2001; 413: 211-218
• 50 Holley A, Duchamp A, Revial MF, Juge A.. Qualitative and quantitative discrimination in the frog olfactory receptors: analysis from electrophysiological data. Annals of the New York Academy of Sciences 1974; 237: 102-114
• 51 Kurian SM, Naressi RG, Manoel D, Barwich A-S, Malnic B, Saraiva LR.. Odor coding in the mammalian olfactory epithelium. Cell Tissue Res 2021; 383: 445-456
• 52 Horowitz LF, Saraiva LR, Kuang D, Yoon K, Buck LB.. Olfactory receptor patterning in a higher primate. The Journal of neuroscience: the official journal of the Society for Neuroscience 2014; 34: 12241-12252
• 53 Liberles SD, Buck LB.. A second class of chemosensory receptors in the olfactory epithelium. Nature 2006; 442: 645-650
• 54 Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J. et al. Human trace amine-associated receptor TAAR5 can be activated by trimethylamine. PLOS ONE 2013; 8: e54950
• 55 Durante MA, Kurtenbach S, Sargi ZB, Harbour JW, Choi R, Kurtenbach S. et al. Single-cell analysis of olfactory neurogenesis and differentiation in adult humans. Nature neuroscience 2020; 23: 323-326
• 56 Brann JH, Firestein SJ.. A lifetime of neurogenesis in the olfactory system. Front. Neurosci. 2014; 8: 182
• 57 Graziadei P, Karlan MS, Monti GA, Bernstein JJ.. Neurogenesis of sensory neurons in the primate olfactory system after section of the fila olfactoria. Brain research 1980; 186: 289-300
• 58 Fjaeldstad A, Fernandes HM, van Hartevelt TJ, Gleesborg C, Møller A, Ovesen T. et al. Brain fingerprints of olfaction: a novel structural method for assessing olfactory cortical networks in health and disease. Sci Rep 2017; 7: 42534
• 59 Hummel T, Welge-Lussen A.. Taste and smell: An update: 33 figures, 1 in color, and 12 tables, 2006, Vol 63. Basel: Karger; 2006
• 60 Frasnelli J, Manescu S.. The Intranasal Trigeminal System. In: Springer Handbook of Odor. Springer; Cham: 2017: 113-114
• 61 Hummel T, Frasnelli J.. Chapter 8 – The intranasal trigeminal system. In: Doty RL (ed). Handbook of Clinical Neurology: Smell and Taste. Elsevier; 2019: 119-134
• 62 Daiber P, Genovese F, Schriever VA, Hummel T, Möhrlen F, Frings S.. Neuropeptide receptors provide a signalling pathway for trigeminal modulation of olfactory transduction. The European journal of neuroscience 2013; 37: 572-582
• 63 Doty RL, Brugger WE, Jurs PC, Orndorff MA, Snyder PJ, Lowry L.. Intranasal trigeminal stimulation from odorous volatiles: Psychometric responses from anosmic and normal humans. Physiology & behavior 1978; 20: 175-185
• 64 Hummel T, Iannilli E, Frasnelli J, Boyle J, Gerber J.. Central processing of trigeminal activation in humans. Annals of the New York Academy of Sciences 2009; 1170: 190-195
• 65 Mihara S, Shibamoto T.. The role of flavor and fragrance chemicals in TRPA1 (transient receptor potential cation channel, member A1) activity associated with allergies. Allergy, asthma, and clinical immunology: official journal of the Canadian Society of Allergy and Clinical Immunology 2015; 11: 11
• 66 Konstantinidis I, Tsakiropoulou E, Chatziavramidis A, Ikonomidis C, Markou K.. Intranasal trigeminal function in patients with empty nose syndrome. The Laryngoscope 2017; 127: 1263-1267
• 67 Li C, Farag AA, Maza G, McGhee S, Ciccone MA, Deshpande B. et al. Investigation of the abnormal nasal aerodynamics and trigeminal functions among empty nose syndrome patients. International forum of allergy & rhinology 2018; 8: 444-452
• 68 Scheibe M, Schulze S, Mueller CA, Schuster B, Hummel T.. Intranasal trigeminal sensitivity: measurements before and after nasal surgery. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2014; 271: 87-92
• 69 Zhao K, Jiang J, Blacker K, Lyman B, Dalton P, Cowart BJ. et al. Regional peak mucosal cooling predicts the perception of nasal patency. The Laryngoscope 2014; 124: 589-595
• 70 Delank KW, Fechner G.. Zur Pathophysiologie der posttraumatischen Riechstörungen. Laryngol. Rhinol. Otol 1996; 75: 154-159
• 71 Lötsch J, Daiker H, Hähner A, Ultsch A, Hummel T.. Drug-target based cross-sectional analysis of olfactory drug effects. Eur J Clin Pharmacol 2016; 71: 461-471
• 72 Hannum ME, Ramirez VA, Lipson SJ, Herriman RD, Toskala AK, Lin C. et al. Objective Sensory Testing Methods Reveal a Higher Prevalence of Olfactory Loss in COVID-19-Positive Patients Compared to Subjective Methods: A Systematic Review and Meta-Analysis. Chemical senses 2020; 45: 865-874
• 73 Bartheld CS, von Hagen MM, Butowt R.. Prevalence of Chemosensory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis Reveals Significant Ethnic Differences. ACS Chem. Neurosci 2020; 19: 2944-2961
• 74 Tong JY, Wong A, Zhu D, Fastenberg JH, Tham T.. The Prevalence of Olfactory and Gustatory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2020; 163: 3-11
• 75 Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L. et al. Self-reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross-sectional Study. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2020; 71: 889-890
• 76 Lechien JR, Michel J, Radulesco T, Chiesa-Estomba CM, Vaira LA, Riu Gde. et al. Clinical and Radiological Evaluations of COVID-19 Patients With Anosmia: Preliminary Report. The Laryngoscope 2020; 130: 2526-2531
• 77 Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C. et al. Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection. JAMA 2020; 323: 2089-2090
• 78 Niklassen AS, Draf J, Huart C, Hintschich C, Bocksberger S, Trecca EMC. et al. COVID-19: Recovery from chemosensory dysfunction. A multicentre study on smell and taste. The Laryngoscope. 2021
• 79 Borsetto D, Hopkins C, Philips V, Obholzer R, Tirelli G, Polesel J. et al. Self-reported alteration of sense of smell or taste in patients with COVID-19: a systematic review and meta-analysis on 3563 patients. Rhinology 2020; 58: 430-436
• 80 Boscolo-Rizzo P, Tirelli G, Meloni P, Hopkins C, Madeddu G, Vito Ade. et al. Coronavirus disease 2019 (COVID-19)-related smell and taste impairment with widespread diffusion of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Omicron variant. International forum of allergy & rhinology 2022; 12: 1273-1281
• 81 Hintschich CA, Vielsmeier V, Bohr C, Hagemann J, Klimek L.. Prevalence of acute olfactory dysfunction differs between variants of SARS-CoV-2-results from chemosensitive testing in wild type, VOC alpha (B.1.1.7) and VOC delta (B.1617.2). Eur Arch Otorhinolaryngol 2022; 279: 5445-5447
• 82 Dehgani-Mobaraki P, Patel Z, Zaidi AK, Giannandrea D, Hopkins C.. The Omicron variant of SARS-CoV-2 and its effect on the olfactory system. International forum of allergy & rhinology. 2022
• 83 Gane SB, Kelly C, Hopkins C.. Isolated sudden onset anosmia in COVID-19 infection. A novel syndrome?. Rhinology 2020; 58: 299-301
• 84 Hopkins C, Surda P, Kumar N.. Presentation of new onset anosmia during the COVID-19 pandemic. Rhinology 2020; 58: 295-298
• 85 Haehner A, Draf J, Dräger S, With K, de Hummel T.. Predictive Value of Sudden Olfactory Loss in the Diagnosis of COVID-19. ORL J Otorhinolaryngol Relat Spec 2020; 82: 175-180
• 86 Huart C, Philpott C, Konstantinidis I, Altundag A, Whitcroft KL, Trecca EMC. et al. Comparison of COVID-19 and common cold chemosensory dysfunction. Rhinology 2020; 58: 623-625
• 87 Parma V, Ohla K, Veldhuizen MG, Niv MY, Kelly CE, Bakke AJ. et al. More than smell – COVID-19 is associated with severe impairment of smell, taste, and chemesthesis. Chemical senses 2020; 45: 609-622
• 88 Duyan M, Ozturan IU, Altas M.. Delayed Parosmia Following SARS-CoV-2 Infection: a Rare Late Complication of COVID-19. SN comprehensive clinical medicine 2021; 3: 1200-1202
• 89 Lerner DK, Garvey KL, Arrighi-Allisan AE, Filimonov A, Filip P, Shah J. et al. Clinical Features of Parosmia Associated With COVID-19 Infection. The Laryngoscope 2022; 132: 633-639
• 90 Hopkins C, Surda P, Whitehead E, Kumar BN.. Early recovery following new onset anosmia during the COVID-19 pandemic – an observational cohort study. J Otolaryngol Head Neck Surg 2020; 49: 26
• 91 Lee Y, Min P, Lee S, Kim SW.. Prevalence and Duration of Acute Loss of Smell or Taste in COVID-19 Patients. J Korean Med Sci 2020; 35: e174
• 92 Boscolo-Rizzo P, Menegaldo A, Fabbris C, Spinato G, Borsetto D, Vaira LA. et al. Six-Month Psychophysical Evaluation of Olfactory Dysfunction in Patients with COVID-19. Chem. Senses. 2021
• 93 Vaira LA, Hopkins C, Petrocelli M, Lechien JR, Chiesa-Estomba CM, Salzano G. et al. Smell and taste recovery in coronavirus disease 2019 patients: a 60-day objective and prospective study. J Laryngol Otol 2020; 134: 703-709
• 94 Lechien JR, Chiesa-Estomba CM, Beckers E, Mustin V, Ducarme M, Journe F. et al. Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients. Journal of internal medicine 2021; 290: 451-461
• 95 Boscolo-Rizzo P, Fabbris C, Polesel J, Emanuelli E, Tirelli G, Spinato G. et al. Two-Year Prevalence and Recovery Rate of Altered Sense of Smell or Taste in Patients With Mildly Symptomatic COVID-19. JAMA Otolaryngol Head Neck Surg. 2022
• 96 Prem B, Liu DT, Besser G, Renner B, Mueller CA.. Retronasal olfactory testing in early diagnosed and suspected COVID-19 patients: a 7-week follow-up study. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2022; 279: 257-265
• 97 Tognetti A, Thunell E, Olsson MJ, Greilert N, Havervall S, Thålin C. et al. High prevalence of olfactory disorders 18 months after contracting COVID-19. medRxiv 2022; 269490
• 98 Hummel T, Lotsch J.. Prognostic factors of olfactory dysfunction. Arch Otolaryngol Head Neck Surg 2010; 136: 347-351
• 99 Liu DT, Sabha M, Damm M, Philpott C, Oleszkiewicz A, Hähner A. et al. Parosmia is Associated with Relevant Olfactory Recovery After Olfactory Training. The Laryngoscope 2021; 131: 618-623
• 100 Brann DH, Tsukahara T, Weinreb C, Lipovsek M, van den Berge K, Gong B. et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Science Advances 2020; 6
• 101 Najafloo R, Majidi J, Asghari A, Aleemardani M, Kamrava SK, Simorgh S. et al. Mechanism of Anosmia Caused by Symptoms of COVID-19 and Emerging Treatments. ACS Chem Neurosci 2021; 12: 3795-3805
• 102 Zazhytska M, Kodra A, Hoagland DA, Frere J, Fullard JF, Shayya H. et al. Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia. Cell 2022; 185: 1052-1064
• 103 Melo de GD, Lazarini F, Levallois S, Hautefort C, Michel V, Larrous F. et al. COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters. Science Translational Medicine 2021; 13
• 104 Kirschenbaum D, Imbach LL, Ulrich S, Rushing EJ, Keller E, Reimann RR. et al. Inflammatory olfactory neuropathy in two patients with COVID-19. Lancet 2020; 396: 166
• 105 Politi LS, Salsano E, Grimaldi M.. Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia. JAMA Neurol 2020; 77: 1028-1029
• 106 Xydakis MS, Albers MW, Holbrook EH, Lyon DM, Shih RY, Frasnelli JA. et al. Post-viral effects of COVID-19 in the olfactory system and their implications. Lancet Neurol. 2021
• 107 Deems RO, Friedman MI, Friedman LS, Maddrey WC.. Clinical manifestations of olfactory and gustatory disorders associated with hepatic and renal disease. In: Getchell TV, Doty RL, Bartoshuk L, Snow J (eds). Smell and taste in health and disease. New York: Raven Press; 1991: 805-816
• 108 Temmel AF, Quint C, Schickinger-Fischer B, Klimek L, Stoller E, Hummel T.. Characteristics of olfactory disorders in relation to major causes of olfactory loss. Arch Otolaryngol Head Neck Surg 2002; 128: 635-641
• 109 Doty RL.. Clinical Disorders of Olfaction. In: Doty RL (ed). Handbook of Olfaction and Gustation. John Wiley & Sons, Inc; 2015: 375-401
• 110 Philpott C, DeVere R.. Post-infectious and post-traumatic olfactory loss. In: Welge-Luessen A, Hummel T (eds). Management of smell and taste disorders. Stuttgart: Thieme; 2014: 91-105
• 111 Suzuki M, Saito K, Min WP, Vladau C, Toida K, Itoh H. et al. Identification of viruses in patients with postviral olfactory dysfunction. The Laryngoscope 2007; 117: 272-7
• 112 Jafek BW, Murrow B, Michaels R, Restrepo D, Linschoten M.. Biopsies of human olfactory epithelium. Chem. Senses 2002; 27: 623-628
• 113 Loo AT, Youngentob SL, Kent PF, Schwob JE.. The aging olfactory epithelium: neurogenesis, response to damage, and odorant-induced activity. Int. J. Dev. Neurosci 1996; 14: 881-900
• 114 Whitcroft KL, Cuevas M, Haehner A, Hummel T.. Patterns of olfactory impairment reflect underlying disease etiology. The Laryngoscope 2017; 127: 291-295
• 115 Reden J, Mueller A, Mueller C, Konstantinidis I, Frasnelli J, Landis BN. et al. Recovery of olfactory function following closed head injury or infections of the upper respiratory tract. Arch Otolaryngol Head Neck Surg 2006; 132: 265-269
• 116 Hendriks A.. Olfactory dysfunction. Rhinology 1988; 26: 229-251
• 117 Mori J, Aiba T, Sugiura M, Matsumoto K, Tomiyama K, Okuda F. et al. Clinical study of olfactory disturbance. Acta Otolaryngol Suppl (Stockh) 1998; 538: 197-201
• 118 Duncan HJ, Seiden AM.. Long-term follow-up of olfactory loss secondary to head trauma and upper respiratory tract infection. Arch Otolaryngol Head Neck Surg 1995; 121: 1183-1187
• 119 The Olfactory System and the Nasal Mucosa as Portals of Entry of Viruses, Drugs, and Other Exogenous Agents into the Brain. In: Handbook of Olfaction and Gustation. CRC Press; 2003:979–1020
• 120 Youngentob SL, Schwob JE, Saha S, Manglapus G, Jubelt B.. Functional consequences following infection of the olfactory system by intranasal infusion of the olfactory bulb line variant (OBLV) of mouse hepatitis strain JHM. Chemical senses 2001; 26: 953-963
• 121 Yamagishi M, Fujiwara M, Nakamura H.. Olfactory mucosal findings and clinical course in patients with olfactory disorders following upper respiratory viral infection. Rhinology 1994; 32: 113-118
• 122 Mueller A, Rodewald A, Reden J, Gerber J, Kummer R, von Hummel T.. Reduced olfactory bulb volume in post-traumatic and post-infectious olfactory dysfunction. Neuroreport 2005; 16: 475-478
• 123 Damm M, Temmel A, Welge-Lüssen A, Eckel HE, Kreft MP, Klussmann JP. et al. Epidemiologie und Therapie von Riechstörungen in Deutschland, Österreich und der Schweiz. HNO 2004; 52: 112-120
• 124 Rombaux P, Huart C, Levie P, Cingi C, Hummel T.. Olfaction in Chronic Rhinosinusitis. Current allergy and asthma reports 2016; 16: 41
• 125 Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S. et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 2020; 58: 1-464
• 126 Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M. et al. Clinical practice guideline (update): adult sinusitis. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery 2015; 152: S1-S39
• 127 Stuck BA, Popert U, Beule A, Jobst D, Klimek L, LAudien M. et al. Rhinosinusitis. AWMF Leitlinien. 2017 https://www.awmf.org/leitlinien/detail/ll/017-049.html
• 128 Lane AP, Turner J, May L, Reed R.. A genetic model of chronic rhinosinusitis-associated olfactory inflammation reveals reversible functional impairment and dramatic neuroepithelial reorganization. The Journal of neuroscience: the official journal of the Society for Neuroscience 2010; 30: 2324-2329
• 129 Pozharskaya T, Liang J, Lane AP.. Regulation of inflammation-associated olfactory neuronal death and regeneration by the type II tumor necrosis factor receptor. International forum of allergy & rhinology 2013; 3: 740-747
• 130 Gudziol V, Hummel T.. Effects of pentoxifylline on olfactory sensitivity: a postmarketing surveillance study. Arch Otolaryngol Head Neck Surg 2009; 135: 291-295
• 131 Han P, Whitcroft KL, Fischer J, Gerber J, Cuevas M, Andrews P. et al. Olfactory brain gray matter volume reduction in patients with chronic rhinosinusitis. International forum of allergy & rhinology 2017; 7: 551-556
• 132 Rombaux P, Potier H, Bertrand B, Duprez T, Hummel T.. Olfactory bulb volume in patients with sinonasal disease. Am J Rhinol 2008; 22: 598-601
• 133 Whitcroft KL, Noltus J, Andrews P, Hummel T.. Sinonasal surgery alters brain structure and function: Neuroanatomical correlates of olfactory dysfunction. J Neurosci Res 2021; 99: 2156-2171
• 134 Enriquez K, Lehrer E, Mullol J.. The optimal evaluation and management of patients with a gradual onset of olfactory loss. Current opinion in otolaryngology & head and neck surgery 2014; 22: 34-41
• 135 Hernandez AK, Juratli L, Haehner A, Hsieh JW, Landis BN, Hummel T.. Assessment of olfactory fluctuations in a clinical context. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery. 2022
• 136 Jafek BW, Moran DT, Eller PM, Rowley J.C., Jafek TB.. Steroid-dependent anosmia. Arch. Otolaryngol. Head Neck Surg.. 1987 113. 547-549
• 137 Seiden AM.. Olfactory loss secondary to nasal and sinus pathology. In: Seiden AM (ed). Taste and smell disorders. New York: Thieme; 1997: 52-71
• 138 Richard M, Costanzo, Laurence J, DiNardo, and Evan R.Reiter. Head Injury and Taste. In: Handbook of Olfaction and Gustation. CRC Press; 2003: 1638-1649
• 139 Holbrook EH, Leopold DA, Schwob JE.. Abnormalities of axon growth in human olfactory mucosa. The Laryngoscope 2005; 115: 2144-2154
• 140 Shiga H, Taki J, Okuda K, Watanabe N, Tonami H, Nakagawa H. et al. Prognostic value of olfactory nerve damage measured with thallium-based olfactory imaging in patients with idiopathic olfactory dysfunction. Scientific reports 2017; 7: 3581
• 141 Lotsch J, Reither N, Bogdanov V, Hahner A, Ultsch A, Hill K. et al. A brain-lesion pattern based algorithm for the diagnosis of posttraumatic olfactory loss. Rhinology 2015; 53: 365-370
• 142 Schofield PW, Doty RL.. The influence of head injury on olfactory and gustatory function. Handbook of clinical neurology 2019; 164: 409-429
• 143 Costanzo RM, Zasler ND.. Epidemiology and pathophysiology of olfactory and gustatory dysfunction in head trauma, Vol 7. 1992
• 144 Zang Y, Hähner A, Negoias S, Lakner T, Hummel T.. Apparently Minor Head Trauma Can Lead to Anosmia: A Case Report. ORL J Otorhinolaryngol Relat Spec 2021; 83: 2-6
• 145 Christensen MD, Holbrook EH, Costanzo RM, Schwob JE.. Rhinotopy is disrupted during the re-innervation of the olfactory bulb that follows transection of the olfactory nerve. Chemical senses 2001; 26: 359-369
• 146 Yee KK, Costanzo RM.. Changes in odor quality discrimination following recovery from olfactory nerve transection. Chemical senses 1998; 23: 513-519
• 147 Doty RL, Yousem DM, Pham LT, Kreshak AA, Geckle R, Lee WW.. Olfactory dysfunction in patients with head trauma. Arch Neurol 1997; 54: 1131-1140
• 148 Fan L-Y, Kuo C-L, Lirng J-F, Shu C-H.. Investigation of prognostic factors for post-traumatic olfactory dysfunction. Journal of the Chinese Medical Association: JCMA 2015; 78: 299-303
• 149 Mueller CA, Hummel T.. Recovery of olfactory function after nine years of post-traumatic anosmia: a case report. J Med Case Rep 2009; 3: 9283
• 150 Sumner D.. Post-traumatic anosmia. Brain 1964; 87: 107-120
• 151 Haehner A, Hummel T, Reichmann H.. Olfactory dysfunction as a diagnostic marker for Parkinson’s disease. Expert Rev Neurother 2009; 9: 1773-1779
• 152 Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Movement disorders: official journal of the Movement Disorder Society 2015; 30: 1591-1601
• 153 Haehner A, Masala C, Walter S, Reichmann H, Hummel T.. Incidence of Parkinson’s disease in a large patient cohort with idiopathic smell and taste loss. Journal of neurology 2019; 266: 339-345
• 154 Roos DS, Klein M, Deeg DJH, Doty RL, Berendse HW.. Prevalence of Prodromal Symptoms of Parkinson’s Disease in the Late Middle-Aged Population. J Parkinsons Dis 2022; 12: 967-974
• 155 Doty RL, Hawkes CH.. Chemosensory dysfunction in neurodegenerative diseases. Handb Clin Neurol 2019; 164: 325-360
• 156 Conti MZ, Vicini-Chilovi B, Riva M, Zanetti M, Liberini P, Padovani A. et al. Odor identification deficit predicts clinical conversion from mild cognitive impairment to dementia due to Alzheimer’s disease. Arch. Clin. Neuropsychol. 2013; 28: 391-399
• 157 Leon-Sarmiento FE, Leon-Ariza DS, Doty RL.. Dysfunctional chemosensation in myasthenia gravis: a systematic review. J Clin Neuromuscul Dis 2013; 15: 1-6
• 158 Lucassen EB, Turel A, Knehans A, Huang X, Eslinger P.. Olfactory dysfunction in Multiple Sclerosis: A scoping review of the literature. Mult Scler Relat Disord 2016; 6: 1-9
• 159 Kohler CG, Moberg PJ, Gur RE, O’Connor MJ, Sperling MR, Doty RL.. Olfactory dysfunction in schizophrenia and temporal lobe epilepsy. Neuropsychiatry Neuropsychol Behav Neurol 2001; 4: 83-88
• 160 Negoias S, Croy I, Gerber J, Puschmann S, Petrowski K, Joraschky P. et al. Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience 2010; 169: 415-421
• 161 Moberg PJ, Kamath V, Marchetto DM, Calkins ME, Doty RL, Hahn CG. et al. Meta-analysis of olfactory function in schizophrenia, first-degree family members, and youths at-risk for psychosis. Schizophr Bull 2014; 40: 50-59
• 162 Attems J, Walker L, Jellinger KA.. Olfactory bulb involvement in neurodegenerative diseases. Acta neuropathologica 2014; 127: 459-475
• 163 Witt M, Bormann K, Gudziol V, Pehlke K, Barth K, Minovi A. et al. Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord 2009; 24: 906-914
• 164 Doty RL.. Treatments for smell and taste disorders: A critical review. Handb Clin Neurol 2019; 164: 455-479
• 165 Pinto JM, Wroblewski KE, Kern DW, Schumm LP, McClintock MK. , . 2014 Oct 1, et al. Olfactory dysfunction predicts 5-year mortality in older adults. PLOS ONE 2014; 9: e107541
• 166 Schubert CR, Fischer ME, Pinto AA, Klein BEK, Klein R, Tweed TS. et al. Sensory Impairments and Risk of Mortality in Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences 2017; 72: 710-715
• 167 Liu B, Luo Z, Pinto JM, Shiroma EJ, Tranah GJ, Wirdefeldt K. et al. Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults: A Cohort Study. Annals of internal medicine. 2019
• 168 Doty RL, Kamath V.. The influences of age on olfaction: a review. Front. Psychol. 2014; 5: 20
• 169 Fonteyn S, Huart C, Deggouj N, Collet S, Eloy P, Rombaux P.. Non-sinonasal-related olfactory dysfunction: A cohort of 496 patients. Eur Ann Otorhinolaryngol Head Neck Dis 2014; 131: 87-91 DOI: 10.1016/j.anorl.2013.03.006.. Epub 2014 Mar 26
• 170 Sendon A.. Olfato, psicología y psicoanálisis. Enfoque multidisciplinario. In: In G. Soler (Ed.). Olfato y Gusto; 223-230
• 171 Han P, Musch M, Abolmaali N, Hummel T.. Improved Odor Identification Ability and Increased Regional Gray Matter Volume After Olfactory Training in Patients With Idiopathic Olfactory Loss. i-Perception 2021; 12 20416695211005811
• 172 Doty RL. (ed). Handbook of Olfaction and Gustation. John Wiley & Sons, Inc; 2015
• 173 Ros C, Alobid I, Centellas S, Balasch J, Mullol J, Castelo-Branco C.. Loss of smell but not taste in adult women with Turner’s syndrome and other congenital hypogonadisms. Maturitas 2012; 73: 244-250
• 174 Iannaccone A, Mykytyn K, Persico AM, Searby CC, Baldi A, Jablonski MM. et al. Clinical evidence of decreased olfaction in Bardet-Biedl syndrome caused by a deletion in the BBS4 gene. Am J Med Genet A. 2005; 132A: 343-346
• 175 Boesveldt S, Lindau ST, McClintock MK, Hummel T, Lundstrom JN, Lindstrom JN.. Gustatory and olfactory dysfunction in older adults: a national probability study. Rhinology 2011; 49: 324-330
• 176 Ottaviano G, Cantone E, D’Errico A, Salvalaggio A, Citton V, Scarpa B. et al. Sniffin’ Sticks and olfactory system imaging in patients with Kallmann syndrome. International forum of allergy & rhinology 2015; 5: 855-861
• 177 Yousem DM, Geckle RJ, Bilker W, McKeown DA, Doty RL.. MR evaluation of patients with congenital hyposmia or anosmia. Am J Radiol 1996; 166: 439-443
• 178 Abolmaali ND, Hietschold V, Vogl TJ, Hüttenbrink KB, Hummel T.. MR evaluation in patients with isolated anosmia since birth or early childhood. AJNR Am J Neuroradiol 2002; 23: 157-164
• 179 Karstensen HG, Mang Y, Fark T, Hummel T, Tommerup N.. The first mutation in CNGA2 in two brothers with anosmia. Clin Genet 2015; 88: 293-296
• 180 Weiss T, Soroka T, Gorodisky L, Shushan S, Snitz K, Weissgross R. et al. Human Olfaction without Apparent Olfactory Bulbs. Neuron 2020; 105: 35-45
• 181 Rombaux P, Mouraux A, Bertrand B, Duprez T, Hummel T.. Can we smell without an olfactory bulb?. American journal of rhinology 2007; 21: 548-550
• 182 Pfaar O, Hüttenbrink KB, Hummel T.. Assessment of olfactory function after septoplasty: A longitudinal study. Rhinology 2004; 42: 195-199
• 183 Alobid I, Enseñat J, Mariño-Sánchez F, Notaris M, de Centellas S, Mullol J. et al. Impairment of olfaction and mucociliary clearance after expanded endonasal approach using vascularized septal flap reconstruction for skull base tumors. Neurosurgery 2013; 72: 540-546
• 184 Gouveri E, Katotomichelakis M, Gouveris H, Danielides V, Maltezos E, Papanas N.. Olfactory dysfunction in type 2 diabetes mellitus: an additional manifestation of microvascular disease?. Angiology 2014; 65: 869-876
• 185 Risberg-Berlin B, Möller RY, Finizia C.. Effectiveness of olfactory rehabilitation with the nasal airflow-inducing maneuver after total laryngectomy: one-year follow-up study. Archives of otolaryngology – head & neck surgery 2007; 133: 650-654
• 186 Atanasova B, Graux J, El Hage W, Hommet C, Camus V, Belzung C.. Olfaction: a potential cognitive marker of psychiatric disorders. Neuroscience and biobehavioral reviews 2008; 32: 1315-1325
• 187 Kayser J, Tenke CE, Kroppmann CJ, Alschuler DM, Ben-David S, Fekri S. et al. Olfaction in the psychosis prodrome: electrophysiological and behavioral measures of odor detection. Int J Psychophysiol 2013; 90: 190-206
• 188 Blau JN, Solomon F.. Smell and other sensory disturbances in migraine. J. Neurol 1985; 232: 275-276
• 189 Snyder RD, Drummond PD.. Olfaction in migraine. Cephalalgia 1997; 17: 729-32
• 190 Holscher T, Seibt A, Appold S, Dorr W, Herrmann T, Huttenbrink KB. et al. Effects of radiotherapy on olfactory function. Radiother Oncol 2005; 77: 157-163
• 191 Maurage P, Callot C, Chang B, Philippot P, Rombaux P, de Timary P. Olfactory impairment is correlated with confabulation in alcoholism: towards a multimodal testing of orbitofrontal cortex. PLOS ONE 2011; 6: e23190
• 192 Maurage P, Callot C, Philippot P, Rombaux P, de Timary P. Chemosensory event-related potentials in alcoholism: a specific impairment for olfactory function, Vol 88. 2011
• 193 Venstrom D, Amoore JE.. Olfactory threshold in relation to age, sex, or smoking. J. Food Sci 1968; 33: 264-265
• 194 Mullol J, Alobid I, Marino-Sanchez F, Quinto L, Haro J, de Bernal-Sprekelsen M. et al. Furthering the understanding of olfaction, prevalence of loss of smell and risk factors: a population-based survey (OLFACAT study). BMJ Open 2012; 2: e001256 DOI: 10.1136/bmjopen-2012-001256.. Print 2012
• 195 Fjaeldstad AW, Ovesen T, Hummel T.. The Association Between Smoking on Olfactory Dysfunction in 3,900 Patients With Olfactory Loss. The Laryngoscope 2021; 131: E8-E13
• 196 Frye RE, Schwartz BS, Doty RL.. Dose-related effects of cigarette smoking on olfactory function. JAMA 1990; 263: 1233-1236
• 197 Katotomichelakis M, Balatsouras D, Tripsianis G, Davris S, Maroudias N, Danielides V. et al. The effect of smoking on the olfactory function. Rhinology 2007; 45: 273-280
• 198 Vent J, Robinson AM, Gentry-Nielsen MJ, Conley DB, Hallworth R, Leopold DA. et al. Pathology of the olfactory epithelium: smoking and ethanol exposure. The Laryngoscope 2004; 114: 1383-1388
• 199 Yee KK, Pribitkin EA, Cowart BJ, Vainius AA, Klock CT, Rosen D. et al. Smoking-associated squamous metaplasia in olfactory mucosa of patients with chronic rhinosinusitis. Toxicol Pathol 2009; 37: 594-598
• 200 Halabe-Cherem J, Salado-Burbano JC, Nellen-Hummel H.. Parosmia agradable a materia fecal propia posterior a la infección por SARS-CoV-2. Gaceta medica de Mexico 2021; 157: 636-638
• 201 Landis BN, Frasnelli J, Hummel T.. Euosmia: a rare form of parosmia. Acta Otolaryngol 2006; 126: 101-103
• 202 Lin S-H, Chu S-T, Yuan B-C, Shu C-H.. Survey of the Frequency of Olfactory Dysfunction in Taiwan. Journal of the Chinese Medical Association 2009; 72: 68-71
• 203 Nordin S, Brämerson A, Millqvist E, Bende M.. Prevalence of parosmia: the Skövde population-based studies. Rhinology 2007; 45: 50-53
• 204 Nordin S, Murphy C, Davidson TM, Quinonez C, Jalowayski AA, Ellison DW.. Prevalence and assessment of qualitative olfactory dysfunction in different age groups The Laryngoscope 1996; 106: 739-744
• 205 Reden J, Maroldt H, Fritz A, Zahnert T, Hummel T.. A study on the prognostic significance of qualitative olfactory dysfunction. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2007; 264: 139-144
• 206 Pellegrino R, Mainland JD, Kelly CE, Parker JK, Hummel T.. Prevalence and correlates of parosmia and phantosmia among smell disorders. Chemical senses 2021; 46
• 207 Frasnelli J, Hummel T.. Olfactory dysfunction and daily life. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2005; 262: 231-235
• 208 Burges Watson DL, Campbell M, Hopkins C, Smith B, Kelly C, Deary V.. Altered smell and taste: Anosmia, parosmia and the impact of long Covid-19. PLOS ONE 2021; 16: e0256998
• 209 Deems DA, Doty RL, Settle RG, Moore-Gillon V, Shaman P, Mester AF. et al. Smell and taste disorders: a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch. Otorhinolaryngol. Head Neck Surg 1991; 117: 519-528
• 210 Hofmann FB.. Über Geruchsstörungen nach Katarrhen der Nasenhöhle. (Zur Theorie des Geruchssinnes). Muench Med Wochenschr 1918; 65: 1369
• 211 McMillan Carr V, Ring G, Youngentob SL, Schwob JE, Farbman AI.. Altered epithelial density and expansion of bulbar projections of a discrete HSP70 immunoreactive subpopulation of rat olfactory receptor neurons in reconstituting olfactory epithelium following exposure to methyl bromide. J Comp Neurol 2004; 469: 475-493
• 212 Cheung MC, Jang W, Schwob JE, Wachowiak M.. Functional recovery of odor representations in regenerated sensory inputs to the olfactory bulb. Frontiers in neural circuits 2013; 7: 207
• 213 Costanzo RM.. Rewiring the olfactory bulb: changes in odor maps following recovery from nerve transection. Chem Senses 2000; 25: 199-205
• 214 Schwob JE, Youngentob SL, Ring G, Iwema CL, Mezza RC.. Reinnervation of the rat olfactory bulb after methyl bromide-induced lesion: timing and extent of reinnervation. J Comp Neurol 1999; 412: 439-457
• 215 John JAS, Key B.. Axon mis-targeting in the olfactory bulb during regeneration of olfactory neuroepithelium. Chem Senses 2003; 28: 773-779
• 216 Rombaux P, Mouraux A, Bertrand B, Nicolas G, Duprez T, Hummel T.. Olfactory function and olfactory bulb volume in patients with postinfectious olfactory loss. The Laryngoscope 2006; 116: 436-439
• 217 Bitter T, Siegert F, Gudziol H, Burmeister HP, Mentzel HJ, Hummel T. et al. Gray matter alterations in parosmia. Neuroscience 2011; 177: 177-182
• 218 Iannilli E, Leopold DA, Hornung DE, Hummel T.. Advances in Understanding Parosmia: An fMRI Study. ORL J Otorhinolaryngol Relat Spec 2019; 81: 185-192
• 219 Christopher H. Hawkes, Richard L. Doty. Non-neurodegenerative Disorders of Olfaction. In: Smell and Taste Disorders. Cambridge University Press; 2018: 182-247
• 220 Parker JK, Kelly CE, Gane SB.. Molecular Mechanism of Parosmia. medRxiv 2021; 21251085
• 221 Keller A, Malaspina D.. Hidden consequences of olfactory dysfunction: a patient report series. BMC Ear Nose Throat Disord 2013; 13: 8
• 222 Parker JK, Kelly CE, Smith BC, Kirkwood AF, Hopkins C, Gane S.. Patients’ Perspectives on Qualitative Olfactory Dysfunction: Thematic Analysis of Social Media Posts. JMIR formative research 2021; 5: e29086
• 223 Leopold D.. Distortion of olfactory perception: diagnosis and treatment. Chem. Senses 2002; 27: 611-615
• 224 Landis BN, Frasnelli J, Croy I, Hummel T.. Evaluating the clinical usefulness of structured questions in parosmia assessment. The Laryngoscope 2010; 120: 1707-1713
• 225 Hummel T, Hummel C, Welge-Luessen A.. Assessment of Olfaction and Gustation. In: Welge-Luessen A, Hummel T (eds). Management of Smell and Taste Disorders – A Practical Guide for Clinicians. Stuttgart: Thieme; 2013: 58-75
• 226 Liu DT, Welge-Lüssen A, Besser G, Mueller CA, Renner B.. Assessment of odor hedonic perception: the Sniffin’ sticks parosmia test (SSParoT). Scientific reports 2020; 10: 18019
• 227 Sekine R, Menzel S, Hähner A, Mori E, Hummel T.. Assessment of postviral qualitative olfactory dysfunction using the short SSParoT in patients with and without parosmia. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2022; 1-4
• 228 Frasnelli J, Landis BN, Heilmann S, Hauswald B, Huttenbrink KB, Lacroix JS. et al. Clinical presentation of qualitative olfactory dysfunction. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2004; 261: 411-415
• 229 Sjölund S, Larsson M, Olofsson JK, Seubert J, Laukka EJ.. Phantom Smells: Prevalence and Correlates in a Population-Based Sample of Older Adults. Chemical senses 2017; 42: 309-318
• 230 Bainbridge KE, Byrd-Clark D, Leopold D.. Factors Associated With Phantom Odor Perception Among US Adults: Findings From the National Health and Nutrition Examination Survey. JAMA otolaryngology – head & neck surgery 2018; 144: 807-814
• 231 Croy I, Nordin S, Hummel T.. Olfactory disorders and quality of life –an updated review. Chemical senses 2014; 39: 185-194
• 232 Ohayon MM.. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 2000; 97: 153-164
• 233 Holbrook EH, Puram SV, See RB, Tripp AG, Nair DG.. Induction of smell through transethmoid electrical stimulation of the olfactory bulb. International forum of allergy & rhinology 2019; 9: 158-164
• 234 Kumar G, Juhász C, Sood S, Asano E.. Olfactory hallucinations elicited by electrical stimulation via subdural electrodes: effects of direct stimulation of olfactory bulb and tract. Epilepsy & behavior: E&B 2012; 24: 264-268
• 235 Bérard N, Landis BN, Legrand L, Tyrand R, Grouiller F, Vulliémoz S. et al. Electrical stimulation of the medial orbitofrontal cortex in humans elicits pleasant olfactory perceptions. Epilepsy & behavior: E&B 2021; 114: 107559
• 236 Kaufman MD, Lassiter KR, Shenoy BV.. Paroxysmal unilateral dysosmia: a cured patient. Annals of neurology 1988; 24: 450-451
• 237 Markert JM, Hartshorn DO, Farhat SM.. Paroxysmal bilateral dysosmia treated by resection of the olfactory bulbs. Surg Neurol 1993; 40: 160-163
• 238 Leopold DA, Loehrl TA, Schwob JE.. Long-term follow-up of surgically treated phantosmia. Arch Otolaryngol Head Neck Surg 2002; 128: 642-7
• 239 Morrissey DK, Pratap U, Brown C, Wormald P-J.. The role of surgery in the management of phantosmia. The Laryngoscope 2016; 126: 575-578
• 240 Fikentscher R, Gudziol H, Roseburg B.. Einteilung und Begriffsbestimmung der Riech- und Schmeckstörungen. Laryngo-Rhino-Otol 1987; 66: 355-357
• 241 Landis BN, Reden J, Haehner A.. Idiopathic phantosmia: outcome and clinical significance. ORL J Otorhinolaryngol Relat Spec 2010; 72: 252-255
• 242 Whitcroft KL, Hummel T.. Olfactory Dysfunction in COVID-19: Diagnosis and Management. JAMA 2020; 323: 2512-2514
• 243 Damm M, Hüttenbrink KB, Hummel T, Landis B, Göktas Ö, Muttray A, Blankenburg M, Höglinger G, Schmitl L.. AWMF Leitlinien “Riech- und Schmeckstörungen”. 2017 https://www.awmf.org/uploads/tx_szleitlinien/017-050l_S2k_Riech-und-Schmeckst%C3%B6rungen_2017-03.pdf
• 244 Soler ZM, Hyer JM, Karnezis TT, Schlosser RJ.. The Olfactory Cleft Endoscopy Scale correlates with olfactory metrics in patients with chronic rhinosinusitis. International forum of allergy & rhinology 2016; 6: 293-298
• 245 Lund VJ, Kennedy DW.. Quantification for staging sinusitis. The Staging and Therapy Group. The Annals of otology, rhinology & laryngology. Supplement 1995; 167: 17-21
• 246 Hummel T, Landis BN, Huttenbrink KB.. Smell and taste disorders. GMS Curr Top Otorhinolaryngol Head Neck Surg 2011; 10:: Doc04
• 247 Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP.. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol 2009; 34: 447-454
• 248 Soler ZM, Smith TL, Alt JA, Ramakrishnan VR, Mace JC, Schlosser RJ.. Olfactory-specific quality of life outcomes after endoscopic sinus surgery. International forum of allergy & rhinology 2016; 6: 407-413
• 249 Zou L-Q, Linden L, Cuevas M, Metasch M-L, Welge-Lüssen A, Hähner A. et al. Self-reported mini olfactory questionnaire (Self-MOQ): A simple and useful measurement for the screening of olfactory dysfunction. The Laryngoscope 2020; 130: E786-E790
• 250 Landis BN, Hummel T, Hugentobler M, Giger R, Lacroix JS.. Ratings of overall olfactory function. Chemical senses 2003; 28: 691-694
• 251 Philpott CM, Wolstenholme CR, Goodenough PC, Clark A, Murty GE.. Comparison of subjective perception with objective measurement of olfaction. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2006; 134: 488-490
• 252 Philpott CM, Rimal D, Tassone P, Prinsley PR, Premachandra DJ.. A study of olfactory testing in patients with rhinological pathology in the ENT clinic. Rhinology 2008; 46: 34-39
• 253 Wehling E, Lundervold AJ, Espeset T, Reinvang I, Bramerson A, Nordin S.. Even cognitively well-functioning adults are unaware of their olfactory dysfunction: Implications for ENT clinicians and researchers. Rhinology 2015; 53: 89-94
• 254 Hedner M, Larsson M, Arnold N, Zucco GM, Hummel T.. Cognitive factors in odor detection, odor discrimination, and odor identification tasks. J Clin Exp Neuropsychol 2010; 32: 1062-1067
• 255 Sorokowska A, Albrecht E, Hummel T.. Reading first or smelling first? Effects of presentation order on odor identification. Atten Percept Psychophys 2015; 77: 731-736
• 256 Doty RL, McKeown DA, Lee WW, Shaman P.. A study of the test-retest reliability of ten olfactory tests. Chem Senses 1995; 20: 645-656
• 257 Doty RL, Smith R, McKeown DA, Raj J.. Tests of human olfactory function: principle component analysis suggests that most measure a common source of variance. Percept Psychophys 1994; 56: 701-707
• 258 Jones-Gotman M, Zatorre RJ.. Olfactory identification deficits in patients with focal cerebral excision. Neuropsychologia 1988; 26: 387-400
• 259 Hornung DE, Kurtz DB, Bradshaw CB, Seipel DM, Kent PF, Blair DC. et al. The olfactory loss that accompanies an HIV infection. Physiol Behav 1998; 15: 549-556
• 260 Lotsch J, Reichmann H, Hummel T.. Different odor tests contribute differently to the evaluation of olfactory loss. Chemical senses 2008; 33: 17-21
• 261 Cain WS, Gent JF, Goodspeed RB, Leonard G.. Evaluation of olfactory dysfunction in the Connecticut Chemosensory Clinical Research Center (CCCRC). The Laryngoscope 1988; 98: 83-88
• 262 Doty RL, Shaman P, Dann M.. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiology & behavior 1984; 32: 489-502
• 263 Picillo M, Iavarone A, Pellecchia MT, Amboni M, Erro R, Moccia M. et al. Validation of an Italian version of the 40-item University of Pennsylvania Smell Identification Test that is physician administered: our experience on one hundred and thirty-eight healthy subjects. Clinical otolaryngology: official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial. Surgery 2014; 39: 53-57
• 264 Taherkhani S, Moztarzadeh F, Mehdizadeh Seraj J, Hashemi Nazari SS, Taherkhani F, Gharehdaghi J. et al. Iran Smell Identification Test (Iran-SIT): a Modified Version of the University of Pennsylvania Smell Identification Test (UPSIT) for Iranian Population. Chem. Percept 2015; 8: 183-191
• 265 Thamboo A, Santos RCD, Naidoo L, Rahmanian R, Chilvers MA, Chadha NK.. Use of the SNOT-22 and UPSIT to appropriately select pediatric patients with cystic fibrosis who should be referred to an otolaryngologist: cross-sectional study. JAMA otolaryngology – head & neck surgery 2014; 140: 934-939
• 266 Razmpa E, Saedi B, Safavi A, Mohammadi S.. Olfactory function after nasal plastic surgery. B-ENT 2013; 9: 269-275
• 267 Saedi B, Sadeghi M, Yazdani N, Afshari A.. Effectiveness of FESS in Smell Improvement of Sinusitis Patients. Indian J Otolaryngol Head Neck Surg 2013; 65: 283-287
• 268 Shemshadi H, Azimian M, Onsori MA, AzizAbadi Farahani M.. Olfactory function following open rhinoplasty: A 6-month follow-up study. BMC Ear Nose Throat Disord 2008; 8: 6
• 269 Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G.. ‘Sniffin’ sticks’: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chemical senses 1997; 22: 39-52
• 270 Gudziol V, Lötsch J, Hähner A, Zahnert T, Hummel T.. Clinical significance of results from olfactory testing. The Laryngoscope 2006; 116: 1858-1863
• 271 Gudziol H, Wächter R.. Gibt es olfaktorisch evozierte Atemänderungen?. Laryngo-Rhino-Otol 2004; 83: 367-373
• 272 Gudziol H, Stark D, Lehnich H, Bitter T, Guntinas-Lichius O.. Hyposmiker haben weniger evozierte respiratorische Orientierungsreaktionen als Normosmiker. Laryngo-Rhino-Otol 2010; 89: 477-482
• 273 Schriever VA, Agosin E, Altundag A, Avni H, Cao Van H, Cornejo C. et al. Development of an International Odor Identification Test for Children: The Universal Sniff Test. J Pediatr 2018; 198: 265-272
• 274 Cameron EL, Doty RL.. Odor identification testing in children and young adults using the smell wheel. Int J Pediatr Otorhinolaryngol 2013; 77: 346-350
• 275 Kobal G, Klimek L, Wolfensberger M, Gudziol H, Temmel A, Owen CM. et al. Multicenter investigation of 1,036 subjects using a standardized method for the assessment of olfactory function combining tests of odor identification, odor discrimination, and olfactory thresholds. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2000; 257: 205-211
• 276 Klimek L, Hummel T, Moll B, Kobal G, Mann WJ.. Lateralized and bilateral olfactory function in patients with chronic sinusitis compared with healthy control subjects. The Laryngoscope 1998; 108: 111-114
• 277 Welge-Lüssen A, Gudziol V, Wolfensberger M, Hummel T.. Olfactory testing in clinical settings – is there additional benefit from unilateral testing?. Rhinology 2010; 48: 156-159
• 278 Gudziol V, Hummel C, Negoias S, Ishimaru T, Hummel T.. Lateralized differences in olfactory function. The Laryngoscope 2007; 117: 808-811
• 279 Huart C, Rombaux P, Gérard T, Hanseeuw B, Lhommel R, Quenon L. et al. Unirhinal Olfactory Testing for the Diagnostic Workup of Mild Cognitive Impairment. Journal of Alzheimer’s Disease 2015; 47: 253
• 280 Doty R, Marcus A, Lee WW.. Development of the 12-item cross-cultural smell identification test (CC-SIT). The Laryngoscope 1996; 106: 353-356
• 281 Hummel T, Konnerth CG, Rosenheim K, Kobal G.. Screening of olfactory function with a four-minute odor identification test: reliability, normative data, and investigations in patients with olfactory loss. The Annals of otology, rhinology, and laryngology 2001; 110: 976-981
• 282 Jackman AH, Doty RL.. Utility of a three-item smell identification test in detecting olfactory dysfunction. The Laryngoscope 2005; 115: 2209-2212
• 283 Mueller C, Renner B.. A new procedure for the short screening of olfactory function using five items from the “Sniffin’ Sticks” identification test kit. Am J Rhinol 2006; 20: 113-116
• 284 Gupta S, Kallogjeri D, Farrell NF, Lee JJ, Smith HJ, Khan AM. et al. Development and Validation of a Novel At-home Smell Assessment. JAMA otolaryngology – head & neck surgery 2022; 148: 252-258
• 285 Parma V, Hannum ME, O’Leary M, Pellegrino R, Rawson NE, Reed DR. et al. SCENTinel 1.0: Development of a Rapid Test to Screen for Smell Loss. Chemical senses 2021; 46
• 286 Sheen F, Tan V, Lim AJ, Haldar S, Sengupta S, Allen D. et al. The COVOSMIA-19 trial: Preliminary application of the Singapore smell and taste test to objectively measure smell and taste function with COVID-19. Food Qual Pref 2022; 97: 104482
• 287 Li Z, Stolper S, Draf J, Haehner A, Hummel T.. Smell, taste and trigeminal function: similarities and differences between results from home tests and examinations in the clinic. Rhinology 2022; DOI: 10.4193/Rhin21.430.
• 288 Negoias S, Meves B, Zang Y, Haehner A, Hummel T.. Characteristics of Olfactory Disorder With and Without Reported Flavor Loss. The Laryngoscope 2020; 130: 2869-2873
• 289 Heilmann S, Strehle G, Rosenheim K, Damm M, Hummel T.. Clinical assessment of retronasal olfactory function. Arch Otolaryngol Head Neck Surg 2002; 128: 414-418
• 290 Renner B, Mueller CA, Dreier J, Faulhaber S, Rascher W, Kobal G.. The candy smell test: a new test for retronasal olfactory performance. Laryngoscope 2009; 119: 487-495
• 291 Yoshino A, Goektas G, Mahmut MK, Zhu Y, Goektas O, Komachi T. et al. A New Method for Assessment of Retronasal Olfactory Function. The Laryngoscope 2021; 131: E324-e330
• 292 Rombaux P, Huart C, Deggouj N, Duprez T, Hummel T.. Prognostic value of olfactory bulb volume measurement for recovery in postinfectious and posttraumatic olfactory loss. Otolaryngology—head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery 2012; 147: 1136-1141
• 293 Huart C, Rombaux P, Hummel T, Mouraux A.. Clinical usefulness and feasibility of time-frequency analysis of chemosensory event-related potentials. Rhinology 2013; 51: 210-221
• 294 Lundström JN, Gordon AR, Alden EC, Boesveldt S, Albrecht J.. Methods for building an inexpensive computer-controlled olfactometer for temporally-precise experiments. Int J Psychophysiol 2010; 78: 179-189
• 295 Lundström JN, Boesveldt S, Albrecht J.. Central Processing of the Chemical Senses: an Overview. ACS Chem Neurosci 2011; 2: 5-16
• 296 Zang Y, Han P, Joshi A, Hummel T.. Individual variability of olfactory fMRI in normosmia and olfactory dysfunction. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2021; 278: 379-387
• 297 Alobid I, Benítez P, Cardelús S, Borja Callejas de F, Lehrer-Coriat E, Pujols L. et al. Oral plus nasal corticosteroids improve smell, nasal congestion, and inflammation in sino-nasal polyposis. The Laryngoscope 2014; 124: 50-56
• 298 Banglawala SM, Oyer SL, Lohia S, Psaltis AJ, Soler ZM, Schlosser RJ.. Olfactory outcomes in chronic rhinosinusitis with nasal polyposis after medical treatments: a systematic review and meta-analysis. International forum of allergy & rhinology 2014; 4: 986-994
• 299 Golding-Wood DG, Holmstrom M, Darby Y, Scadding GK, Lund VJ.. The treatment of hyposmia with intranasal steroids. J. Laryngol. Otol 1996; 110: 132-135
• 300 Chong LY, Head K, Hopkins C, Philpott C, Burton MJ, Schilder AGM.. Different types of intranasal steroids for chronic rhinosinusitis. The Cochrane database of systematic reviews 2016; 4: CD011993
• 301 Chong LY, Head K, Hopkins C, Philpott C, Schilder AGM, Burton MJ.. Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis. The Cochrane database of systematic reviews 2016; 4: CD011996
• 302 Head K, Chong LY, Hopkins C, Philpott C, Schilder AGM, Burton MJ.. Short-course oral steroids as an adjunct therapy for chronic rhinosinusitis. The Cochrane database of systematic reviews 2016; 4: CD011992
• 303 Head K, Chong LY, Hopkins C, Philpott C, Burton MJ, Schilder AGM.. Short-course oral steroids alone for chronic rhinosinusitis. The Cochrane database of systematic reviews 2016; 4: CD011991
• 304 Orlandi RR, Kingdom TT, Hwang PH, Smith TL, Alt JA, Baroody FM. et al. International Consensus Statement on Allergy and Rhinology: Rhinosinusitis. International forum of allergy & rhinology 2016; 6 (Suppl. 01) S22-209
• 305 Hopkins C, Philpott C, Crowe S, Regan S, Degun A, Papachristou I. et al. Identifying the most important outcomes for systematic reviews of interventions for rhinosinusitis in adults: working with Patients, Public and Practitioners. Rhinology 2016; 54: 20-26
• 306 Rimmer J, Fokkens W, Chong LY, Hopkins C.. Surgical versus medical interventions for chronic rhinosinusitis with nasal polyps. The Cochrane database of systematic reviews 2014; CD006991
• 307 Mainland JD, Barlow LA, Munger SD, Millar SE, Vergara MN, Jiang P. et al. Identifying treatments for taste and smell disorders: gaps and opportunities. Chemical senses 2020; 45: 493-502
• 308 Patel ZM, Holbrook EH, Turner JH, Adappa ND, Albers MW, Altundag A. et al. International consensus statement on allergy and rhinology: Olfaction. International forum of allergy & rhinology 2022; 12: 327-680
• 309 Ikeda K, Sakurada T, Suzaki Y, Takasaka T.. Efficacy of systemic corticosteroid treatment for anosmia with nasal and paranasal sinus disease. Rhinology 1995; 33: 162-165
• 310 Genetzaki S, Tsakiropoulou E, Nikolaidis V, Markou K, Konstantinidis I.. Postinfectious Olfactory Dysfunction: Oral Steroids and Olfactory Training versus Olfactory Training Alone: Is There any Benefit from Steroids?. ORL 2021; 83: 387-394
• 311 Heilmann S, Just T, Goktas O, Hauswald B, Huttenbrink KB, Hummel T.. [Effects of systemic or topical administration of corticosteroids and vitamin B in patients with olfactory loss]. Laryngorhinootologie 2004; 83: 729-734
• 312 Stenner M, Vent J, Huttenbrink KB, Hummel T, Damm M.. Topical therapy in anosmia: relevance of steroid-responsiveness. The Laryngoscope 2008; 118: 1681-1686
• 313 Fukazawa K.. A local steroid injection method for olfactory loss due to upper respiratory infection. Chemical senses 2005; 30 Suppl 1 i212-3
• 314 Le Bon SD, Pisarski N, Verbeke J, Prunier L, Cavelier G, Thill MP. et al. Psychophysical evaluation of chemosensory functions 5 weeks after olfactory loss due to COVID-19: a prospective cohort study on 72 patients. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2021; 278: 101-108
• 315 Vaira LA, Hopkins C, Petrocelli M, Lechien JR, Cutrupi S, Salzano G. et al. Efficacy of corticosteroid therapy in the treatment of long- lasting olfactory disorders in COVID-19 patients. Rhinology 2021; 59: 21-25
• 316 Fujii M, Fukazawa K, Hatta C, Yasuno H, Sakagami M.. Olfactory acuity after total laryngectomy. Chemical senses 2002; 27: 117-21
• 317 Jiang R-S, Wu S-H, Liang K-L, Shiao J-Y, Hsin C-H, Su M-C.. Steroid treatment of posttraumatic anosmia. Eur Arch Otorhinolaryngol 2010; 267: 1563-1567
• 318 Bratt M, Moen KG, Nordgård S, Helvik A-S, Skandsen T.. Treatment of posttraumatic olfactory dysfunction with corticosteroids and olfactory training. Acta oto-laryngologica 2020; 140: 761-767
• 319 Jiang RS, Twu CW, Liang KL.. Medical treatment of traumatic anosmia. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2015; 152: 954-958
• 320 Scheibe M, Bethge C, Witt M, Hummel T.. Intranasal administration of drugs. Archives of otolaryngology – head & neck surgery 2008; 134: 643-646
• 321 Shu CH, Lee PL, Shiao AS, Chen KT, Lan MY.. Topical corticosteroid applied with a squirt system being more effective than with nasal spray for steroid-dependent olfactory impairment. The Laryngoscope 2012; 122: 747-750
• 322 Benninger MS, Hadley JA, Osguthorpe JD, Marple BF, Leopold DA, Derebery MJ. et al. Techniques of intranasal steroid use. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery 2004; 130: 5-24
• 323 Blomqvist EH, Lundblad L, Bergstedt H, Stjarne P.. Placebo-controlled, randomized, double-blind study evaluating the efficacy of fluticasone propionate nasal spray for the treatment of patients with hyposmia/anosmia. Acta Otolaryngol 2003; 123: 862-868
• 324 Heilmann S, Huettenbrink KB, Hummel T.. Local and systemic administration of corticosteroids in the treatment of olfactory loss. Am J Rhinol 2004; 18: 29-33
• 325 Fleiner F, Lau L, Goktas O.. Active olfactory training for the treatment of smelling disorders. Ear Nose Throat J 2012; 91: 198-203 215
• 326 Kim DH, Kim SW, Hwang SH, Kim BG, Kang JM, Cho JH. et al. Prognosis of Olfactory Dysfunction according to Etiology and Timing of Treatment. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery 2017; 156: 371-377
• 327 Hintschich CA, Dietz M, Haehner A, Hummel T.. Topical Administration of Mometasone Is Not Helpful in Post-COVID-19 Olfactory Dysfunction. Life 2022; 12: 1483
• 328 Kasiri H, Rouhani N, Salehifar E, Ghazaeian M, Fallah S.. Mometasone furoate nasal spray in the treatment of patients with COVID-19 olfactory dysfunction: A randomized, double blind clinical trial. Int Immunopharmacol 2021; 98: 107871
• 329 Abdelalim AA, Mohamady AA, Elsayed RA, Elawady MA, Ghallab AF.. Corticosteroid nasal spray for recovery of smell sensation in COVID-19 patients: A randomized controlled trial. Am J Otolaryngol 2021; 42: 102884
• 330 Nguyen TP, Patel ZM.. Budesonide irrigation with olfactory training improves outcomes compared with olfactory training alone in patients with olfactory loss. International forum of allergy & rhinology 2018; 8: 977-981
• 331 Asvapoositkul V, Samuthpongtorn J, Aeumjaturapat S, Snidvongs K, Chusakul S, Seresirikachorn K. et al. Therapeutic options of post-COVID-19 related olfactory dysfunction: a systematic review and meta-analysis. Rhinology. 2022
• 332 Addison AB, Wong B, Ahmed T, Macchi A, Konstantinidis I, Huart C. et al. Clinical Olfactory Working Group Consensus Statement on the Treatment of Post Infectious Olfactory Dysfunction. The Journal of allergy and clinical immunology. 2021
• 333 Henkin RI, Hosein S, Stateman WA, Knoppel AB, Abdelmeguid M.. Improved smell function with increased nasal mucus sonic hedgehog in hyposmic patients after treatment with oral theophylline. Am J Otolaryngol 2017; 38: 143-147
• 334 Hosein W, Henkin RI.. Therapeutic diminution of Interleukin-10 with intranasal theophylline administration in hyposmic patients. American journal of otolaryngology 2022; 43: 103375
• 335 Henkin RI, Velicu I, Schmidt L.. An open-label controlled trial of theophylline for treatment of patients with hyposmia. Am J Med Sci 2009; 337: 396-406
• 336 Henkin RI, Schultz M, Minnick-Poppe L.. Intranasal theophylline treatment of hyposmia and hypogeusia: a pilot study. Arch Otolaryngol Head Neck Surg 2012; 138: 1064-1070
• 337 Lee JJ, Peterson AM, Kallogjeri D, Jiramongkolchai P, Kukuljan S, Schneider JS. et al. Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction. American journal of otolaryngology 2022; 43: 103299
• 338 Meusel T, Albinus J, Welge-Luessen A, Hahner A, Hummel T.. Short-term effect of caffeine on olfactory function in hyposmic patients. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2016; 273: 2091-2095
• 339 Gudziol V, Pietsch J, Witt M, Hummel T.. Theophylline induces changes in the electro-olfactogram of the mouse. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2010; 267: 239-243
• 340 Gudziol V, Mück-Weymann M, Seizinger O, Rauh R, Siffert W, Hummel T.. Sildenafil affects olfactory function. J Urol 2007; 177: 258-61 discussion 261
• 341 Zufall F, Shepherd GM, Firestein S.. Inhibition of the olfactory cyclic nucleotide gated ion channel by intracellular calcium. Proceedings. Biological sciences 1991; 246: 225-230
• 342 Panagiotopoulos G, Naxakis S, Papavasiliou A, Filipakis K, Papatheodorou G, Goumas P.. Decreasing nasal mucus Ca++ improves hyposmia. Rhinology 2005; 43: 130-134
• 343 Whitcroft KL, Merkonidis C, Cuevas M, Haehner A, Philpott C, Hummel T.. Intranasal sodium citrate solution improves olfaction in post-viral hyposmia. Rhinology 2016; 54: 368-374
• 344 Philpott CM, Erskine SE, Clark A, Leeper A, Salam M, Sharma R. et al. A randomised controlled trial of sodium citrate spray for non-conductive olfactory disorders. Clin Otolaryngol 2017; 42: 1295-1302
• 345 Whitcroft KL, Gunder N, Cuevas M, Andrews P, Menzel S, Haehner A. et al. Intranasal sodium citrate in quantitative and qualitative olfactory dysfunction: results from a prospective, controlled trial of prolonged use in 60 patients. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery. 2021
• 346 Abdelazim MH, Abdelazim AH.. Effect of Sodium Gluconate on Decreasing Elevated Nasal Calcium and Improving Olfactory Function Post COVID-19 Infection. American journal of rhinology & allergy. 2022 19458924221120116
• 347 Abdelazim MH, Abdelazim AH, Ismaiel WF, Alsobky ME, Younes A, Hadeya AM. et al. Effect of intra-nasal nitrilotriacetic acid trisodium salt in lowering elevated calcium cations and improving olfactory dysfunction in COVID-19 patients. Eur Arch Otorhinolaryngol 2022; 4623-4628
• 348 Abdelazim MH, Abdelazim AH, Moneir W.. The effect of intra-nasal tetra sodium pyrophosphate on decreasing elevated nasal calcium and improving olfactory function post COVID-19: a randomized controlled trial. Allergy, asthma, and clinical immunology: official journal of the Canadian Society of Allergy and Clinical Immunology 2022; 18: 67
• 349 Rawson NE, LaMantia A-S.. A speculative essay on retinoic acid regulation of neural stem cells in the developing and aging olfactory system. Experimental Gerontology 2007; 42: 46-53
• 350 Rawson NE.. Olfactory loss in aging. Sci Aging Knowledge Environ 2006; 2006: pe6
• 351 Anchan RM, Drake DP, Haines CF, Gerwe EA, LaMantia AS.. Disruption of local retinoid-mediated gene expression accompanies abnormal development in the mammalian olfactory pathway. J Comp Neurol 1997; 379: 171-184
• 352 Zhang QY.. Retinoic acid biosynthetic activity and retinoid receptors in the olfactory mucosa of adult mice. Biochemical and biophysical research communications 1999; 256: 346-351
• 353 Paschaki M, Cammas L, Muta Y, Matsuoka Y, Mak S-S, Rataj-Baniowska M. et al. Retinoic acid regulates olfactory progenitor cell fate and differentiation. Neural development 2013; 8: 13
• 354 Whitesides J, Hall M, Anchan R, LaMantia AS.. Retinoid signaling distinguishes a subpopulation of olfactory receptor neurons in the developing and adult mouse. J Comp Neurol 1998; 394: 445-461
• 355 Etchamendy N, Enderlin V, Marighetto A, Vouimba R-M, Pallet V, Jaffard R. et al. Alleviation of a Selective Age-Related Relational Memory Deficit in Mice by Pharmacologically Induced Normalization of Brain Retinoid Signaling. J Neurosci 2001; 21: 6423-6429
• 356 Duncan RB, Briggs M.. Treatment of uncomplicated anosmia by vitamin A. Arch.Otolaryng.(Chic.) 1962; 75: 116
• 357 Kartal D, Yaşar M, Kartal L, Özcan I, Borlu M.. Effects of isotretinoin on the olfactory function in patients with acne. Anais Brasileiros de Dermatologia 2017; 92: 191-195
• 358 Reden J, Lill K, Zahnert T, Haehner A, Hummel T.. Olfactory function in patients with postinfectious and posttraumatic smell disorders before and after treatment with vitamin A: a double-blind, placebo-controlled, randomized clinical trial. The Laryngoscope 2012; 122: 1906-1909
• 359 Hummel T, Whitcroft KL, Rueter G, Haehner A.. Intranasal vitamin A is beneficial in post-infectious olfactory loss. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2017; 274: 2819-2825
• 360 Health Research Authority. Vitamin A Proof of Concept Study Post-Viral Olfactory Loss; 2022. https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/vitamin-a-proof-of-concept-study-post-viral-olfactory-loss/ (accessed 02. Oktober 2022)
• 361 Wang L, Chen L, Jacob T.. Evidence for peripheral plasticity in human odour response. J. Physiol 2004; 554: 236-244
• 362 Riechtraining. https://www.uniklinikum-dresden.de/de/das-klinikum/kliniken-polikliniken-institute/hno/forschung/interdisziplinaeres-zentrum-fuer-riechen-und-schmecken/downloads/videos/riechtraining/riechtraining-deutsch/@@view/++widget++form.widgets.IVideo.video_file/@@stream (accessed 03. Oktober 2022)
• 363 Youngentob SL, Kent PF.. Enhancement of odorant-induced mucosal activity patterns in rats trained on an odorant. Brain Res 1995; 670: 82-88
• 364 Hummel T, Stupka G, Haehner A, Poletti SC.. Olfactory training changes electrophysiological responses at the level of the olfactory epithelium. Rhinology 2018; 56: 330-335
• 365 Kim BY, Park JY, Kim EJ, Kim BG.. Olfactory Ensheathing Cells Mediate Neuroplastic Mechanisms After Olfactory Training in Mouse Model. Am J Rhinol Allerg 2020; 34: 217-229
• 366 Watt WC, Sakano H, Lee Z-Y, Reusch JE, Trinh K, Storm DR.. Odorant Stimulation Enhances Survival of Olfactory Sensory Neurons via MAPK and CREB. Neuron 2004; 41: 955-967
• 367 Negoias S, Hummel T, Symmank A, Schellong J, Joraschky P, Croy I.. Olfactory bulb volume predicts therapeutic outcome in major depression disorder. Brain Imaging Behav 2016; 10: 367-372
• 368 Al Aïn S, Poupon D, Hétu S, Mercier N, Steffener J, Frasnelli J.. Smell training improves olfactory function and alters brain structure. NeuroImage 2019; 189: 45-54
• 369 Kollndorfer K, Fischmeister FPS, Kowalczyk K, Hoche E, Mueller CA, Trattnig S. et al. Olfactory training induces changes in regional functional connectivity in patients with long-term smell loss. Neuroimage Clin 2015; 9: 401-410
• 370 Hummel T, Rissom K, Reden J, Hahner A, Weidenbecher M, Huttenbrink KB.. Effects of olfactory training in patients with olfactory loss. The Laryngoscope 2009; 119: 496-499
• 371 Geissler K, Reimann H, Gudziol H, Bitter T, Guntinas-Lichius O.. Olfactory training for patients with olfactory loss after upper respiratory tract infections. Eur Arch Otorhinolaryngol 2014; 271: 1557-62 DOI: 10.1007/s00405-013-2747-y.. Epub 2013 Oct 6
• 372 Pieniak M, Oleszkiewicz A, Avaro V, Calegari F, Hummel T.. Olfactory training – Thirteen years of research reviewed. Neurosci Biobehav Rev 2022; 141: 104853
• 373 Damm M, Pikart LK, Reimann H, Burkert S, Göktas Ö, Haxel B. et al. Olfactory training is helpful in postinfectious olfactory loss: a randomized, controlled, multicenter study. The Laryngoscope 2014; 124: 826-831
• 374 Altundag A, Cayonu M, Kayabasoglu G, Salihoglu M, Tekeli H, Saglam O. et al. Modified olfactory training in patients with postinfectious olfactory loss. The Laryngoscope 2015; 125: 1763-1766
• 375 Altundag A, Yilmaz E, Kesimli MC.. Modified Olfactory Training Is an Effective Treatment Method for COVID-19 Induced Parosmia. The Laryngoscope 2022; 132: 1433-1438
• 376 Kattar N, Do TM, Unis GD, Migneron MR, Thomas AJ, McCoul ED.. Olfactory Training for Postviral Olfactory Dysfunction: Systematic Review and Meta-analysis. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2021 194599820943550
• 377 Konstantinidis I, Tsakiropoulou E, Bekiaridou P, Kazantzidou C, Constantinidis J.. Use of olfactory training in post-traumatic and postinfectious olfactory dysfunction. Laryngoscope. 2013; 123: 85-90
• 378 Langdon C, Lehrer E, Berenguer J, Laxe S, Alobid I, Quintó L. et al. Olfactory Training in Post-Traumatic Smell Impairment: Mild Improvement in Threshold Performances: Results from a Randomized Controlled Trial. Journal of neurotrauma 2018; 35: 2641-2652
• 379 Jiang R-S, Twu C-W, Liang K-L.. The effect of olfactory training on the odor threshold in patients with traumatic anosmia. American journal of rhinology & allergy 2017; 31: 317-322
• 380 Jiang R-S, Twu C-W, Liang K-L.. The effect of olfactory training on odor identification in patients with traumatic anosmia. International forum of allergy & rhinology 2019; 9: 1244-1251
• 381 Haehner A, Tosch C, Wolz M, Klingelhoefer L, Fauser M, Storch A. et al. Olfactory training in patients with Parkinson’s disease. PLOS ONE 2013; 8: e61680
• 382 Pekala K, Chandra RK, Turner JH.. Efficacy of olfactory training in patients with olfactory loss: a systematic review and meta-analysis. International forum of allergy & rhinology 2016; 6: 299-307
• 383 Sorokowska A, Drechsler E, Karwowski M, Hummel T.. Effects of olfactory training: a meta-analysis. Rhinology 2017; 55: 17-26
• 384 Sharma R, Lakhani R, Rimmer J, Hopkins C.. Surgical interventions for chronic rhinosinusitis with nasal polyps. The Cochrane database of systematic reviews 2014; 11: CD006990
• 385 Kohli P, Naik AN, Farhood Z, Ong AA, Nguyen SA, Soler ZM. et al. Olfactory Outcomes after Endoscopic Sinus Surgery for Chronic Rhinosinusitis: A Meta-analysis. Otolaryngology – head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery 2016; 155: 936-948
• 386 Pade J, Hummel T.. Olfactory function following nasal surgery. The Laryngoscope 2008; 118: 1260-1264
• 387 Whitcroft KL, Fischer J, Han P, Raue C, Bensafi M, Gudziol V. et al. Structural Plasticity of the Primary and Secondary Olfactory cortices: Increased Gray Matter Volume Following Surgical Treatment for Chronic Rhinosinusitis. Neuroscience 2018; 395: 22-34
• 388 Schriever VA, Gupta N, Pade J, Szewczynska M, Hummel T.. Olfactory function following nasal surgery: a 1-year follow-up. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2013; 270: 107-111
• 389 Pfaff MJ, Bertrand AA, Lipman KJ, Shah A, Nolan I, Krishna V. et al. The Effect of Functional Nasal Surgery on Olfactory Function. Plastic and reconstructive surgery 2021; 147: 707-718
• 390 Damm M, Eckel HE, Jungehulsing M, Hummel T.. Olfactory changes at threshold and suprathreshold levels following septoplasty with partial inferior turbinectomy. The Annals of otology, rhinology, and laryngology 2003; 112: 91-97
• 391 Besser G, Liu DT, Sharma G, Bartosik TJ, Kaphle S, Enßlin M. et al. Ortho- and retronasal olfactory performance in rhinosurgical procedures: a longitudinal comparative study. Eur Arch Otorhinolaryngol 2021; 278: 397-403
• 392 Elbistanli MS, Koçak HE, Çelik M, Acipayam H, Alakhras WME, Koç AK. et al. Significance of Medial Osteotomy on the Olfactory Function in Patients Who Underwent Septorhinoplasty. The. Journal of craniofacial surgery 2019; 30: e106-e109
• 393 Poirrier A-L, Ahluwalia S, Goodson A, Ellis M, Bentley M, Andrews P.. Is the Sino-Nasal Outcome Test-22 a suitable evaluation for septorhinoplasty?. The Laryngoscope 2013; 123: 76-81
• 394 Randhawa PS, Watson N, Lechner M, Ritchie L, Choudhury N, Andrews PJ.. The outcome of septorhinoplasty surgery on olfactory function. Clinical otolaryngology: official journal of ENT-UK; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery 2016; 41: 15-20
• 395 Ulusoy S, Dinç ME, Dalğıç A, Dizdar D, Avınçsal MÖ, Külekçi M.. Effects of Spreader Grafts on Olfactory Function in Septorhinoplasty. Aesthetic plastic surgery 2016; 40: 106-113
• 396 Jankowski R, Bodino C.. Olfaction in patients with nasal polyposis: effects of systemic steroids and radical ethmoidectomy with middle turbinate resection (nasalization). Rhinology 2003; 41: 220-230
• 397 Kuffler DP.. Platelet-Rich Plasma Promotes Axon Regeneration, Wound Healing, and Pain Reduction: Fact or Fiction. Molecular neurobiology 2015; 52: 990-1014
• 398 Anitua E, Pascual C, Pérez-Gonzalez R, Antequera D, Padilla S, Orive G. et al. Intranasal delivery of plasma and platelet growth factors using PRGF-Endoret system enhances neurogenesis in a mouse model of Alzheimer’s disease. PLOS ONE 2013; 8: e73118
• 399 Yasak AG, Yigit O, Araz Server E, Durna Dastan S, Gul M.. The effectiveness of platelet-rich plasma in an anosmia-induced mice model. The Laryngoscope 2018; 128: E157-E162
• 400 Mavrogeni P, Kanakopoulos A, Maihoub S, Krasznai M, Szirmai A.. Anosmia treatment by platelet rich plasma injection. The international tinnitus journal 2017; 20: 102-105
• 401 Yan CH, Mundy DC, Patel ZM.. The use of platelet-rich plasma in treatment of olfactory dysfunction: A pilot study. Laryngoscope investigative otolaryngology 2020; 5: 187-193
• 402 Klug T, Rosen D, Chaskes M, Souza GD, Pribitkin E.. Treatment of refractory anosmia with topical platelet rich plasma. Otolaryngology – Head and Neck Surgery 2021; P344-P345
• 403 Greiner RS, Moriguchi T, Slotnick BM, Hutton A, Salem N.. Olfactory discrimination deficits in n−3 fatty acid-deficient rats. Physiology & behavior 2001; 72: 379-385
• 404 Gopinath B, Sue CM, Flood VM, Burlutsky G, Mitchell P.. Dietary intakes of fats, fish and nuts and olfactory impairment in older adults. British Journal of Nutrition 2015; 114: 240-247
• 405 Rondanelli M, Opizzi A, Faliva M, Mozzoni M, Antoniello N, Cazzola R. et al. Effects of a diet integration with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan in elderly patients suffering from mild cognitive impairment. Nutritional neuroscience 2012; 15: 46-54
• 406 Yan CH, Rathor A, Krook K, Ma Y, Rotella MR, Dodd RL. et al. Effect of Omega-3 Supplementation in Patients With Smell Dysfunction Following Endoscopic Sellar and Parasellar Tumor Resection: A Multicenter Prospective Randomized Controlled Trial. Neurosurgery 2020; 87: E91-e98
• 407 Hernandez AK, Woosch D, Haehner A, Hummel T.. Omega-3 supplementation in postviral olfactory dysfunction: a pilot study. Rhinology 2022; 60: 139-144
• 408 Di Stadio A, D’Ascanio L, Vaira LA, Cantone E, Luca de P, Cingolani C. et al. Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial. Current neuropharmacology 2022; 20: 2001-2012
• 409 Drews T, Nehring M, Werner A, Hummel T.. The sense of smell is not strongly affected by ambient temperature and humidity: a prospective study in a controlled environment. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery 2021; 278: 1465-1469
• 410 Hashem-Dabaghian F, Ali Azimi S, Bahrami M, Latifi S-A, Enayati A, Qaraaty M.. Effect of Lavender (Lavandula angustifolia L.) syrup on olfactory dysfunction in COVID-19 infection: A pilot controlled clinical trial. Avicenna journal of phytomedicine 2022; 12: 1-7
• 411 Janowitz T, Gablenz E, Pattinson D, Wang TC, Conigliaro J, Tracey K. et al. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series. Gut 2020; 69: 1592-1597
• 412 Liu LD, Duricka DL.. Stellate ganglion block reduces symptoms of Long COVID: A case series. Journal of neuroimmunology 2022; 362: 577784
• 413 Noda T, Shiga H, Yamada K, Harita M, Nakamura Y, Ishikura T. et al. Effects of Tokishakuyakusan on Regeneration of Murine Olfactory Neurons In Vivo and In Vitro. Chemical senses 2019; 44: 327-338
• 414 Ogawa T, Nakamura K, Yamamoto S, Tojima I, Shimizu T.. Recovery Over Time and Prognostic Factors in Treated Patients with Post-Infectious Olfactory Dysfunction: A Retrospective Study. The. Annals of otology, rhinology, and laryngology 2020; 129: 977-982
• 415 Vityala Y, Kadyrova A, Zhumabaeva S, Bazarbaeva A, Mamatov S.. Use of B-complex vitamins and olfactory training for treating COVID-19-related anosmia. Clinical case reports 2021; 9: e05069
• 416 Coleman ER, Grosberg BM, Robbins MS.. Olfactory hallucinations in primary headache disorders: case series and literature review. Cephalalgia: an international journal of headache 2011; 31: 1477-1489
• 417 Fjaeldstad AW.. Recovery from 3 Years of Daily Olfactory Distortions after Short-Term Treatment with GABA-Analogue. ORL 2022; 1-4
• 418 Majumdar S, Jones NS, McKerrow WS, Scadding G.. The management of idiopathic olfactory hallucinations: a study of two patients. The Laryngoscope 2003; 113: 879-881
• 419 Leopold DA, Hornung DE.. Olfactory cocainization is not an effective long-term treatment for phantosmia. Chemical senses 2013; 38: 803-806
• 420 Leopold DA, Schwob JE, Youngentob SL, Hornung DE, Wright HN, Mozell MM.. Successful treatment of phantosmia with preservation of olfaction. Arch. Otolaryngol. Head Neck Surg. 1991; 117: 1402-1406
• 421 Saussez S, Vaira LA, Chiesa-Estomba CM, Le Bon S-D, Horoi M, Deiana G. et al. Short-Term Efficacy and Safety of Oral and Nasal Corticosteroids in COVID-19 Patients with Olfactory Dysfunction: A European Multicenter Study. Pathogens (Basel, Switzerland) 2021; 10
• 422 Hummel T, Heilmann S, Hüttenbriuk KB.. Lipoic acid in the treatment of smell dysfunction following viral infection of the upper respiratory tract. The Laryngoscope 2002; 112: 2076-2080
• 423 Liu J, Pinheiro-Neto CD, Zhao J, Chen Z, Wang Y.. A novel surgical treatment for long lasting unilateral peripheral parosmia: Olfactory cleft blocking technique. Auris, nasus, larynx 2021; 48: 1209-1213
• 424 Mudry A, Mills M.. The early history of the cochlear implant: a retrospective. JAMA otolaryngology – head & neck surgery 2013; 139: 446-453
• 425 Aronsohn E.. Experimentelle Untersuchungen zur Physiologie des Geruchs. Archiv f.Physiologie von Dr.Emil du Bois-Reymond 1886; 321
• 426 Uziel A.. Stimulation of human olfactory neuro-epithelium by longterm continuous electrical currents.) Stimulation du neuro-epith’lium olfactiff chez l’homme par des courants ‘lectriques continus de longue dur’e. (Fre./Eng.Abstr.). J.Physiol.(Paris) 1973; 66: 409
• 427 Straschill M, Stahl H, Gorkisch K.. Effects of electrical stimulation of the human olfactory mucosa. Appl. Neurophysiol. 1983; 46: 286-289
• 428 Ishimaru T, Shimada T, Sakumoto M, Miwa T, Kimura Y, Furukawa M.. Olfactory evoked potential produced by electrical stimulation of the human olfactory mucosa. Chem Senses 1997; 22: 77-81
• 429 Weiss T, Shushan S, Ravia A, Hahamy A, Secundo L, Weissbrod A. et al. From Nose to Brain: Un-Sensed Electrical Currents Applied in the Nose Alter Activity in Deep Brain Structures. Cerebral cortex (New York, N.Y.: 1991) 2016; 26: 4180-4191
• 430 Penfield W, Jasper H.. Epilepsy and the functional anatomy of the human brain. 1954
• 431 Andy OJ.. The amygdala and hippocampus in olfactory aura. Electroencephalogr Clin Neurophysiol 1967; 23: 292
• 432 Nashold BS, Wilson WP, Slaughter DG.. Sensations evoked by stimulation in the midbrain of man. Journal of neurosurgery 1969; 30: 14-24
• 433 Hummel T, Jahnke U, Sommer U, Reichmann H, Müller A.. Olfactory function in patients with idiopathic Parkinson’s disease: Effects of deep brain stimulation in the subthalamic nucleus. J. Neural Transm. 2004 Oct 27 [Epub ahead of print]
• 434 Fonoff ET, Oliveira de YSA, Driollet S, Garrido GJ, Andrade DC, deSallem F. et al. Pet findings in reversible improvement of olfactory dysfunction after STN stimulation in a Parkinson’s disease patient. Movement disorders: official journal of the Movement Disorder Society 2010; 25: 2466-2468
• 435 Mazzola L, Royet J-P, Catenoix H, Montavont A, Isnard J, Mauguière F.. Gustatory and olfactory responses to stimulation of the human insula. Annals of neurology 2017; 82: 360-370
• 436 Rose H2020; 2022. https://rose-h2020.eu/ (accessed 03. Oktober 2022)
• 437 Morrison EE, Graziadei PP.. Transplants of olfactory mucosa in the rat brain I. A light microscopic study of transplant organization. Brain research 1983; 279: 241-245
• 438 Holbrook EH, DiNardo LJ, Costanzo RM.. Olfactory epithelium grafts in the cerebral cortex: an immunohistochemical analysis. The Laryngoscope 2001; 111: 1964-9
• 439 Yagi S, Costanzo RM.. Grafting the olfactory epithelium to the olfactory bulb. American journal of rhinology & allergy 2009; 23: 239-243
• 440 Tsujigiwa H, Nishizaki K, Teshima T, Takeda Y, Yoshinobu J, Takeuchi A. et al. The engraftment of transplanted bone marrow-derived cells into the olfactory epithelium. Brain research 2005; 1052: 10-15
• 441 Ochi N, Doi K, Uranagase M, Nishikawa T, Katsunuma S, Nibu K.. Bone marrow stem cell transplantation to olfactory epithelium. The Annals of otology, rhinology, and laryngology 2010; 119: 535-540
• 442 Díaz D, Lepousez G, Gheusi G, Alonso JR, Lledo P-M, Weruaga E.. Bone marrow cell transplantation restores olfaction in the degenerated olfactory bulb. J. Neurosci. 2012; 32: 9053-9058
• 443 Kurtenbach S, Goss GM, Goncalves S, Choi R, Hare JM, Chaudhari N. et al. Cell-Based Therapy Restores Olfactory Function in an Inducible Model of Hyposmia. Stem Cell Reports 2019; 12: 1354-1365
• 444 Dörig P, Gunder N, Witt M, Welge-Lüssen A, Hummel T.. [Future therapeutic strategies for olfactory disorders: electrical stimulation, stem cell therapy, and transplantation of olfactory epithelium-an overview]. HNO 2021; 69: 623-632
• 445 Croy I, Olgun S, Mueller L, Schmidt A, Muench M, Hummel C. et al. Peripheral adaptive filtering in human olfaction? Three studies on prevalence and effects of olfactory training in specific anosmia in more than 1600 participants. Cortex 2015; 73: 180-187
• 446 Takagi SF.. A Standardized Olfactometer in Japan A Review Over Ten Years. Ann N Y Acad Sci 1987; 510: 113-118
• 447 Cardesín A, Alobid I, Benítez P, Sierra E, Haro de J, Bernal-Sprekelsen M. et al. Barcelona Smell Test – 24 (BAST-24): validation and smell characteristics in the healthy Spanish population. Rhinology 2006; 44: 83-89
• 448 Simmen D, Briner HR, Hess K.. Screeningtest des Geruchssinnes mit Riechdisketten. Laryngorhinootologie 1999; 78: 125-30
• 449 Lotsch J, Ultsch A, Hummel T.. How Many and Which Odor Identification Items Are Needed to Establish Normal Olfactory Function?. Chemical senses 2016; 41: 339-344

Publication History

Article published online:
02 May 2023