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
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
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
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
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 10th 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
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. 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. 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.
