Clinical manifestations

Presentation and course

Various expressions are used by patients to describe disorders of smell or olfaction (Table 1).

Table 1. Terminology For Olfactory Function

Patients with olfactory symptoms generally report diminution or absence of olfactory sensation (hyposmia or anosmia, respectively) and forms of distorted olfaction (parosmia). Except in unusual circumstances, hyperosmia is a subjective sensation of hyperacuteness of olfaction. There is, for example, no evidence that pregnant women or migraineurs experience an objective increase in olfactory sensitivity.

When patients report alterations in the quality of olfaction in response to an odorant (ie, parosmias), the perceptions are almost universally unpleasant, a condition referred to as aliosmia (the perception of unpleasant odors from nominally pleasant odorants). Aliosmias, for example, may involve the perception of fecal or rotten smells (cacosmia) or of chemical or burned smells (torquosmia).

The terminology for alterations in the quality of olfactory perception (eg, cacosmia, torquosmia) can also be employed with hallucinated odors (phantosmias). Thus, one can speak of a "cacosmic phantosmia" for the hallucination of a fecal odor or a "torquosmic phantosmia" for the hallucination of a burned odor (83).

In addition, complaints of impaired “taste” are often symptoms of olfactory dysfunction because much of the flavor of a meal derives from olfactory stimulation. Indeed, the complex sensory experience of “flavor” while consuming foods and drinks cannot be constructed simply from combinations of the basic taste qualities (sweet, salty, sour, bitter, and umami/savory).

While chairman of the Department of Ophthalmology at Harvard Medical School, American ophthalmologist David G Cogan (1908-1993) distinguished "irritative" and "release" hallucinations in patients without psychosis in an influential paper in 1973 (34).

An "irritative" mechanism for hallucinations is supported by any of the following: (1) stereotyped content; (2) lack of awareness of the hallucinatory nature of the perception ("hallucinosis"); and (3) evidence of an irritative process (eg, migraine, tumor, seizures) (34; 19). In general, a "release" mechanism for hallucinations is supported by (1) a sensory deficit in the same modality as unimodal hallucinations, with onset of hallucinations in conjunction with or following the sensory deficit; (2) variable content; (3) awareness of the hallucinatory nature of the perception; and (4) no evidence of seizures or other irritative phenomena (including no other positive motor or sensory phenomena, not paroxysmal in character, and no epileptiform discharges on electroencephalography) (34; 121; 19). Release hallucinations can occur in normal individuals with pansensory deprivation (85; 84). Similarly, modality-specific release hallucinations can occur experimentally (84; 142) or pathologically (81; 121; 120) with unimodal sensory deprivation.

Congenital anosmia. Individuals with congenital anosmia typically lack any olfactory epithelium. In a case series of congenital anosmia involving detailed chemosensory evaluation followed by the performance of biopsies of the olfactory region, olfactory epithelium was not found in any of the biopsy specimens (98), suggesting that either the olfactory placode does not form normally or that it degenerates and is replaced with respiratory epithelium. Two olfactory placodes arise as thickened ectoderm from the frontonasal process. In the sixth week of development, the center of each placode grows inwards to form the two nasal pits. The invaginations give rise to the olfactory epithelium that lines the roof of the nasal cavity, whereas the raised margins are divided into medial and lateral nasal processes that give rise to the nose, the philtrum of the upper lip, and the primary palate.

Congenital anosmia may occur with hypoplastic or aplastic olfactory bulbs accompanied by a shallow olfactory sulcus, which is best appreciated on coronal MRI in comparison with normal olfactory bulbs (02; 36). The prevalence of isolated congenital anosmia in the general population is estimated to be 1 in 5000 to 10,000 (36).

Congenital anosmia is found more often as an isolated symptom but can occur in association with a syndrome, such as Kallmann syndrome. Kallmann syndrome or hypogonadotropic hypogonadism-1 (HH1) with anosmia is most often an X-linked recessive disorder caused by mutation (often a deletion) in the KAL1 gene (ANOS1; OMIM 300836) on chromosome Xp22.3 (although rare autosomal dominant and autosomal recessive forms due to mutations in other genes have been reported). The disorder, with an estimated prevalence of 1 in 84,000 men (67), is characterized by incomplete or absent sexual maturation by the age of 18 years in conjunction with low levels of circulating gonadotropins and testosterone but without other abnormalities of the hypothalamic-pituitary axis and in conjunction with congenital anosmia. In the presence of anosmia, congenital hypogonadotropic hypogonadism is called "Kallmann syndrome"; in the presence of normal olfaction, it is called “normosmic idiopathic hypogonadotropic hypogonadism” (166). About half of the cases of congenital hypogonadotropic hypogonadism are associated with anosmia. Males with Kallmann syndrome show anosmia due to agenesis of the olfactory lobes and hypogonadism secondary to a deficiency of hypothalamic gonadotropin-releasing hormone (134). In a Kallmann fetus, luteinizing hormone-releasing hormone (LHRH)-expressing cells were absent in the brain despite dense clusters of LHRH cells and fibers in the nose (190). LHRH-containing cells and neurites ended in a tangle beneath the forebrain, within the dural layers of the meninges on the dorsal surface of the cribriform plate of the ethmoid bone (190).

Dysosmia in COVID-19. Chemosensory deficit may be the first symptom ("sentinel symptom") in patients with COVID-19, but there is a wide variation in the proportion of cases in which this is reported to occur (31; 69; 100; 157; 182; 29; 160). A meta-analysis of eight studies, collectively involving 11,054 COVID-19 patients, reported that olfactory and gustatory symptoms appear prior to general COVID-19 symptoms in 65% and 54% of the patients, respectively, based on European, U.S., and Iranian data (185). However, a systematic review of 17 studies found that the onset of dysosmia and dysgeusia occurred 4 to 5 days after other symptoms of the infection and that these chemosensory symptoms typically improved after 1 week, with more significant improvements in the first 2 weeks (186).

Most patients with olfactory and gustatory dysfunction do not present associated nasal congestion or rhinorrhea, and a small group of patients present these alterations in isolation (09; 71; 198). As the disease progresses, patients may experience mild nasal congestion and posterior rhinorrhea, or they may progress without anterior rhinorrhea (76). New-onset chemosensory dysfunction is also common in patients with symptomatic COVID-19 after complete vaccination, and in one study of 153 such patients, approximately half reported associated rhinorrhea, which is a much higher proportion than in unvaccinated cases (204).

Available reports present conflicting data on whether COVID-19 severity is associated with either the degree of olfactory dysfunction or the prognosis for recovery of olfaction, but multiple reports suggest that chemosensory symptoms are most common among those with milder presentations of COVID-19 (22; 37; 164; 187).

Psychophysical testing showed significantly reduced intensity perception and identification ability for both taste and smell functions in COVID-19 patients (25). Smell and taste loss in COVID-19 are closely associated, although a minority of individuals can experience one or the other (26). The taste of salt may be less severely affected than other taste qualities.

Despite the large number of cases, the pathogenesis of the olfactory dysfunction in COVID-19 has not yet been fully elucidated. A report describing clinical, radiological, and pathological features of a woman who presented with anosmia persisting for more than 3 months after SARS-CoV-2 infection demonstrated significant disruption of the olfactory epithelium from a biopsy, shifting the focus away from invasion of the olfactory bulb and toward the olfactory receptors and the olfactory epithelium (205). Psychophysical tests revealed severe hyposmia and moderate hypogeusia. MRI showed that the olfactory bulb and clefts were of normal volume and were without signal anomalies. She subsequently underwent a biopsy of her left olfactory epithelium. There was extensive loss of surface epithelium, with no associated surface fibrin or inflammatory exudate. Immunohistochemical staining for pancytokeratin AE1/AE3 antibodies demonstrated only focal residual attenuated surface epithelium. There was strong nuclear and cytoplasmic positivity for S100 immunostain in scattered cells within Bowman glands and some small nerve bundles, which is thought to possibly be of trigeminal origin. Immunostaining for the angiotensin-converting enzyme 2 receptor showed focal membrane staining in the S100-positive cells in Bowman glands. There was focal staining for synaptophysin, and neurofilament immunostain highlighted small neurites and nerve bundles in the lamina propria.

Presbyosmia. Presbyosmia (literally “elderly olfaction” or “old age olfaction”) is the gradual loss of olfactory abilities that occurs in most people as they grow older. Clinically significant olfactory loss is common in the elderly but frequently unrecognized, partly because deficits typically accumulate gradually over decades. Indeed, self-reported olfactory impairment significantly underestimates prevalence rates obtained by olfactory testing (148). Because chemosensory impairment is so prevalent among the elderly, many elderly people complain that food lacks flavor, and the elderly account for a disproportionate number of accidental gas poisoning cases (49).

Dysosmia in alpha-synucleinopathies. Olfactory deficits involving odor detection, identification, and discrimination are present in more than 90% of patients with early-stage Parkinson disease (92; 46; 14; 53). Occasionally, patients with Parkinson disease may develop pleasant olfactory hallucinations (phantosmias) (112). Impaired olfaction can predate the motor symptoms of Parkinson disease by at least 4 years (180). Idiopathic olfactory dysfunction in first-degree relatives of patients with Parkinson disease is also associated with an increased risk of developing Parkinson disease within 2 to 5 years (161). Olfactory defects in Parkinson disease do not progress markedly with development of motor manifestations (46) and do not correlate well with most other manifestations of the disease (207), except with autonomic defects (73) and cognitive dysfunction, including memory impairment (07). Anosmia in Parkinson disease is associated with autonomic failure, including baroreflex failure and noradrenergic denervation of the heart and other organs, independent of parkinsonism or striatal dopaminergic denervation (73).

Dementia with Lewy bodies is closely allied with both Parkinson disease and Alzheimer disease and is anatomically characterized by the presence of Lewy bodies in both the neocortex and subcortical structures. In dementia with Lewy bodies there is a loss of dopamine-producing neurons in the substantia nigra, similar to that seen in Parkinson disease, and a loss of acetylcholine-producing neurons in the basal nucleus of Meynert, similar to that seen in Alzheimer disease. In dementia with Lewy bodies, as in Parkinson disease, olfactory dysfunction is nearly universal, develops early (before any movement or cognitive disorder), and is often severe (79). Nevertheless, the addition of anosmia to the consensus criteria for dementia with Lewy bodies did not significantly improve overall diagnostic performance (140; 156; 213).

Odor identification is also impaired in patients with REM sleep behavior disorder, a common and very early feature of Lewy body alpha-synucleinopathies (200; 65; 144).

Dysosmia with other neurodegenerative diseases. Although hyposmia is a frequent and early abnormality with alpha-synucleinopathies (ie, Parkinson disease, dementia with Lewy bodies, REM sleep behavior disorder), this is not so with other forms of parkinsonism, including multiple system atrophy, vascular parkinsonism, progressive supranuclear palsy, or corticobasal degeneration, nor is hyposmia a feature of essential tremor (209; 102; 192; 158). Most studies of olfaction in corticobasal degeneration have reported relatively mild deficits, but dysosmia can be moderate or severe in this disorder (158). A mild olfactory loss develops later in multiple system atrophy (102) and is associated with characteristic glial cytoplasmic inclusions in the olfactory bulb and some degree of neuronal loss in the anterior olfactory nucleus; it is unclear if this is of clinical significance (108). Olfactory deficits may also occur with motor neuron disease, but smell testing is not likely to be of clinical value in this condition (58; 79).

Some degree of olfactory loss has also been reported in various other dementing disorders, including Alzheimer disease and frontotemporal dementia (48; 197; 137; 211; 215; 213; 126). Olfactory impairment is more marked early in the course in patients with dementia with Lewy bodies than in those with either Alzheimer disease or frontotemporal dementia (213). Nevertheless, olfactory deficits in Alzheimer disease may be detectable before the appearance of overt memory loss (126), increase with severity of dementia (147; 191; 214), and correlate with the density of neurofibrillary tangles in the entorrhinal cortex and hippocampus (215) and with cortical Lewy body pathology (140). However, it is still unclear whether Alzheimer disease is associated with clinically meaningful hyposmia in the absence of Lewy body pathology (140). Olfactory dysfunction, if apparent in Alzheimer disease, can sometimes help in the differential diagnosis with depression (197; 137). Frontotemporal dementia is also associated with relatively mild olfactory deficits, which are comparable to those seen in Alzheimer disease (139).

Prognosis and complications

For patients with olfactory dysfunction, the prognosis primarily depends on etiology and the degree of residual function but also secondarily on gender, parosmia, smoking habits, and age (94). Male gender, initial presence of parosmia, smoking, and older age are negative prognostic factors (94).

Disorders of the chemosensory senses, smell, and taste are usually less disabling than disorders of the other special senses (vision and hearing). Nevertheless, olfactory impairment significantly contributes to perceived disability and lower quality of life among elderly patients and is a significant predictor of subsequent cognitive decline (143; 148; 215; 189).

Dysosmia in COVID-19. COVID-19-associated chemosensory loss has a substantial negative impact on health-related quality of life beyond mere inconvenience (33; 60). Indeed, altered taste and smell with Covid-19 may cause severe disruption of daily living and quality of life that impacts psychological well-being, physical health, and interpersonal relationships (23; 33; 60). Affected individuals variously reported reduced desire and ability to eat and prepare food; weight gain, weight loss, and nutritional insufficiency; reduced emotional well-being; and impaired intimacy and social bonding (23; 71). "Reduced enjoyment of food" was the most common complaint (87%) in one study (33).

Among healthcare workers who contract COVID-19, olfactory and gustatory loss were associated with emotional distress, anxiety, and depression (54). Moreover, the psychological impact tends to persist even after recovery from the disease, adding to the risk of work-related distress.

The loss of smell and taste improves at a high rate after disease onset in most series (17; 69; 97; 133; 175; 22; 153; 183; 198; 203; 26; 29), but a substantial proportion (approximately 4% to 5%) of patients with Covid-19 might develop long-lasting change in their sense of smell or taste (202). Rapid recovery of olfaction is observed in two thirds of COVID-19-infected people, but the remainder experience a slower pattern of recovery (107). By 1 month, almost all patients have a significant improvement in olfactory threshold and odor discrimination, but not odor identification (97; 153). The recovery of gustation typically occurs before the recovery of olfaction (76). The mean duration of anosmia is 7 days (106), but many of these progress from anosmia to hyposmia and parosmia.

Nevertheless, some series report that between one third and one half of patients have persistent qualitative changes in olfaction (parosmia or phantosmia) that are typically accompanied by qualitative disorders of gustation (parageusia and phantageusia) (146; 64; 70; 89; 193; 130). Some experience long-term deficits with no self-reported improvement at 6 months (64; 70; 88; 89). Persistent parosmia is common, even in those who report at least some recovery of olfactory function (88; 89).

Persistent loss of smell or taste was not associated with persistent SARS-CoV-2 infection (17).

Age under 40 years and the presence of nasal congestion at the time of COVID-19 infection were associated with improved rates of smell recovery, whereas difficulty breathing at the time of COVID-19 infection and prior head trauma were associated with worsened rates of recovery (32).

Biological basis

Etiology and pathogenesis

The nasopharynx and the olfactory pathways. Olfaction is the sensation of smell that results from detecting odorous substances aerosolized in the environment.

The nasal passages are divided in the midline by the nasal septum. Each lateral nasal wall is formed by several turbinates, spongy curled bones covered by mucosa. The turbinates protrude into the nasal passages and serve to humidify, warm, and cleanse air passing through the nasal passages to the lungs. The irregular path of airflow through the nose results in turbulence, which helps direct air and odorant molecules superiorly toward the olfactory epithelium, facilitating olfaction. The nasal passages also provide openings into various air spaces: the frontal, maxillary, ethmoid, and sphenoid sinuses; the sphenoethmoidal recess; and the middle ear (via the Eustachian tube).

The olfactory receptor cells are in a patch of specialized epithelium--the olfactory epithelium--that straddles the crest of the nasal vault on each side. In two young men, German anatomist Albert von Brunn (1849-1895) (his full name was Ferdinand Albert Wilhelm von Brunn) determined the extent of the olfactory epithelium to be approximately 50 cm², which led to the eponym "Brunn membrane" for the olfactory epithelium (20). Brunn elaborated the histology of the olfactory epithelium and teased apart the component cells, distinguishing particular olfactory receptor cells and supporting cells. Olfactory receptor cells are bipolar neurons characterized by a tapered shape and the presence of cilia protruding into the nasal vault, where they can detect odorant stimuli that have dissolved in the nasal mucus. Olfactory receptor neurons are activated when airborne molecules in inspired air bind to olfactory receptors expressed on their cilia. Olfactory cilia are constantly replaced, an ability not characteristic of the other sensory receptors.

The olfactory epithelium is a pseudostratified epithelium composed mainly by sustentacular cells, globose basal cells, horizontal globose cells, and both immature and mature olfactory sensory neurons; the olfactory ensheathing cells are an important cell type populating the submucosa (110).

In the nose, mature olfactory sensory neurons expressing the same odorant receptors gene are stochastically distributed within a spatially restricted area of the olfactory epithelium, also known as a “zone.” Early studies identified four non-overlapping odorant receptor expression zones, but later studies identified 9 to 12 partially overlapping zones (110).

Each mature olfactory sensory neuron expresses one allele of a single odorant receptor gene: the "one neuron - one receptor" rule (110).

Most intact odorant receptors are expressed in the olfactory epithelium across a large dynamic range, with only a minority being expressed at very high levels (110).

Odorants are detected by odorant receptors in a combinatorial fashion: one odorant can activate multiple odorant receptors, and each odorant receptor can detect more than one odorant. Recent studies that analyzed the responses of odorant receptors to specific odorants presented as part of odor mixtures found that odorants, in addition to their agonist role, can also modulate odorant receptor activity, serving as antagonists, inverse agonists, partial agonists, and synergistic ligands (110).

An inverse agonist binds to the same receptor as an agonist but brings about the opposite response to that of an agonist, whereas an antagonist binding to such a receptor will disrupt the interaction and the function of both the agonist and the inverse agonist at the receptor.

The olfactory receptors (also known as odorant receptors) on the cilia of the olfactory receptor neurons belong to a G-protein-coupled receptor superfamily (specifically the class A rhodopsin-like family of G protein-coupled receptors). The olfactory receptors form a multigene family consisting of around 800 genes in humans.

The neural processes of the bipolar olfactory receptor neurons pass upward through small holes in the cribriform plate of the ethmoid bone on the cranial floor of the anterior fossa.

The (olfactory) glomeruli are spherical structures in the olfactory bulb where synapses form between the terminals of the olfactory nerve and the dendrites of mitral, periglomerular, and tufted cells. All glomeruli are located near the surface of the olfactory bulb. A glomerulus is made up of a globular tangle of axons from the olfactory receptor neurons and dendrites from the mitral and tufted cells of the olfactory bulb. Each glomerulus is surrounded by various juxtaglomerular neurons (eg, periglomerular, short axon, and external tufted cells) and astrocytes. In humans, there are roughly 1100 to 1200 glomeruli, but the number decreases with age; few remain by the age of 80.

The olfactory bulb and the olfactory tract lie in the olfactory sulcus on the underside of the frontal lobe, between the gyrus rectus and the orbital frontal gyri. The olfactory tract divides at the olfactory trigone into medial, middle, and lateral roots. The entire length from the olfactory bulb to the trigone rests above the skull floor of the anterior fossa, at the level of the bridge of the nose when projected from outside the skull. Although located just lateral to the midline, they, nevertheless, are anterior to the midline chiasm and infundibulum.