Aetiology

Initial consideration should be given to the 3 most common causes of olfactory loss: prior viral infection, head injury, and chronic rhinosinusitis.[25]​ Each of these 3 causes accounts for 10% to 20% of cases.[16][17][18]​

Less common causes include exposure to toxic chemicals, radiation, or medications (e.g., chemotherapeutic drugs, zinc gluconate nasal spray); prior neurosurgical or craniofacial surgery; neurodegenerative disease; autoimmune disease; and intracranial neoplasms. Rarely, patients will present with a loss of smell that appears to be congenital or related to advancing age. Unfortunately, in many cases, the precise aetiology of olfactory loss remains unknown.

Postviral upper respiratory infection

Most people will experience a temporary loss of smell during an acute viral upper respiratory infection (URI). However, in relatively rare cases, the loss will persist after resolution of all other cold and flu symptoms. It appears to be a sensory loss, as biopsy studies have demonstrated degenerative changes in the olfactory neuronal receptors or neuroepithelium in the olfactory cleft.[19] These patients may be anosmic or hyposmic, and many may have associated dysosmia. It seems to occur more commonly in an older age group and affects twice as many women as men. A viral-induced loss does not fluctuate, but as many as 66% of patients may experience some spontaneous recovery over a period of several years.[28] A retrospective study looking at a large number of patients found that the incidence of recovery was inversely related to age at onset, with 38.7% of patients overall demonstrating clinically significant improvement.[29]

The prevalence of olfactory loss associated with early COVID-19 variants (between 48% and 86%) was reported to be higher than that attributable to other viral infections.​[10]​​[11][12][30]​​[31] However, later COVID-19 variants (e.g., Omicron) appear to cause less olfactory dysfunction than the earlier variants.​[14][32]​​​​​​ Complete anosmia has been commonly reported in COVID-19 patients, with significant (if not complete) recovery within a matter of weeks to months.​[7][31]​​​​​​ Patients may report spontaneous onset of dysosmia, which may present several months after COVID-19 symptom onset.[33] The clinical course may be explained by COVID-19 infecting supporting (sustentacular) cells of the olfactory neuroepithelium, rather than olfactory neuronal receptors.[34] Long-term prognosis in these patients is still being assessed.[35]

Head injury

Overall, approximately 5%-17% of patients suffering head injury will have an associated olfactory loss; incidence increases with the severity of the injury and length of post-traumatic amnesia.[36]​​[37][38]​​​​ Post-traumatic olfactory impairment more commonly follows a frontal or occipital blow and is related to coup-contrecoup forces that cause a shearing of the olfactory filaments as they pass through the cribriform plate. These patients tend to be anosmic, and are generally between the ages of 20 and 50 years and male (consistent with the group more at risk for head trauma). In other cases, it may be due to a concussive injury resulting from a frontal or occipital blow, and patients may experience some recovery of function, typically within the first year following the injury. The reported incidence of anosmia following traumatic brain injury varies markedly with severity of injury (4% to 60%).​[39][40][41]​​​

Chronic nasal or sinus disease

Chronic nasal and sinus pathologies that cause an olfactory loss generally do so by obstructing the nasal vault, thereby preventing access of odorants to the olfactory receptors. This causes a conductive loss rather than a sensorineural loss, although some evidence suggests there may also be inflammatory changes within the olfactory neuroepithelium.[42][43][44] Such obstruction may be due to frank nasal polyps but may also occur from secondary oedema due to localised pathology within the ethmoid sinuses without polyps. One literature review found the prevalence of olfactory dysfunction in patients with chronic rhinosinusitis approached 70%, depending on the testing method used.[45] However, patients may not complain of nasal obstruction or other nasal symptoms, but may simply present with a loss of smell.[17] This can make the diagnosis difficult, especially when trying to distinguish from a viral aetiology. The distinction is important, because chronic rhinosinusitis can be treated effectively to restore the sense of smell.[21][Figure caption and citation for the preceding image starts]: Examination of the right nasal cavity using rigid nasal endoscopy; a polyp can be seen protruding from the superior meatus (arrow), while the middle meatus is clear; a = middle turbinate, b = superior turbinate, c = septumFrom the collection of Dr Allen M. Seiden [Citation ends].com.bmj.content.model.assessment.Caption@44e7aa99

Toxic exposure

Most cases occur in the workplace. But increased exposure to ambient air pollutants may be associated with olfactory dysfunction.[46]​​

Exposure to a variety of toxic industrial and environmental agents has been associated with a loss of smell, although many of the reports in the literature are anecdotal.[47][48]​ Such reports often involve sudden excessive exposure, rather than low-grade exposure over many years. Common toxic exposures include phosphorus fire, chlorine gas, metal dusts, solvents, acid fumes, oil vapours, and some household cleaners. Although its incidence is probably underestimated, toxic exposure accounts for approximately 5% of olfactory disorders.[48]

Several medications (e.g., amfetamines, oestrogen, naphazoline, phenothiazines, prolonged use of nasal decongestants) may affect sense of smell. Olfactory loss following the use of an over-the-counter (OTC) zinc gluconate nasal spray (for the common cold) has been described.[49]​ The olfactory loss is thought to occur following exposure of the olfactory epithelium to the zinc cation.[50]

Chemotherapeutic agents can produce loss of both smell and taste, and radiotherapy to the head and neck will cause a transient loss of both senses.[51][52][53]

Post-surgery

Olfactory loss commonly occurs following neurosurgical procedures on the anterior cranial fossa through an anterior craniotomy approach, as well as following certain craniofacial procedures. This is expected and, therefore, these patients rarely present for further olfactory testing.

Olfactory loss may occur following endoscopic sinus surgery, due to direct injury to the olfactory cleft or scarring that obstructs the cleft. However, this is very uncommon, occurring in probably less than 2% of cases.[54]​ Most instances of persisting olfactory loss following sinus surgery are due to chronic inflammatory sinus disease.

Neurodegenerative diseases

Olfactory loss has been noted to be an early symptom of several neurodegenerative disorders, notably Alzheimer's disease and Parkinson's disease, although whether the loss reflects a true deficit or dementia is unclear.[55] Studies have found that faster olfactory decline in dementia-free older adults may predict higher incidence of subsequent cognitive impairment or dementia.[56]

In Alzheimer's disease, neurofibrillary tangles and plaques appear to involve areas of the brain associated with olfaction, including the olfactory bulbs. Patients with Alzheimer's disease and olfactory loss may often be unaware of their smell deficit and therefore not seek medical attention.[57]

In patients with Parkinson's disease, impaired odour identification is associated with more rapid neurological degeneration, particularly gait disturbance.[58] Studies in people with Parkinson's disease suggest that olfactory impairment is due at least in part to central nervous system decline.[59]

Autoimmune diseases

Granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and sarcoidosis may manifest in the nose and will often cause an inflammatory obstruction of the olfactory cleft (although sarcoidosis may involve neural structures as well). Sinus disease may be the first manifestation of granulomatosis with polyangiitis, with later development of pulmonary and renal symptoms.[60]

Sjogren's disease has been associated with olfactory loss, possibly related to very dry nasal mucosa or lymphocytic infiltration and destruction of exocrine glands.[61]​ Most of these patients will probably have other symptoms in addition to olfactory dysfunction.

Sinonasal malignancies

Sinonasal tumours, both benign and malignant, can cause an obstructive olfactory loss, but these patients more often present due to other nasal symptoms, such as nasal obstruction or epistaxis.[16][17][62]

Esthesioneuroblastoma, an uncommon malignant neoplasm believed to arise from the olfactory neuroepithelium, can cause anosmia. These patients typically present with other nasal symptoms.

A tumour of the anterior cranial fossa, such as an olfactory groove meningioma, can cause olfactory loss. However, patients generally present with headache, cognitive deficits, or vision loss, or develop other focal neurological signs that cause them to seek medical attention.

Genetic syndromes

Congenital anosmia accounts for approximately 3% of cases.[17] Although several well-described congenital syndromes, such as Turner's syndrome and Kallmann's syndrome, have been associated with olfactory loss, in most patients the loss of smell is an isolated finding. Patients will describe having no recollection of ever being able to smell.[63] An MRI scan may demonstrate hypoplasia or aplasia of the olfactory bulb or tract; or, rarely, a frontal lobe encephalocele; or it may be normal.[64]

Ageing

Olfactory loss may occur with advancing age, but usually does not become significant until after the seventh decade. Even then, it tends to occur gradually along with diminution of the other senses, so that patients typically accept this limitation and rarely present for evaluation. It is important, however, not to attribute an olfactory loss to age when an older patient presents for evaluation.

Chemosensory test results must be compared with age-matched controls.[65]​​

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