Introduction

Anosmia (lack of sense of smell) can have a devastating impact on sufferers, not only due to loss of the olfactory experience but also by causing dysfunction in the ability to taste food. Furthermore, harmful smells such as a gas leak, fire or spoiled food cannot be detected. Presentation may range from a reduction in sense of smell (hyposmia) through to complete loss (anosmia), or disturbances in normal smell such as cacosmia (perception of an unpleasant smell) and phantosmia (smelling something despite the absence of a stimulus). Anosmia is a relatively common symptom, even more so due to the Covid-19 pandemic in which anosmia is a common symptom. Diagnostic pathways are dependent on the setting in which the patient is seen (general practice or a specialist clinic with access to specialised equipment) and the presence of red flags, which may indicate a more serious cause.^1,2

The olfactory pathway

An understanding of the pathway by which smells are detected and processed is key to understanding the diagnostic pathways in assessing olfactory disturbance. Smells are detected from airborne molecules that pass into the nostrils, channelled by the ridges on the side of the nose (turbinates) into an area at the apex of the nasal cavity where the lining (epithelium) contains specialised detectors - the olfactory neuroepithelium. Air also reaches the neuroepithelium via a retrograde pathway during swallowing, which is an important part of tasting food. From here, a series of olfactory nerves pass through a perforated section of bone in the base of the skull called the cribriform plate to the olfactory bulb in the frontal region of the brain. As the nerves pass through the cribriform plate, they are particularly susceptible to injury due to head trauma, due to shearing of the nerves. From the olfactory bulb, impulses pass to the frontal cortex and also the hypothalamus and thalamus, hippocampus and amygdala (explaining why smell has a complex association with memory and emotions). Anything which obstructs the flow of air to the olfactory neuroepithelium or which affects the neuronal or brain pathways involved in smell may cause a disturbance in the sense of smell.^2,4

Causes of anosmia due to nasal obstruction or damage to the olfactory neuroepithelium

The following conditions may impede smell molecules from reaching the olfactory neuroepithelium or physically damage it.^1,2,3

• Chronic or acute rhinosinusitis
• Nasal polyposis
• Allergic rhinitis (including hay fever)
• Gross deviation of the nasal septum
• Granulomatous disease of the nasal mucosa, eg, Wegener’s granulomatosis
• Intranasal/nasopharyngeal tumours (rare)
• After Functional endoscopic sinus surgery (FESS)
• Other surgical causes, e.g. post post-laryngectomy

Causes of anosmia due to nerve damage or intracranial causes

The following conditions affect the olfactory nerves, brain or olfactory bulb, thereby causing anosmia.^1,2,3

• Viral/post-viral, including COVID-19
• Traumatic head injury
• Medication side effects (eg, ACE inhibitors, diuretics, Calcium channel blockers)
• Illicit drugs and alcohol (eg, tobacco smoking, cocaine, other drugs taken intranasally, alcohol)
• Neurological disorders (Temporal lobe epilepsy, multiple sclerosis, cerebrovascular disease)
• Neurodegenerative conditions (Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s dementia)
• Space-occupying lesions (intracranial tumours)
• Congenital eg Kallman’s syndrome, Turner syndrome 

Diagnosis

Clinical history

The clinical history is the most important area in the diagnosis of anosmia and in the identification of “red flags” that may indicate a more serious pathology, such as granulomatous disease or an intranasal or intracranial tumour.

Clinicians should ask about the onset and duration of the symptoms - gradual or sudden onset and any preceding events, particularly current or previous viral symptoms or a preceding head injury (the onset of symptoms may be up to 2-3 weeks after a head injury in traumatic cases).^1,3 

Nasal symptoms should be enquired about, including nasal obstruction, pain in the region of the sinuses, nasal discharge, including its nature, eg, mucus, purulent discharge, bleeding or clear fluid (possible cerebrospinal fluid). Previous nasal and sinus surgery should be noted.^1,3 

A full drug history should be taken, including medications well known to cause olfactory disturbance (ACE inhibitors and calcium channel blockers, β-blockers used in treating high blood pressure) and recreational drug use, including alcohol and tobacco.^1,3

Chronic medical conditions should be identified, including any new symptoms suggestive of Parkinson’s disease (such as a tremor or movement difficulties) or Alzheimer’s disease (such as memory loss), as well as common chronic disorders, particularly diabetes, chronic liver and kidney disease.^1,3

Any neurological symptoms should be noted, particularly visual disturbances, headache, seizures or any focal neurological symptoms (weakness, paralysis of limbs, altered sensations). Additionally, enquiries about mental health are important as half of all patients presenting with olfactory disturbance report concurrent mental health difficulties.^1,5

“Red flags” in the history

The following symptoms should be considered “red flags” indicative of a more serious pathology, such as a tumour or granulomatous disease, such as Wegener’s granulomatosis.^1,5 

• Bleeding (especially if unilateral)
• Unilateral nasal symptoms
• Cacosmia (smelling an unpleasant smell)
• Eye symptoms (orbital swelling, visual symptoms, double vision, paralysis of eye movements)
• Crusting of the nasal cavity or perforation of the nasal septum
• Severe headache, especially in the frontal region
• Vomiting
• New focal neurological symptoms or meningitic symptoms (stiff neck, headache, vomiting)

Examination in primary care (general practice)

Examination of the nose is limited in general practice due to a lack of facilities for nasal endoscopy; however, anterior rhinoscopy can be performed using the auriscope or a head torch/mirror and nasal speculum. Visualisation of the anterior nose may reveal polyps (found in allergic rhinitis and appearing as greyish-white masses in the nose),⁶ crusting or bleeding, oedematous, inflamed mucosa or discharge. A neurological examination focusing on testing the cranial nerves and gross power, tone, and reflexes should be performed, as well as noting signs of Parkinson’s disease (mask-like face, tremor, fenestration, freezing, shuffling gait). Memory testing may be indicated if the history suggests Alzheimer’s disease.^3,5 Fundoscopy will reveal signs of raised intracranial pressure and is useful in identifying cases requiring urgent imaging with MRI.¹ If Covid-19 is suspected, free lateral flow tests are currently only available to high-risk patients in the UK, available from pharmacies. It may, however, be prudent to test patients prior to inviting them to the waiting room, where they may come into contact with vulnerable patients.²

Examination in secondary care (specialist clinics)

Specialist ENT (ear, nose and throat) clinics may have the resources to perform both objective smell testing using orthonasal (smells presented directly to the nostril) smell tests and nasal endoscopy and have the ability to order more complex imaging tests than are available to the general practitioner, such as CT scanning, MRI scan or functional MRI scanning.²

• Orthonasal smell tests are usually one of two formats: UPSIT (University of Pennsylvania smell identification test) or Sniffin’ Sticks. The former uses 40 odours presented to the nose on odour-infused test strips linked to a multiple choice questionnaire, the latter presents 12 odours, and the patient is scored based on identifying the odour, the odour threshold and the ability to discriminate different odours. However, the length of time taken to perform these tests means that many clinicians find them tedious. Modified tests using just 3 odours have been found to have clinical validity, as have self-administered questionnaires, so these may be used in their place in practical clinic settings. (In primary evoked potentials, in which electrical activity in the brain caused by certain smells is measured) It is not routinely performed but has been used in medico-legal cases^7,8

Nasal endoscopy is performed using a rigid nasendoscope. Particular attention is paid to the nasal cleft where the olfactory neuroepithelium lies. Nasal abnormalities, including polyps, crusting or evidence of previous sinus or nasal surgery, may be detected, as well as surveillance to exclude intranasal tumours.³

The flowchart below represents a diagnostic schema based on endoscopy findings and medical history for the diagnosis of anosmia.³ In light of the COVID-19 pandemic that has occurred subsequent to the development of this flowchart, testing for COVID-19 is prudent in cases where the history is suggestive or in sudden onset anosmia without head trauma.²

Flowchart representing the diagnostic pathways in anosmia³

Imaging in olfactory disturbance

Whilst imaging can be used to evaluate hyposmia, it is not the primary investigation of choice. MRI is the imaging method of choice; both conventional MRI and functional MRI (fMRI) have been used in diagnosis.⁹ SPECT (single positron emission computerised tomography) and PET (positron emission tomography) scans have been used, but primarily in research settings.² However, one study found that in idiopathic anosmia, only 4.6% had abnormal MRI scans.² MRI scanning of all patients with idiopathic loss is not cost-effective, as detecting a single abnormality based on one study of 130 patients with idiopathic anosmia would cost $325,000, assuming each MRI costs $2500.¹⁰ However, in cases where a tumour is suspected (headaches, seizures, focal neurological symptoms, abnormal fundoscopy), MRI should be performed. In post-traumatic anosmia, however, another study found 86% of cases had MRI abnormalities, so it is useful in this group. This is incorporated into the diagnostic flow chart below.

Diagnostic flowchart indicating the diagnostic pathway and patients in whom initial MRI may be useful²

A practical approach to primary care management

As the vast majority of cases presenting to the GP will be of sinonasal cause (chronic rhinosinusitis, allergic rhinitis), anosmia persisting for more than 2 weeks should be treated with a trial of intranasal steroid sprays, eg, beconase, flixonase. At the clinician’s discretion, more potent steroid drops, eg, fluticasone nasules, may be used. In cases of nasal polyps, a medical polypectomy should be considered, combining potent steroid drops with a short course of oral steroids.⁶ There is some evidence for the use of oral steroids in anosmia caused by allergic rhinitis and chronic rhinosinusitis, which may be used at the clinician's discretion.¹ The current recommendation for anosmia following COVID-19 is for a 2-week course of oral steroids if the anosmia persists more than 2 weeks, not to be started until all COVID-19 symptoms have subsided.¹

Patients who fail to respond to topical treatment, any patients with red flag symptoms or signs, patients with greater than 6 weeks of olfactory dysfunction or atypical presentations should be referred to secondary care ENT, with the exception of post-COVID patients, who should be allowed 3 months for the anosmia to settle spontaneously before referral.¹

Summary

Anosmia (loss of sense of smell) and hyposmia (reduction in sense of smell) are common presentations to general practitioners. Whilst they may be due to a wide variety of causes, chronic rhinosinusitis, allergic rhinitis, head injury, and post-viral anosmia are the most common causes. Certain red flag symptoms raise the possibility of more sinister causes, although these are relatively rare. A detailed clinical history is paramount. In secondary care, objective smell tests and nasal endoscopy are useful in further investigating the problem. Imaging using MRI is useful in cases of traumatic head injury and in the presence of red flag symptoms in which there is suspicion of an intracranial tumour, although they are not cost-effective in the routine investigation of idiopathic hyposmia. In most cases in general practice, a routine trial of intranasal steroids is practical before referral, as is screening for COVID-19 if suspected.