Causes (etiology) of olfactory disorders

Olfaction is the ability to sense and recognize odors. Physiologically, the mechanism of smell is realized through the interaction of a chemical stimulus (aromatic molecule) with special receptors in the nasal cavity, which are capable of converting this stimulus into electrical energy and transmitting it along the membrane of nerve cells to the “analytical center” of the central nervous system. Not all living beings have this “analytical center” located in the brain; the sense of smell appears in the chain of living species at a stage when the brain has not yet formed and its function is performed by an accumulation of specialized sensitive cells, which was one of the first to arise during evolutionary development.

It has been reliably proven that, acting subconsciously, the sense of smell influences the emotions of humans and animals, both positive and negative.

In the photo – olfactory bulbs (receptors) on the nasal mucosa

Smell disorders in humans

Recent epidemiological studies have shown that the prevalence of impaired sense of smell is much wider than self-reported by patients. To identify it, it is necessary to use olfactory threshold tests, which reveal a fairly high prevalence hyposmia и anosmia in certain groups, especially older people. Various pathological processes such as chronic inflammation, head injury, aging, autoimmunity, endocrine disorders and toxic exposures can contribute to the deterioration of the sense of smell with varying prognostic outcomes. For a wide range of diseases, olfactory disorders are a characteristic feature and an early sign. This is particularly true for neurodegenerative diseases (NDs) and some mental disorders.

Patients with olfactory impairment have a significantly reduced quality of life, and this reduction is often underestimated. Examination and diagnosis can help in early identification of the problem and implementation of treatment and rehabilitation measures for those forms of olfactory impairment that are potentially treatable.

The meaning of loss of smell

Compared to other animals, humans have evolved to lose much of their sense of smell. People use their sense of smell to determine the quality of the food they are about to eat. We use our sense of smell as a protective sense to check whether foods are safe to eat. The specialized literature suggests that approximately 50% of patients with impaired sense of smell may consume spoiled food, and this can cause food poisoning. This relationship indicates the possible protective nature of the sense of smell, which manifests itself most fully in combination with other senses. Potentially harmful habits such as overeating, excessive consumption of sweet and fatty foods are known to cause hypo/anosmia.

LOSS of the sense of smell can affect safety by preventing the detection of smoke, gas and other harmful odors in the air that should signal immediate action. Impaired perception of the patient’s own body odors can lead to both neglect and exaggeration of hygiene measures or excessive use of perfume. Smell loss can be especially insidious and elude detection because, unlike vision or hearing loss, it is not as obvious to others.

The relationship between taste and smell

Taste, smell and touch contribute to the emotional impact of food and drink. The sense of smell plays an important role in the perception of food, its aroma is an important part of the process of enjoying food. During the chewing process, volatile molecules from food move into the nasal cavity through the back of the mouth – this is the so-called “retronasal olfaction phenomenon.”

Olfactory disorders in various diseases

Bilateral anosmia (lack of sense of smell) or hyposmia (decreased sense of smell) is more often observed in diseases of the nasal mucosa. Hyposmia or anosmia on one side is usually a sign of a serious disease, often neurological.

Possible causes of anosmia:

1. Underdevelopment of the olfactory pathways.
2. Diseases of the olfactory mucosa of the nose (rhinitis, nasal tumors, etc.).
3. Rupture of the olfactory filaments during a fracture of the lamina cribrosa of the ethmoid bone due to traumatic brain injury.
4. Destruction of the olfactory bulbs and tracts at the source of the bruise according to the type of counter-impact, observed when falling on the back of the head
5. Inflammation of the ethmoid sinuses (lat. os ethmoidale), an inflammatory process of the adjacent pia mater and surrounding areas.
6. Median tumors or other space-occupying formations of the anterior cranial fossa.

It should be noted that interruption of the integrity of the pathways coming from the primary olfactory centers does not lead to anosmia, since they are bilateral.

Anosmia or hyposmia can significantly impair a person’s quality of life, especially if it lasts for a long time. The global pandemic of the disease COVID-19, one of the symptoms of which is a violation of the sense of smell, has brought this anomaly to the top of the topics discussed in the scientific community. Even in an asymptomatic person, new-onset anosmia or hyposmia can be an early sign of a life-altering disease.

Smell disorders are divided into congenital and acquired. True congenital disorders of smell are rare. A classification according to the degree of impairment of odor perception is also sometimes used:

• Anosmia – inability to perceive odors. It includes complete anosmia, the inability to perceive all odors, and partial anosmia, the inability to perceive some but not all odors.
• Hyposmia (decreased sense of smell);
• Hyperosmia (increased sensitivity to odors).

Qualitative disturbances of the sense of smell – paraosmia and phantosmia:

• Paraosmia – distorted perception of odor in its presence, this condition is also called dysosmia. In particular, when this perception is offensive, it is called cacosmia. Paraosmia should not be confused with olfactory hallucinations.
• A phantasm – a term that characterizes the phenomenon of perception of odor in its absence.

There are attempts to classify the degrees of hyposmia as mild, moderate, severe, and anosmia as complete and partial. Medical publications report that the risk of dangerous events in a patient’s life increases in proportion to the degree of olfactory impairment. When conducting quantitative olfactory tests, it was found that the prevalence of smell disorders varies from 20% to 25% among the general population and reaches 40% among older people. Patients may not be fully aware of the presence or severity of anosmia/hyposmia.

Causes (etiology) of olfactory disorders

According to the type of cause that caused the disorder, all olfactory disorders can be divided into local and systemic.

More often, disturbances in the sense of smell occur due to local diseases of the nose. For example, inflammatory processes in the nasal mucosa can prevent odorants (smelling molecules) from reaching olfactory epithelial cells. Among such diseases, the most common are hay fever, allergic rhinitis, sinusitis, nasal polyposis, as well as trauma or tumors of the nasal cavity, paranasal sinuses or nasopharynx. It is known that impaired sense of smell is associated with numerous systemic diseases: they are caused by certain bacterial, viral and fungal infections, head injuries, and special neurological conditions. Olfactory dysfunction, including olfactory aura, has been reported in epilepsy and migraine. The connection between hyperosmia and osmophobia and migraine has been well studied and described in the medical literature. It is also known that migraines can be induced by certain odors. But the mechanism of this relationship has not yet been studied.

Olfactory disorders are observed in patients with multiple sclerosis, they progress along with the progression of the disease. Neurodegenerative diseases, including Parkinson’s and Alzheimer’s, are often accompanied by impaired sensitivity to odors. Research has shown that olfactory disturbances may be an early sign of these diseases. Some endocrinological diseases are associated with disturbances of the sense of smell. Among them diabetes, Addison’s disease, Cushing’s syndrome and hypothyroidism.

The literature describes hypo- and anosmia in patients with kidney and liver diseases. Reduced and perverted sensitivity to odors can be caused by medications, primarily antibiotics and antidepressants.

CAUSES OF HYPO- and ANOSMIA:

Smell disorders during aging

Decreased olfactory function is very common in older people. Special tests register a violation of the sense of smell in more than 50% of people aged 65 to 80 years and in 62-80% of people over 80 years of age. Olfactory impairment significantly impacts physical well-being, quality of life, nutritional status, and daily safety and is associated with increased mortality. Multiple factors contribute to age-related loss of olfactory sensitivity, including nasal engorgement, environmental damage to the olfactory epithelium, decreased enzyme metabolism in the nasopharyngeal mucosa, loss of sensitivity of odorant receptor cells, and changes in neurotransmitter and neuromodulator systems. In addition, structural and functional abnormalities of the olfactory epithelium, olfactory bulb, central olfactory cortex and the main olfactory circuits, caused by the synthesis of abnormal proteins in the neurons of these zones, can lead to impaired olfactory sensitivity during aging and neurodegenerative diseases. Impaired odor recognition directly correlates with decreased cognitive abilities and memory impairment. It is believed that a decrease in the sense of smell represents an early and important warning of the onset of neurodegenerative disorders, especially Parkinson’s disease and Alzheimer’s disease, and in mild cognitive impairment, olfactory impairment may herald progression to dementia. Further research is needed on the potential role of olfactory dysfunction in the early diagnosis and treatment of neurodegenerative diseases.

Olfactory impairment as a concomitant pathology and symptom of diseases

Smell impairments are recorded in many diseases. Often the root cause of such disorders is very difficult to determine, and the exact mechanisms involved in the pathophysiology of anosmia are also not fully understood. The unexplained onset of hypo- or anosmia should raise suspicions about the possible onset of a neurodegenerative or other disease that may be characterized by such a symptom. Currently, in the context of the global COVID-19 pandemic, the occurrence of anosmia should be considered a red flag of this infection.

infectious processes

Everyone knows that bacteria and viruses can cause smell disturbances. Most often this occurs due to locally widespread infection of the nasal mucosa and diseases of the upper respiratory tract. Patients often complain of impaired sense of smell with chronic sinusitis, and it may persist even after medical or surgical treatment. It is believed that many viruses cause damage to the olfactory epithelium, and this is the cause of long-term smell disorders. Post-viral olfactory disorders are usually associated with common ARVI or influenza; their prevalence ranges from 11 to 40%, making them the most common causes of smell impairment. Women are affected more often than men; the most susceptible age group is patients 30–70 years old. In recent years, scientists have been able to prove that some types of viruses can directly infect olfactory neurons and lead to infection of the central nervous system through the olfactory nerve. A recent study demonstrated that patients with odor perception changes that persist after clinical recovery exhibit shedding of viral particles in the nasopharyngeal mucosa. Nasal discharge was studied in a group of 24 patients with hypo-, ano- and dysosmia after acute respiratory viral infection: rhinoviruses were found in 14 patients, Epstein-Barr virus in three, and coronavirus and parainfluenza virus in another patient. Olfactory testing showed no significant improvement at 4, 8, 11, and 24 weeks after the first visit in four patients, two of whom continued to complain of olfactory dysfunction even 6 months after the first visit. This finding sheds light on the role of long-term viral persistence in maintaining olfactory dysfunction. In such cases, spontaneous recovery is possible, which usually occurs within a period of 1 month to 2 years.

The mechanisms underlying damage to the sense of smell during infections are varied and not fully understood: sometimes it is the result of preventing odorant molecules from reaching the neuroepithelium due to edema and excess mucus, or dysfunction of the olfactory analyzer as a result of inflammation of the nasal mucosa. In some cases, post-viral anosmia may be of central origin, as evidenced by a decrease in the metabolism of the region of the brain in which olfactory information is processed.

Prolonged post-viral anosmia is difficult to treat, and the result is more difficult to achieve, the longer the dysfunction exists. There is still no effective conventional therapy; in some cases, local administration of anti-inflammatory drugs or steroids is effective; in recent years, olfactory training has become increasingly widespread.

COVID-19 and anosmia

The COVID-19 pandemic has prompted researchers to study the disease’s connection to anosmia. In addition to general clinical signs such as dry cough, fever, sore throat, shortness of breath and headache, a striking symptom of the disease is anosmia or hyposmia, which occurs in the first days of illness, often without any other signs of infection. The prevalence of olfactory dysfunction in patients with COVID-19 averages 50–70%.

SARS-CoV-2, which is capable of infecting various target organs, penetrates cells using molecules of the angiotensin-converting factor receptor (ACE2), and it is also able to penetrate cells of the central nervous system. It has been suggested that the virus can do this in two possible ways – through the circulatory system and through the labyrinths of the ethmoid bone, where the olfactory nerve enters the cranial cavity. It is possible that it is at this moment that it disrupts the functioning of the olfactory analyzer. As in other parts of the body, in the nasal cavity SARS-CoV-2 interacts with the ACE2 receptor, which is expressed on mucosal cells and is involved in respiratory inflammatory processes by regulating the levels of inflammatory peptides such as bradykinin. However, patients who have lost their sense of smell due to COVID-19 do not experience significant symptoms of rhinitis or other inflammation in the nasal cavity. Therefore, one hypothesis may be that olfactory disturbances are caused by viral damage to the olfactory neurons themselves. Before the 2020 pandemic, damage to the olfactory analyzer by another type of coronavirus had already been described. In 2006, Hwang described a case of anosmia secondary to SARS-CoV-1 infection. Anosmia in the described case persisted for two years. It is hypothesized that penetration of the virus into neurons causes a reduction in their lifespan, and that the virus damages the olfactory bulb, not the epithelium. The exact pathogenesis of neuronal death is not yet known. Back in 2008, the effect of SARS-CoV infection on the central nervous system of laboratory animals was studied, and the authors, having found no signs of an inflammatory process, hypothesized that the death of neurons occurs due to a hurricane of cytokines, in particular IL-6, produced by neurons during viral stimulation.

However, observations of patients affected by the current SARS-CoV-2 epidemic demonstrate a high rate of recovery of the sense of smell – usually within 1-2 weeks after its loss, and the frequency of symptoms of damage to the central nervous system (about 25%) is much lower than the frequency of olfactory disorders . It is reasonable to assume that anosmia is not caused by irreversible viral damage to neurons. It is possible that the virus may target other cells that express the ACE2 receptor, such as olfactory epithelial cells, supporting cells, microvillous cells, Bowman cells (goblet cells), or other cells necessary for normal neuronal function. Brann et al suggested that loss of smell in patients with COVID-19 develops due to viral infection of supporting cells and vascular pericytes of the olfactory epithelium and olfactory bulb, which in turn alters the function of olfactory neurons. Another hypothesis implicates progenitor stem cells that express ACE2 at lower levels as the cause of long-term olfactory impairment. The study authors conclude that the exact pathogenetic mechanism of anosmia in COVID-19 is still unclear. Data from large cohorts of patients will need to be analyzed to determine the exact frequency and cause of these symptoms, as well as to study the progression of recovery over time.

The proximity of the peripheral olfactory receptor zone to brain structures deserves special attention. Contrary to the assumptions of scientists, clinical practice demonstrates the absence of direct viral damage to the central nervous system in COVID-19. Possible mechanisms of antiviral protection of the nervous system were presented in the press release: “Microglia in the olfactory bulb have a nose for protecting the brain from infection» National Institute of Neurological Disorders and Stroke (NINDS, USA) June 5, 2020, and on the NIH website (https://www.nih.gov). Researchers have identified a specific line of defense that limits infection to the olfactory bulb and protects neurons from viral damage. Although the location of neurons makes them easy targets, viral respiratory infections rarely spread from the olfactory bulb to the rest of the brain, where they could cause potentially fatal encephalitis. (The study was published in the journal Science Immunology). Using labeled viral particles that can be tracked using fluorescence microscopy, the researchers found that viral infection was stopped just before it could move from the nasal epithelium directly to the brain.

“Airborne respiratory viruses constantly test the strength of our immune system, but we rarely see viral infections that lead to brain damage and neurological disease,” said study leader Dr. McGavern. “This means that the mucosal immune system The membranes of the nose are surprisingly well adapted to protect the brain.”

Additional experiments showed that microglia (a special type of cells of the central nervous system, which are phagocytes capable of destroying infectious pathogens. Microglia cells are formed from blood monocytes and become active during the development of the inflammatory process. The activation process causes glial cells to change, release numerous processes, like an amoeba ), plays an underappreciated role in helping the immune system recognize the virus and limiting the neurons themselves from damage.

During the process of evolution, a number of protective mechanisms have formed in the nervous system that prevent microorganisms and viruses from entering the brain. When inhaled, airborne viruses pass through the nasal passages and interact with the olfactory epithelium. The processes of peripheral neurons (axons) of the olfactory system pass through small holes in the ethmoid bone, which forms the roof of the nasal cavity, this provides access to odors present in the air. It is this anatomical structure that may be an easy way to bypass traditional CNS barriers and provide infectious pathogens with a direct path to the brain. If a virus infects the processes of neurons in the respiratory tract, the virus has a chance to enter the brain and eventually cause encephalitis or meningitis. Since such complications do not occur often, there are certainly additional immune mechanisms that provide protection at the interface between the olfactory neurons of the nose and the rest of the brain. These mechanisms are just beginning to be studied and are not yet fully understood by scientists. A team of US researchers led by Dr. McGavern demonstrated that cytotoxic T lymphocytes, which carry the CD8 marker on their surface and are responsible for controlling viruses, are very important for protecting the brain from the spread of infections from the nasal cavity. It has been shown that CD8 T cells do not interact directly with infected neurons. Instead, they activate microglial cells. Glial cells are members of the immune system in the central nervous system, and act as collectors of cellular debris and dead cells. During the development of a viral infection, microglia ingest viral particles and present them to the immune system for further development of a specific immune response. The general scheme of the development of the immune response at the border between the nasal mucosa and the brain is as follows:

• infected olfactory neurons “transmit” viral particles to microglial cells,
• Microglial cells process the absorbed virus and release it onto their membrane in combination with special molecules. It is in this form that the infectious pathogen can be noticed by immune cells and trigger the formation of an immune response. This process is called “antigen presentation”;
• T cells “notice” the virus presented on the membrane of the glial cell and trigger an antiviral response that clears the neuron of viral particles, thereby ensuring the safety of the nerve cells.

Since microglial cells, unlike neurons, are quite easily restored, this method of interaction during the development of immunity makes sense from an evolutionary point of view. Sensory olfactory neurons, which begin in the nose and end in the brain, because of their location, often take the hit of infection, and, unlike other neurons of the central nervous system, are capable of regeneration after the infection is complete. The immune response in the nasal cavity does not protect the olfactory neurons and sense of smell, it serves a more important function – it protects the brain and central nervous system from encephalitis or meningitis. Olfactory cells can most often recover over time.

Anosmia and somatic pathology

Many diseases that occur with the accumulation of toxic molecules in the body can affect the sense of smell. In particular, hyposmia and anosmia may be accompanied by acute and chronic liver diseases. Moreover, the severity of its manifestation is positively influenced by taking vitamin A. Chronic renal failure may also cause hyposmia, which correlates with the severity of kidney damage. An interesting fact is that olfactory disorders regress after kidney transplantation, but do not improve with hemodialysis. Another category of patients with impaired sense of smell are patients with AIDS, especially its neurological forms. A change in odor may also accompany the flow hypothyroidism and pseudohypoparathyroidism. In addition, taste and smell disturbances have been described in patients with adrenal disease, both insufficiency and Cushing’s disease. In adrenal insufficiency, glucocorticoid replacement therapy may lead to regressive olfactory hypersensitivity. Olfactory disturbances in patients with diabetes mellitus may be associated with vascular manifestations of diabetes due to ischemic changes in the olfactory neuroepithelium. Olfactory impairment has been described in many systemic diseases, such as Horton’s arteritis и Sjogren’s syndrome.

Sjogren’s syndrome

There is a complex relationship between the functioning of the immune system and the sense of smell. Changes in the immune system can affect the perception of odors. Sjögren’s syndrome (SS) is an autoimmune disease that affects multiple organ systems, including the salivary and lacrimal glands. Impaired sense of smell and taste are common symptoms reported by patients with SSc, most commonly hyposmia. In such patients, the ability to recognize or detect specific odors is not completely lost. The mechanism that is responsible for hyposmia in Sjogren’s syndrome is a decrease in the synthesis of mucins (the main component of nasal mucus with which molecules of aromatic substances interact, which is necessary for the perception of odors), recurrent rhinosinusitis, ulcers of the nasal septum, crusting and immunological inflammation.