Introduction

Olfactory and gustatory disorders can be due to a wide variety of causes and can profoundly influence a patient′s quality of life. This chapter covers toxicants, industrial agents, and therapeutic agents that cause olfactory dysfunction, idiopathic olfactory loss, congenital anosmia, endocrine diseases associated with olfactory dysfunction, postsurgical olfactory dysfunction, and tumor-related olfactory disorders. Miscellaneous causes of olfactory dysfunction, as defined in this chapter, account for less than 10% of cases.1,2 A detailed history and examination is necessary to determine any lifestyle factors or toxicant or drug consumption that may be related to olfactory dysfunction. Counseling of the patient is mandatory to reduce toxicant exposure; change any implicated medications; give an accurate prognosis; or treat, as soon as possible, a tumor for which olfactory dysfunction is the sole and primary manifestation.

Diagnosis of olfactory dysfunction is often difficult, especially for toxicant and therapeutic agent exposure. The patient′s history, including the delay between exposure and clinical manifestation, is the keystone of diagnosis. Moreover, the clinician must consider that combinations of causal factors may be present. This is especially true for a patient in whom a therapeutic agent is suspected to be the causative agent. It should also be stressed that in this category of miscellaneous causes of olfactory dysfunction, olfactory function needs to be objectively evaluated (see Chapter 6) because clinical findings may lead to legal action, changes in prescribed medications, changes in professional habit, or decisions concerning the surgical management of the patient.

Toxicants and Industrial Agents

Although many reports in the literature suggest that a wide variety of toxicants may have a deleterious effect on the chemosensory function in general and on the olfaction in particular, specific information regarding the pathophysiology, the time–dose effect, and the potential of recovery is poor. The olfactory neuroepithelium is highly sensitive to the chemical or microbiological environment because it acts as an interface between the outside world in the upper airways and the inside world in the central nervous system. Many defense mechanisms exist at the olfactory neuroepithelial level to induce detoxification and rapid regeneration after chronic and repetitive or acute and brief exposure to irritants and toxins.

Exposure to toxic volatiles at levels sufficient to impair olfaction usually occurs by accident. The list of chemicals that is theoretically toxic to the olfactory system is extensive and reported cases are numerous even though toxicant exposure is thought to be responsible for less than 2% of cases of olfactory dysfunction ( Table 9.1 ).1,2 The degree of exposure, concentration, and intrinsic toxicity of the agent, as well as local conditions at the neuroepithelial level, may greatly influence the significance of the damage and its clinical manifestation.3,4

Chronic exposure to benzene (an industrial solvent used in the production of drugs, plastic, synthetic rubbers, and dyes), butyl acetate (a solvent used in the production of lacquers and synthetic fruit flavoring in foods), formaldehyde (a precursor of many chemical products used for resin and polymer formation), and paint solvent can cause varying degrees of olfactory dysfunction. Others compounds such as industrial dusts (cotton, silicone, cement, lead, coal, chromium, and nickel) and chemicals such as sulfuric acid, trichloroethylene and hydrogen have been also associated with olfactory dysfunction.

Chronic exposure to cadmium has been well reported in a large cohort of workers who handle electrical batteries containing cadmium and can lead to olfactory disorder. Chronic exposure to gases (carbon disulfide, carbon monoxide, sulfur dioxide) or to solvents (acetone, acetophenone, turpentine) can also induce smell disorders.5–12

Pathophysiology focuses mainly on histological damage (replacement of the neuroepithelium by respiratory epithelium), decreased function in the Bowman gland, and direct toxicity to the olfactory receptor cell (by the molecule itself, or after enzymatic activation to the proximate toxicant). The health of the host is important and may influence the outcome of exposure of the olfactory epithelium to toxins. An upper respiratory infection, for example, may induce severe olfactory dysfunction if present at the same time as a toxic exposure that would not inflict severe damage if present alone.

Exposure of the olfactory neuroepithelium to a toxic agent stimulates defense mechanisms such as secretion of enzymes or proteins that protect the integrity of the neuroepithelium, or activation of the trigeminal reflex, which has a direct role in eliminating and reducing the risk of olfactory damage by inducing glandular secretions, sneezing, and watery discharge from the nasal mucosa and the eye. Protection of the olfactory neuroepithelium is achieved through structural recovery of olfactory tissue, an increase in metabolizing enzymes that facilitate olfactory receptor neuron (ORN) recovery, and an increase in metal chelating agents. Localization of membrane transporters and efflux mechanisms also protect the integrity of the neuroepithelium.

Epidemiological studies in workplaces known to be causative for olfactory dysfunction should be performed, along with animal studies to test compounds for potential olfactory toxicity. In the absence of such evidence, the precautionary principle should be applied to workers in whom toxicant-related olfactory dysfunction is suspected.13

Therapeutic Agents

Drug-induced olfactory dysfunction is often reversible and related to the duration of intake. In drug-related chemosensory dysfunction, taste is much more affected than smell14,15 and qualitative disorders are more common than quantitative disorders.16 Many different therapeutic agents may be responsible ( Table 9.2 ), and documentation of the time course between medication intake and the development of clinical symptoms is essential. In clinical practice, it is sometimes difficult to differentiate between drug-induced chemosensory dysfunction and other conditions such as postinfectious olfactory loss. A comprehensive history is essential to aid the diagnosis. The condition for which the medication has been prescribed must be considered as a possible cause, as well as endocrine disorders, chronic renal failure, chronic hepatic dysfunction, severe infection, or diabetes. Therapeutic agents can cause olfactory dysfunction at the periphery and at receptor level. Typically, the olfactory dysfunction is reversible once the medical treatment is discontinued (if possible). Recovery depends on many factors, such as age, sex, environmental status (e.g., tobacco intake, exposure to other toxicants), and sinonasal status (e.g., chronic rhinosinusitis, allergy). Therapeutic agents leading to a negative effect on olfactory perception may be distinguished as a class effect (e.g., quinolone antibiotics) or on an individual basis with single cases reported. Informing the pharmaceutical company of the potential association between a medication and a side effect on olfactory function is also mandatory.

Idiopathic Olfactory Disorder

Despite extensive work-up with psychophysical testing (uni- or bilateral), electrophysiological recording, structural magnetic resonance imaging (MRI), patient history, and endonasal endoscopic examination of the olfactory cleft, no explanation for olfactory symptoms is found in a significant number of patients. This is classified as idiopathic olfactory loss.

In a large cohort of patients, olfactory loss was classed as idiopathic in up to 18% of cases.17 This must be a diagnosis of exclusion made after complete and extensive evaluation of the confirmed olfactory dysfunction. In patients with idiopathic olfactory loss, the olfactory bulb (OB) is smaller than in controls, which seems to suggest an involvement of the OB in its pathophysiology.18 An unsuccessful oral corticosteroid trial should also serve as a diagnostic criterion.19 Care must also be taken to remember that olfactory dysfunction may be a preclinical sign of neurodegenerative disorder (e.g., Alzheimer or Parkinson diseases). It is generally assumed that patients with idiopathic olfactory loss need to be re-examined after several months, with endonasal endoscopic examination, psychophysical testing, and even structural imaging, to rule out any developing disease such as neurodegenerative diseases.