There are several causes of olfactory dysfunction. The most frequent are chronic rhinosinusitis, postinfectious olfactory loss, and posttraumatic olfactory loss. These three etiologies account for up to two-third of the patients with olfactory disorder (Murphy et al. 2003; Rombaux et al. 2009b); therefore, we will largely extend on these three pathologies. However, several pathologies might also affect olfactory function, such as neurological disease, metabolic diseases, toxics, and tumoral disease of the sinonasal cavities or brain (Table 10.2). It is therefore essential to investigate about the etiology of olfactory dysfunction. An algorithm for the management of olfactory dysfunction is proposed in Fig. 10.5.

In the literature, chronic rhinosinusitis (CRS) is described as the most common cause of olfactory dysfunction, accounting for 14–30 % of cases (Mott and Leopold 1991; Seiden and Duncan 2001; Raviv and Kern 2004; Holbrook and Leopold 2006). Inversely, olfactory impairment is a common symptom affecting 61–83 % of patients with CRS (Orlandi and Terrell 2002; Bhattacharyya 2003; Litvack et al. 2008; Soler et al. 2008). Nevertheless up to one-quarter of patients with CRS are unaware of their decreased olfactory abilities, probably because the olfactory dysfunction in CRS develops slowly, and in consequence only a few patients note this disorder (Nordin et al. 1995).

Psychophysical test results show that patients with CRS have quantitative disorders, between hyposmia and anosmia (Mott and Leopold 1991; Seiden and Duncan 2001; Raviv and Kern 2004; Holbrook and Leopold 2006; Welge-Luessen 2009), and may report fluctuating symptoms (Apter et al. 1999). Also it is widely known that patients with CRS with polyps have a higher incidence of smell symptoms and anosmia than patients with CRS without polyps (Hellings and Rombaux 2009). Some studies have described that the severity of quantitative disorders is related to the importance of the sinonasal disease (Litvack et al. 2008; Litvack et al. 2009a). Indeed, the mean endoscopy score and the mean CT score are significantly higher (more abnormal) in patients with hyposmia and anosmia than in patients with normosmia (Litvack et al. 2009a). Also, the opacification of the olfactory cleft on the CT scan seems to have a negative correlation with the olfactory function (Chang et al. 2009).

Patients with CRS not only report quantitative olfactory dysfunction but also qualitative dysfunction such as parosmia and phantosmia. However, these symptoms seem less frequent when related to sinonasal disease than to other etiologies (i.e., postinfectious, posttraumatic), and Reden et al. (2007) reported incidence of parosmia and phantosmia in patients with CRS of 28 and 7 %, respectively.

Traditionally, olfactory dysfunction in CRS is explained by a conductive olfactory loss, caused by swollen or hypertrophic nasal mucosa or nasal polyps, inducing an impaired access of odorants to the olfactory cleft. But clinical studies have failed to prove this hypothesis, as there is only little correlation between nasal resistance and the degree of olfactory dysfunction (Doty and Frye 1989). In addition, results of surgical therapy, although improving the nasal patency, are sometimes uncertain when considering the olfactory dysfunction.

Nowadays, it is generally agreed that the olfactory disturbance is due to an inflammatory process in the olfactory cleft (Konstantinidis et al. 2007) rather than a pure obstruction. Indeed, biopsies of the olfactory neuroepithelium in patients suffering from CRS revealed inflammatory and apoptotic pathological changes in the nasal mucosa, including the olfactory receptor neurons and olfactory supporting cells (Naessen 1971; Hellings and Rombaux 2009), and the degree of inflammation in the neuroepithelium was proved to be related to the severity of olfactory dysfunction (Kern 2000). This could be explained by the fact that inflammatory cells release inflammatory mediators, which are known to trigger hypersecretion in respiratory and Bowman’s glands (Getchell and Mellert 1991; Downey et al. 1996; Hellings and Rombaux 2009). Hypersecretion of Bowman’s gland is thought to alter the ion concentrations of olfactory mucus, affecting the olfactory transduction process (Joshi et al. 1987; Kern et al. 1997). Finally, it has been demonstrated that cytokines and mediators, particularly those released by eosinophils, may be toxic to olfactory receptor neurons (Nakashima et al. 1985; Apter et al. 1992).

Patients with nasal polyps show a higher incidence of olfactory disturbances and a higher incidence of anosmia than patients with CRS without polyps. This more severe symptomatology may be explained by the conductive olfactory loss induced by polyps but also by degenerative changes associated with recurrent infections, scarring, chronic nasal medication, exotoxins, and enhanced secretion of cytokines from Staphylococcus aureus infection and neurotoxic cytokines released by a huge eosinophilic population (Joshi et al. 1987; Vento et al. 2001; Litvack et al. 2008; Wang et al. 2010; Bernstein et al. 2011).

Medical imaging is useful in the assessment of patients suffering from sinonasal-related olfactory dysfunction. Using CT scan, Litvack et al. (2009a) have shown that the severity of quantitative olfactory disorder is associated with the importance of the sinonasal disease and that mean CT score is significantly higher in patients with hyposmia and anosmia than in normosmic patient. It was also demonstrated that the opacification of the olfactory cleft has a negative correlation with the olfactory function in patients with CRS and that it is significantly correlated with the postoperative olfactory results: patients with mild opacification having better postoperative results than patients with moderate and severe anterior olfactory cleft opacification (Kim et al. 2011). MRI is also interesting. Indeed, Rombaux et al. (2008) demonstrated that the olfactory bulb volume is correlated with the sinonasal disease score, and patients having a sinonasal disease score ≥12 significantly have larger olfactory bulb volume than patients with higher score. Smaller olfactory bulb volume is thus associated with a higher degree of sinonasal pathology. On contrast the olfactory function of the patients assessed with psychophysical testing was only slightly decreased or was even normal, emphasizing the idea that the olfactory bulb volume changes are more sensitive to subtle changes in the olfactory system than results of psychophysical testing.

Medical and/or surgical treatment must be proposed to patients suffering from sinonasal-related olfactory disorders since (1) they are effective in this pathology and (2) it has been demonstrated that patients reporting an improvement of their olfactory abilities have a better quality of life than patients reporting no improvement (Miwa et al. 2001). Only a few clinical studies have been conducted dealing with the improvement of olfactory function as a primary outcome in sinonasal disease treatment. Clinical trials of medical treatment for smell disorders associated with CRS have evaluated the efficacy of nasal and oral corticosteroid treatment. We found a recent study evaluating the efficacy of antihistamines (levocetirizine) on the smell loss in patients with persistent allergic rhinitis (Guilemany et al. 2012), but we found no studies about other drugs that are currently used in the treatment of CRS (antileukotrienes).

Corticosteroids with their potent anti-inflammatory effects are admitted to be the standard treatment for olfactory disorders induced by CRS. Their action mechanism on olfactory function might be explained by an inhibition of the release of proinflammatory mediators (i.e., cytokines, adhesion molecules, mast cells, basophiles, eosinophils) and a reduction in mucosa swelling (Mygind et al. 2001; Demoly 2008). Following EPOS 2012 recommendations, nasal steroids are recommended as the first-line treatment for CRS with or without nasal polyps (Fokkens et al. 2012). Studies have evaluated the efficacy of different topical corticosteroids such as betamethasone, flunisolide, mometasone furoate, fluticasone propionate, budesonide, and beclomethasone. Studies show that these drugs appear to be highly effective for most of the symptoms associated with CRS, including smell disorder, with a rapid onset of action and a cumulative effect after several days of use. In addition, they have the advantage of being a local therapy with limited side effects. Nevertheless the improvement in olfaction is frequently transient and incomplete (Lildholdt et al. 1995; Golding-Wood et al. 1996; Mott et al. 1997; Blomqvist et al. 2003; Stuck et al. 2003; Hellings and Rombaux 2009). Oral steroids are recommended in the treatment of CRS with nasal polyps as a second-line treatment (Fokkens et al. 2012). Several studies have investigated their efficacy in patients with CRS with or without polyps. They have shown that these potent anti-inflammatory drugs increase the olfactory function and they appear to be more effective than nasal steroids (Heilmann et al. 2004; Vaidyanathan et al. 2011). Moreover, an initial oral steroid therapy followed by topical steroid therapy seems to be more effective than topical steroid therapy alone (Vaidyanathan et al. 2011). Nevertheless oral steroids have important side effects if they are frequently administrated or if their administration is prolonged. Bonfils et al. (2006) evaluated the risk of oral steroid treatment in patients with CRS with nasal polyps and showed that almost 50 % of patients who received more than three short courses of oral steroid treatment had an asymptomatic adrenal insufficiency. Oral corticosteroids should thus be prescribed only if necessary and should be avoided if possible.

Functional endoscopic sinus surgery (FESS) is widely accepted as a treatment for chronic rhinosinusitis with or without nasal polyps after failure of the medical therapy. The only randomized study to attempt comparison between steroid therapy and polypectomy showed significant improvement of subjective and objective olfactory function in both groups, remaining for 1 year. However, these results should be tempered by the fact that the smell evaluation methodology was not described (Lildholdt 1989).

Several studies have investigated the effect of FESS on olfactory function (for a review, see Bonfils et al. 2009). Nevertheless the literature shows that there are major variations in the selection of patients for the surgery, and some studies have poor validity because of poorly defined patient groups, lack of clear inclusion or exclusion criteria, poor description of the surgical procedure, and poor description of the olfactory evaluation tool. In this literature, olfactory function was assessed either by subjective patient self-reported olfactory function or by semi-objective olfactory testing (i.e., UPSIT). Considering patient self-reported olfactory function, authors agree that FESS lead to a significant improvement of olfactory dysfunction (Levine 1990; Lund and MacKay 1994; Klossek et al. 1997; Jakobsen and Svendstrup 2000) (for a review, see Bonfils et al. 2009). Only few studies have investigated the effect of FESS on olfactory function by using semi-objective olfactory testing. They have also shown that FESS has a significant positive effect on olfactory function (Lund and Scadding 1994; Min et al. 1995; Downey et al. 1996; Klimek et al. 1997; Delank and Stoll 1998) (for a review, see Bonfils et al. 2009). Some authors have investigated the correlation between the severity of CRS and surgical outcomes on olfaction. It was reported that the improvement after FESS is significantly better in patients with severe olfactory dysfunction, whereas it is not in patients with mild olfactory dysfunction (Litvack et al. 2009b; Soler et al. 2010). The degree of nasal obstruction, the extent of the rhinosinusitis disease (evaluate by symptom score or CT scan), and the coexistence of nasal polyps or allergic rhinitis do not predict the possibility of olfactory improvement after FESS (Bhattacharyya 2006; Wright and Agrawal 2007; Jiang et al. 2009).

Finally, Gudziol et al. (2009) explored the influence of the treatment of CRS on the olfactory function. They measured olfactory bulb volume, using MRI, and olfactory function of patients suffering from CRS before treatment and 3 months after. They showed that the olfactory bulb volume significantly increases after treatment and that the increase of olfactory bulb volume correlated significantly with an increase in odor thresholds.

Postinfectious olfactory loss is defined as a sudden loss of olfactory function following an upper respiratory tract infection (URTI) and was described for the first time more than 20 years ago (Henkin et al. 1975). The upper respiratory infection subsides over time and leaves the patient with an olfactory dysfunction that persists over a long period. There is a close connection in time between the URTI and the onset of the olfactory disorder (Seiden 2004). The exact pathogenic agent is rarely determined but is assumed to be viral, and so this disease is known as “post-viral” or “postinfectious” olfactory loss. The exact incidence of olfactory dysfunction following URTI is not known as many patients with URTI do not report their symptoms, so the exact incidence of common cold in the population is unknown. However, postinfectious olfactory loss is diagnosed in approximately one-quarter of the patients in groups presenting to specialized centers such as smell and taste clinics (Cain et al. 1988; Deems et al. 1991; Sugiura et al. 1998; Bonfils et al. 1999).

Patients with postinfectious olfactory loss are usually women, and the disease typically occurs between the fourth and the sixth decades of life (Sugiura et al. 1998; Seiden 2004; Rombaux et al. 2009a). Onset of the URTI is often sudden and awareness of the olfactory dysfunction is present when major symptoms secondary to the infection subside. Many patients also have endoscopic or radiological evidence of rhinosinusitis. It is therefore mandatory to treat this condition and observe the impact of this treatment on the sensorineural disorder. Patients usually complain of moderate to severe olfactory loss, but the degree of olfactory loss is usually less severe than in patients with head trauma (Duncan and Seiden 1995). Parosmia and phantosmia are also present and range to 10–50 % (Henkin et al. 1975; Leopold et al. 1991; Reden et al. 2007). Seasonal variation in the incidence of postinfectious olfactory loss has been demonstrated with the highest incidences being in March and May (Konstantinidis et al. 2006). This is probably due to the seasonal variation of viral particles such as parainfluenza virus type 3 (Sugiura et al. 1998; Suzuki et al. 2007; Wang et al. 2007).

Diagnosis should be based on (1) history of an olfactory disorder following a URTI and a close temporal relationship between the two, (2) patency of the olfactory cleft at the endoscopic examination, and (3) absence of any other causes such as toxic exposure (medication taken to treat the URTI and possibly causing an olfactory disorder themselves), an inflammatory process in the nasal fossa (diagnosed with an endoscopic evaluation), or neurological problems such as neurodegenerative diseases.

The exact mechanism leading to postinfectious olfactory loss is not yet fully understood. Viral particles may damage the olfactory receptor neuron and provoke immune response that also leads to damages in the olfactory neuroepithelium and damages the central olfactory pathways. Viruses are also capable of penetrating the brain via the fovea ethmoidalis. Many viruses may cause olfactory impairment, examples being the influenza virus, parainfluenza virus, respiratory syncytial virus, Coxsackie virus, adenovirus, poliovirus, enterovirus, and herpes virus. The exact determination of the viral agent is not useful in the clinic and viral serology is not mandatory. Experimental intranasal infection with influenza virus A leads to increased apoptosis and increased fibrosis in the olfactory neuroepithelium (Mori et al. 2002, 2004). This mechanism is thought of as a protective one that limits the access of viral particles to the brain. Histopathological findings relating to the olfactory neuroepithelium of patients with postinfectious olfactory loss have revealed that severely affected patients have reduced numbers of ciliated olfactory receptor cells (Doty 2008). Moreover, dendrites of the olfactory receptor neurons usually fail to reach the epithelial surface and therefore have no contact with odorant particles. Attempting to correlate the importance of the olfactory neuroepithelial damage with the extent of the olfactory dysfunction as well with the chances of recovery generated conflicting results (Yamagishi et al. 1994; Doty 2008). Overall, postinfectious olfactory loss is probably secondary to a viral attack both at a peripheral level (olfactory neuroepithelium) and at a central level (olfactory bulb), and these two sites interact both in the pathological condition and in the recovery phase.

MRI findings show that olfactory bulb is reduced in patients with postinfectious olfactory loss, and there is a strong correlation between olfactory bulb volume and the olfactory dysfunction, with the lowest olfactory bulb volume being in patients with severe olfactory dysfunction and parosmia (Mueller et al. 2005; Rombaux et al. 2006).

At present there is no medical therapy that has been proven effective. Many drugs have been tried in nonrandomized and uncontrolled trials: topical or systemic corticosteroids (Heilmann et al. 2004), zinc sulfate (Henkin et al. 1976; Aiba et al. 1998), quinoxaline derivative (Quint et al. 2002), alpha lipoic acid (Hummel et al. 2002b), and pentoxifylline (Gudziol and Hummel 2009). Although early promising results with some molecules have been demonstrated, these medications helped patients to achieve partial or full recovery in unpredictable ways (Hummel 2000). Olfactory training has also been provided with some interesting results: 28 % of the patients achieved olfactory improvement (Hummel et al. 2009). Olfactory training was given for 12 weeks based on four different odors (phenylethyl alcohol, eucalyptus, lemon, cloves) and was required at least 10 min twice a day by this protocol. For patients with qualitative disorders such as phantosmia or parosmia, some authors advocate the surgical removal of the neuroepithelium, possibly damaging quantitative capacity but resolving the qualitative problem (Leopold et al. 2002). This option has been adopted in very few cases. Although such treatment is based on empirical grounds, patients with second or multiple episodes of olfactory dysfunction during an URTI should receive corticoid treatment if the olfactory loss persists after the URTI symptoms in order to reduce the risk of viral injury and permanent olfactory dysfunction.