Re-establishment of olfactory and taste functions

Abstract

The incidence of olfactory disorders is appoximately 1-2% and they can seriously impact on the quality of life. Quantitative disorders (hyposmia, anosmia) are distinguished from qualitative disorders (parosmia, phantosmia). Olfactory disorders are classified according to the etiology and therapy is planned according to the underlying pathophysiology. In ENT patients olfactory disorders caused by sinonasal diseases are the most common ones, followed by postviral disorders. Therapy consists of topical and systemic steroids, whereas systemic application seems to be of greater value. It is very difficult to predict the improvement of olfactory function using surgery, moreover, the long term - success in surgery is questionable.

Isolated taste disorders are rare and in most often caused by underlying diseases or side effects of medications. A meticulous history is necessary and helps to choose effective treatment. In selected cases zinc might be useful.

1. Introduction - Olfaction

Smelling is the sensation experienced when the olfactory epithelium of the nose is stimulated by volatile substances. Although human sensory perception has become increasingly focused on visual and auditive impulses, the sense of smell remains of fundamental importance. A functioning olfactory system prevents us from consuming spoilt food, alerts us to the smell of burning, and contributes substantially to the quality of life by enabling flavor perception with food and drink as well as the appreciation of scents, such as perfume or a fresh sea breeze.

1.1 Anatomy and Physiology

The human olfactory epithelium consists of about 6 million neurons, spread over an area of about 2 cm², located in the uppermost region of the nasal cavity (in the area of the upper septum, lamina cribrosa, and superior turbinate) where they are well protected. The dimensions of the olfactory epithelium vary considerably between individuals [1], [2]. In biopsies, olfactory epithelium is frequently determined in dorsoposterior sections of the septum, with abundancies in the area of the superior turbinate [3], [4] and middle turbinate [5] showing greater variability.

The olfactory epithelium consists of various cell types [6]. Bipolar olfactory receptor neurons, embedded in a formation of supporting cells, have immotile cilia at their apical surface that constitute the site of sensory transmission [7]. Normal life span of olfactory neurons ranges from 30 to 90 days [8], but olfactory performance decreases with age, possibly because of accelerated apoptosis [9], and olfactory epithelium is increasingly replaced by respiratory epithelium [10], [11]. Olfactory receptor neurons are continuously regenerated from basal cells that are sometimes referred to as "multipotent stem cells" [12]. Like the cells ensheathing axon bundles, the so-called "olfactory ensheathing cells", basal cells are regarded as a promising target for transplantations in spinal nerve injuries [13], [14].

The axons of bipolar receptor cells combine into about 40 bundles called fila olfactoria that project into the olfactory bulb via the lamina cribrosa. After synaptic transmission within specific glomeruli, the information is forwarded to the olfactory cortex. Central activity after odor stimulation can be visualized by positron emission tomography (PET) [15] or functional magnetic resonance imaging (fMRI) [16].

1.2 Olfactory Performance and Quality of Life

Both quantitative olfactory disorders, such as hyposmia and anosmia, or qualitative disorders, such as phantosmia and parosmia, can seriously impact on the quality of life, often leading to weight loss and even depression [17], [18], [19], [20]. Moreover, olfactory loss is associated with a markedly increased risk of exposure to hazardous events in every-day living, such as intake of spoilt food, burning of meat etc. leading to a fire, or gas leakage [21]. For many affected individuals, the main problem lies in the consumption of bland and tasteless food. Patients with post-traumatic anosmia have meanwhile been shown to also have an elevated gustatory threshold [22].

2. Olfactory Function Tests

2.1 Self-Assessment of Olfactory Function

Despite the importance of olfaction in every-day living, most people can only inadequately assess their own olfactory performance. This is not only true for patients with neurodegenerative diseases [10], [23], but equally applies to subjects with normal olfactory function [24]. Somewhat better correlation between self-assessment and objectively measured olfactory performance is seen in subjects consulting a physician because of an olfactory disorder (personal data). For these reasons, subjective reporting of olfactory performance, e.g., a 'significant improvement', based solely on self-assessment, warrants careful interpretation.

2.2 Objective Assessment of Olfactory Function

Nowadays, a large number of validated test procedures are available. Here, these are described only briefly. Most Anglo-Saxon studies employ either the University of Pennsylvania Smell Identification Test (UPSIT) developed by Doty et al. [25], an abridged version termed 'Cross-Cultural Smell Identification Test' (CC-SIT) [26], or the CCCRC test [27]. European centers tend to use the "Sniffin' Sticks" test battery that assesses odor discrimination, odor identification, and olfactory threshold (Figure 1 (Fig. 1)) [28], [29], [30]. In addition, the Aachen rhinotest [31] and smell diskettes are available screening tests [32], [33]. In Japan, T&T olfactometry [34] or the intravenous Alinamin^® test are used [35]. Specialized centers measure evoked potentials after chemosensory stimulation to objectively test olfactory performance [36], [37].

Figure 1. Sniffin´Sticks^® test battery.

3. Classification of Olfactory Disorders

To effectively treat an olfactory or gustatory disorder and to re-establish olfactory function, it is essential to classify its etiology as accurately as possible. The system to classify olfactory disorders generally used today is in close agreement with the guidelines of the "Arbeitsgemeinschaft Olfaktologie/Gustologie der Deutschen Gesellschaft für HNO Heilkunde, Kopf- und Halschirurgie" [38], [39], see Figure 2 (Fig. 2).

Figure 2. Classification of smelling disorders.

3.1 Epidemiology

In the USA, the incidence of olfactory disorders is estimated to be 1.4% [40], but more recent studies suggest that the actual figure is probably higher [41], [42]. Based on a survey among German, Austrian, and Swiss ear, nose, and throat clinics, olfactory disorders in 72% of all treated patients have a sinonasal origin [43]. Mott & Leopold [44] and Nordin et al. [45] reported similar figures, with the stated proportions of postviral and post-traumatic disturbances depending on the specialization of the respective clinic [17], [20], [46].

4. Treatments

4.1 Olfactory Disorders of Sinonasal Etiology

These olfactory disorders comprise impairments caused by illnesses of the nose or the paranasal sinuses. The olfactory disorder occurs as a result or an accompaniment of the upper respiratory tract infection. Olfactory dysfunction may be conductive in nature or may be caused by damage to the olfactory mucosa; the latter may persist even if the conductive disorder has been corrected. Because the nomenclature used in studies is inconsistent, olfactory disorders of sinonasal etiology are discussed as a group to facility overview. Chronic rhinitis or rhinosinusitis often lead to deterioration of the olfactory threshold [47], [48], while neither the visibility of the olfactory cleft [49], [50] nor nasal breathing [47], [51] correlate with olfactory function as such.

4.1.2 Conservative Therapies

4.1.2.1 Topical Steroids

Two open studies documented a significant improvement of olfactory performance after betamethasone drops [52] or flunisolide drops [53] administered by the so-called "head down forward technique" (see Figure 3 (Fig. 3)). However, Heilmann et al. did not find any significant improvement after administration of topical steroids [54].

Figure 3. Application of nasal spray in the so called: "head down forward position".

In two prospective, double-blind studies, both Tos et al. [55] and Lund et al. [56] reported a significant improvement of the subjective olfactory sensitivity in response to budesonide, but objective olfactory performance was not determined. In contrast to this finding, budesonide spray failed to achieve any significant improvement of olfaction assessed with three substances in a study reported by Lildholdt et al.[57]. Similarly, elNaggar et al. found no real difference in the UPSIT between one side of the nose treated postoperatively with beconase and the untreated control side [58]. Treatment of allergic rhinitis with mometasone spray in 2 double-blind studies using different olfactory tests yielded contradictory results. While Meltzer et al. reported a significant improvement of odor identification at an unchanged odor threshold in the active group [59], Stuck et al. found an improved odor threshold in the absence of improved identification or discrimination [60]. No correlation between olfactory performance and improved nasal breathing was established. Similarly, Hedén Blomqvist et al. [61] documented no further improvement in patients initially responding to a 10-day combination therapy (oral and topical steroids) receiving follow-up treatment with topical steroids in a double-blind study.

4.1.2.2 Summary and Assessment of Topical Steroids

No significant improvement was demonstrated in any of the prospective, double-blind studies in which olfactory performance was determined by means of standardized tests before and after study start, with the exception of an improved odor threshold or identification seen after short-term use of mometasone spray in allergic rhinitis. Application of nasal sprays or drops in the 'head forward' position may possibly be advantageous, as shown by Benninger et al. [62].

4.1.2.3 Oral Steroids

Oral steroids were used successfully already in the fifties in patients with nasal obstruction, polyps, and olfactory disorders [63]. Below, the term 'steroid-dependent anosmia' is used for cases who rapidly experience clear improvement of olfaction after oral steroids but who frequently require a maintenance dose of steroids after surgery to maintain olfactory function [64], [65]. Because olfactory performance often fluctuates as seen in medical histories, the use of oral steroids may serve as a diagnostic tool [66]. In a retrospective study in 55 patients, Heilmann et al. reported a significant improvement of olfactory performance in response to oral steroids, while topical steroids had no measurable effect [54]. In a study by Ikeda et al., oral steroids improved olfactory function in 12 patients with ethmoid sinus disease as determined radiologically [67]. Pathological findings confined to the olfactory cleft have been termed "olfactory cleft disease" by Biacabe et al., who reported improved odor threshold in 50% of cases treated with oral steroids [68].

4.1.2.4 Summary and Assessment of Oral Steroids

Oral steroids are often effective in cases that do not respond to topical steroids. Their specific mechanism of action on olfactory performance remains unclear, but effects via glucocorticoid receptors in the olfactory mucosa [69], [70] or via regulation of adenosine triphosphate (ATP) activity in the olfactory mucosa [71] are being discussed. So far, no placebo-controlled, double-blind studies have been performed.

4.1.2.5 Leukotrienes

Leukotrienes, produced by mast cells and eosinophils, play an important pathophysiologic role in the early phase of allergies [72]. In open studies, leukotriene synthesis inhibitors (Zileuton) and leukotriene antagonists (Montelukast, Zafirlukast) have been shown to alleviate the complaints in patients with polyps [73], but data on olfactory performance are either limited to single observations [73] or rare [74].

4.1.2.6 Antibiotics

In animal models, macrolides reduce the symptoms of chronic inflammation (i.e., enhanced mucociliary transport, reduced secretion of goblet cells, accelerated apoptosis of neutrophils, and diminished gene expression of interleukin-6 [IL-6] and IL-8). In a review, Cervin [75] discusses several clinical studies conducted in Japan in which chronic sinusitis improved in response to prolonged therapy (in some cases for months) with low-dose macrolides. The success rate ranged from 60% to 80%, and neither previous steroid therapy nor surgery had been successful in any of the cases.

No definitive data on the effects of leukotrienes or macrolides on olfactory performance are available.

4.1.3 Surgical Interventions

Usually, surgical therapy of sinonasal olfactory disorders primarily serves to improve drainage (to facilitate healing of the inflammation) or nasal breathing. Thus, surgery aims to directly or indirectly improve olfactory performance by accelerating healing of the inflammation and restoring conduction [76]. Consequently, it is difficult to define predictive factors for the success of olfactory surgery [77], which is reflected in the variable success rates. The successful combination of surgery with subsequent oral steroid therapy [64] encouraged Jafek and Hill [78] to recommend pretreatment with oral steroids. However, even the use of steroid therapy after surgery often only achieves hyposmia [79], [80]. Delank and Stoll achieved normosmia in only 25% of hyposmic patients and in 5% of patients with initial anosmia [81]. These figures are in agreement with data reported by Downey et al. and Kimmelmann et al., who achieved improvements in olfactory function after surgery in only 50% and 66% of cases, respectively [82], [83]. The result was not substantially better if an antibiotic (Co-amoxiclav) was added on to oral steroids in the follow-up treatment [84]. Moreover, all three authors reported postsurgical deterioration of olfactory threshold in up to 34% of cases [83]. This high percentage may be due to the early testing after surgery; ideally, testing of olfactory performance should be done only after approx. 3 months [85]. Significantly improved olfaction was demonstrated both in the "Sniffin' Sticks" screening test and the subjective assessments in 70 patients [86]. If olfactory performance was based on subjective assessments only, a significant improvement was demonstrated in 178 patients receiving topical steroids for one year after surgery [87].

Long-term maintenance of olfactory function after surgery remains critical. Jankowski et al. attempted to achieve this by radical intervention, i.e., 'nazalisation' [88]. The authors failed to document any difference in olfactory performance one year after surgery between patients pretreated with oral steroids for one week and those not receiving any steroid pretreatment. Both patient groups had received an intramuscular depot formulation of steroid (Triamconolon, 80 mg) immediately after surgery [89]. These data are in contrast to the findings reported by Hedén Blomqvist et al. [90]. Patients with symmetrical intranasal conditions received oral cortisone and a 1﷓month therapy with topical steroids before undergoing unilateral endonasal surgery with subsequent topical steroid therapy for 12 months. One year after surgery, there was no significant difference between the nasal sides with respect to olfactory function, while obstruction and secretion were improved on the corrected side.

4.1.3.1 Septoplasty and Septorhinoplasty

Literature data on this topic are scarce. Twenty years ago, Stevens and Stevens documented olfactory threshold improvements [olfactometric method: Elsberg threshold test [91], regarded as inadequate nowadays] after various nasal surgeries (septoplasty, septorhinoplasty, turbinate resection) in 100 patients [92]. While Ophir et al. reported an improved olfactory threshold in 24 patients undergoing inferior turbinectomy [93], Damm et al. primarily found improved odor identification and discrimination after septoplasty and turbinectomy in 30 patients [94].

4.1.3.2 Olfactory Cleft Surgery

In certain cases with pathological findings confined to the olfactory cleft, lateralization of the middle turbinate may be of benefit (see Figure 4 a/b (Fig. 4)), although conclusive data are still missing.

Figure 4.

a) Preoperative findings in a cat scan demonstrating the closed olfactory cleft

b) Postoperative findings demonstrating the opening of the olfactory cleft after lateralisation of the middle turbinate

4.1.3.3 Summary and Assessment of Surgical Interventions

Factors that predict surgical success with respect to olfactory performance have yet to be identified. Similarly, no conclusive data on the correlation between olfactory performance and nasal airflow are available [95]. Comparison of the available studies is hampered by the variable severity of disorders present before surgery, the missing psychometric tests in some cases, and the highly varied conservative therapies applied in addition to surgery. In particular, the data by Hedén Blomqvist et al. [90] indicate that the decision to use surgery in chronic rhinosinusitis to improve olfactory performance should be made with caution for the time being, especially in the absence of additional randomized, controlled studies. Septoplasty to improve olfactory performance remains controversial.

4.1.4 Histology and Experimental Drugs

In chronic sinusitis and steroid-dependent anosmia, initial histologic appearance of the olfactory epithelium may be quite normal [64], [96], while irreversible olfactory receptor damage, epithelial metaplasia, and fibrosis are commonly seen subsequently [97], [98]. Progressing olfactory impairment leads to a loss of olfactory epithelium and olfactory receptor neurons with subsequent destruction of the epithelial structure [99].

Unilateral experimental infection with staphylococci in an animal model revealed that the inflammatory reaction (including epithelial thinning, loss of supporting cells, cilia, and dendrites) as well as apoptotic cell death occur not only on the infected nasal side but are virtually mirrored with a slight delay on the other nasal side [100]. Although the regulatory mechanisms activating apoptosis on the side initially not infected are not understood, it is known that a number of enzymes are responsible for apoptosis, with caspase-3, usually present in cells as inactive procaspase-3, thought to play a key role [101]. Kern et al. [102] measured modest caspase activity in healthy olfactory receptor neurons, whereas elevated caspase activity in olfactory receptor neurons and fila olfactoria as well as epithelial inflammation were evident in sinusitis even if olfaction was clinically normal. If olfactory dysfunction was also present, the inflammatory reaction was more marked and caspase-3 activity responsible for cell death continued to increase [102]. Caspase inhibitors tested successfully in animal models (i.e., for the treatment of ischemia or post-traumatic brain damage) may be the drugs of the future [103].

4.2 Olfactory Disorders of Non-Sinonasal Etiology

4.2.1 Postviral Olfactory Disorders

Every acute infection of the upper respiratory tract may potentially lead to an olfactory disorder, but the exact pathogenesis remains unclear [104]. Elderly subjects and women are affected more often [17], [46], and parosmia as well as dysosmia are common [105], [106]. Akerlund et al. [107] observed an elevated olfactory threshold correlating with nasal congestion in 9 volunteers experimentally infected with coronavirus with subsequent development of a common cold. In 36 volunteers suffering from a common cold, reduced amplitudes of the initial components in olfactory potentials were seen in addition to elevated thresholds, even after use of the nasal decongestant oxymetazoline [108]. This finding indicates that olfactory impairment may, in part, be independent of nasal congestion, thus explaining the failure of oxymetazoline to improve olfaction [109].

4.2.1.1 Histological Findings in Postviral Olfactory Disorders

Biopsies usually reveal a patchwork pattern, i.e., olfactory and respiratory epithelia alternate, and the number of olfactory receptor neurons is reduced. It remains controversial whether the extent of damage observed correlates with olfactory dysfunction [110], [111]. Dendrites of the olfactory receptor neurons often have cytoplasmic inclusions whose function is not yet understood [98].

4.2.1.2 Outlook

In mice, experimental infection with the neurotropic influenza A virus induced apoptosis of infected olfactory neurons, but viral penetration into the central nervous system (CNS) via the olfactory bulb did not occur and the animals survived (inoculation of the virus in the CNS is fatal in 100% of cases) [112]. Consequently, virus-induced apoptosis of olfactory cells via caspase-3 activation may be viewed as a mechanism to protect the organism from viral penetration into the CNS [113].

4.2.1.3 Treatment of Postviral Olfactory Disorders

Treatment with alpha-lipoid acid seems promising. In an open, prospective study, patients [n=23, 19 hyposmic patients, 4 functionally anosmic patients, based on "Sniffin' Sticks" test results [29], [30], received alpha-lipoid acid (600 mg/day) for 4.5 months on average [114]. Six patients experienced mild improvement and 8 patients clear improvement of olfactory performance. However, the authors stated that confirmation of these findings warrants a double-blind study because spontaneous recovery and regeneration are common in postviral olfactory disorders and may occur up to 2 years after viral exposure [105].

4.2.1.4 Treatment of Parosmia / Phantosmia

Apart from various drugs, e.g., antiepileptics, antidepressants, and local anesthetics [115], surgical removal of the olfactory epithelium, reported for the first time in 1991 by Leopold et al. [116], may be of use. Long-term follow-up (for 5 years after surgery) revealed that 7 of 8 patients were completely free of complaints, with only 2 patients showing reduced olfactory performance [117]. Bulbectomy may also be of use in specific cases [118].

4.2.2 Post-Traumatic Olfactory Disorders

Post-traumatic olfactory dysfunction correlates with the severity of trauma [119], but even minor traumas may lead to impaired olfaction. Possible mechanisms are middle-face fractures or traumas directly or indirectly damaging the olfactory region, shearing lesions of the fila olfactoria, or intracranial injuries. Severing of the axons from olfactory receptor neurons eventually leads to retrograde cell death [120]. Nevertheless, spontaneous improvement is possible, as confirmed by Doty et al. in 24 of 66 patients who were re-analyzed after 1 to 13 years [121] as well as Duncan and Seiden in 7 of 20 patients after 2 to 3 years [105]. Using MRI, post-traumatic changes were characterized as encephalomalacias [122] and reduced volumes of the olfactory bulb [121], [123]. Spontaneous recovery is possible because damaged neurons are able to regenerate [124]. Basal cells differentiate into olfactory receptor neurons whose axons extend to the olfactory bulb via the lamina cribrosa to form synapses. The bulb supplies the olfactory receptor neurons with trophic factors essential for their survival [125]. If no contact is established and synapses fail to develop, olfactory receptor neurons will die within a few days [126]. If, however, connection with the bulb is successful, neuronal function is restored [127], [128]. Vitamin A has been shown to markedly accelerate neuronal regeneration in mice [129].

4.2.2.1 Histology of Olfactory Epithelium in Post-Traumatic Olfactory Disorders

Olfactory receptor neurons are shriveled and have only few cilia, suggesting a reduced number of connections with the olfactory bulb [130]. Typically, there are many axons in the vicinity of the basal membrane that appear not to have made any connection with the bulb [131]. The ultrastructural changes correlate with the type and extent of damage [132].

4.2.2.2 Treatment of Post-Traumatic Olfactory Disorders

In a prospective study in 95 patients suffering from post-traumatic olfactory disorders, Aiba et al. reported significant improvement of self-assessed olfactory performance in 2 of 4 patients receiving zinc sulfate (300 mg/day) for > 1 month [133]. In an open, prospective study in anosmic patients receiving either oral caroverine (120 mg/day) or zinc sulfate (400 mg/day) for 4 weeks, Quint et al. [134] reported a significantly improved olfactory threshold in patients receiving caroverine compared with those receiving zinc sulfate. The authors discussed a possible intrabulbous repair mechanism and a neuroprotective effect of the glutamate receptor inhibitor, caroverine, similar to the one present in the inner ear [135]. However, the authors recommended a double-blind study to confirm this notion. In an open, prospective study conducted in Japan, the use of local dexamethasone (4 mg/0.5 mL, 8 times, injected into the mucosa of the upper septum in 2-week intervals), was discussed [136]. All 27 patients treated also received vitamin B₁₂ (750 µg/day to 1500 µg/day) and ATP (300 mg/day). In 6 patients, the recognition threshold was improved, while 4 patients experienced an improved identification threshold. However, the authors did not exclude spontaneous recovery and suggested additional studies.

4.2.3 Congenital Olfactory Disorders

Overall, congenital olfactory disorders are very rare. They tend to show between the age of 5 and 10 years. The best known genetic olfactory disorder is Kallmann's syndrome (hypogonadotropic hypogonadism with anosmia) [137], but isolated anosmia is also known [138]. Neuroradiologic examination revealed marked hypoplasia or the total absence of the olfactory bulb or tract (68-84%) [139], in addition to clearly reduced sulcus depth [140].

4.2.3.1 Histological Findings in Congenital Olfactory Disorders

While Jafek et al. did not find any olfactory epithelium in 36 biopsies of 7 patients with congenital anosmia [141], Leopold et al. described a pathological epithelium with immature olfactory receptor neurons and missing cilia in 2 of 5 patients [142]. In contrast, Rawson et al. succeeded in demonstrating mature olfactory receptor neurons [143].

4.2.3.2 Treatment of Congenital Olfactory Disorders

At present, no treatment options are known.

4.2.4 Toxic Olfactory Disorders

Many substances, such as metals (e.g., lead or cadmium), organic substances (e.g., solvents or formaldehyde), inorganic substances (e.g., chlorine, CO, ammonium chloride), and other substances (e.g., cement dust) may be olfactotoxic [144], [145], [146]. Although the olfactory epithelium is located away from the main airway, 10% to 15% of the inhaled air reaches the olfactory epithelium even without sniffing, thus causing exposure to potentially toxic substances [147]. Chronic exposure is more likely to induce lasting damage than acute exposure [148].

4.2.4.1 Treatment of Toxic Olfactory Disorders

No treatments with proven success exist, and larger studies documenting a clear relationship between exposure and olfactory loss are missing. Nevertheless, careful assessment of the work-place history is essential for all olfactory disorders.

4.2.5 Olfactory Disorders of Other Etiologies

Multiple internal disorders (e.g., hypothyreosis, renal failure, diabetes mellitus), neurologic diseases (e.g., Alzheimer's disease, Parkinson's disease), and psychiatric diseases (e.g., schizophrenia, depression) are accompanied by olfactory disorders [104]. Although literature information is controversial in part, dialysis in chronic renal failure, for example, does not appear to improve olfactory performance [149], nor does antiparkinson medication improve olfaction in Parkinson's disease. In these situations, the primary steps must be to identify and treat the underlying disease. Drugs themselves may induce olfactory disorders but these tend to be transient and reversible in most cases [150], [151].

For a long time, laryngectomized patients were also thought to be anosmic [152]. However, more recent studies showed that the olfactory epithelium usually remains intact even years after laryngectomy [153], [154], and that patients can draw air to the olfactory cleft and regain olfaction by adopting a special yawning technique [155], [156].

4.3 Experimental Drugs and Other Treatments

4.3.1 Hormonal Therapy

Studies by Deems et al. showing that only a small percentage of postmenopausal women with olfactory disorders receive hormonal therapy triggered speculation about a protective effect of hormones [17]. The smaller bulb volume in men suffering from post-traumatic olfactory disorders, relative to that in women [121], as well as olfactory performance in schizophrenic women shown to differ in relation to their menopausal status was interpreted along the same lines [157]. In animal experiments, ovarectomized mice exposed to olfactotoxic substances recovered more quickly if they received hormonal replacement than did those not receiving any hormones [158]. However, a longitudinal study in 62 women failed to confirm these findings; the only finding was a correlation between loss of olfaction and age progression [159].

4.3.2 Dopamine

Although it is established that the neurotransmitter dopamine is present in the olfactory bulb, existence of D2 receptors in the olfactory epithelium has only recently been described [160]. Dopamine triggers neuronal differentiation and maturation in the epithelium in vitro, while on stimulation of the lamina propria, dopamine induces the liberation of substances that block neuronal differentiation [160]. Dopamine led to a significantly reduced rate of apoptosis in olfactory biopsies of schizophrenic patients but clearly accelerated apoptosis in the olfactory epithelium of control subjects [161]. In Parkinson's patients, Huisman et al. determined a doubling of dopaminergic cells in the olfactory bulb and interpreted this as a possible cause of the olfactory disorders seen in Parkinson's disease [162].

4.3.3 Acupuncture

Data confirming the benefit of acupuncture are missing. In an open study, auricular acupuncture improved olfactory threshold in 23 healthy volunteers [163]. In addition, a case report documented restored olfaction after acupuncture in a female patient who had been suffering from anosmia for 2 years [164].

4.3.4 Theophylline

Levy et al. [165] used theophylline (250 to 500 mg, given for 4 to 6 months) in 4 hyposmic patients (allergic rhinitis, n=3; post-traumatic hyposmia, n=1) and reported normal post-treatment olfaction in 2 patients, improved olfaction in 1 patient, and unchanged olfaction in the remaining patient. Functional MRI in 3 patients indicated enhanced central activation after treatment. No additional data are available.

4.3.5 Growth Factors (Transforming Growth Factor)

Olfactory receptor neurons are continuously replaced during the course of life, with the rate highest at younger age [9]. Because the rate of neurogenesis can be manipulated by external factors (e.g., doubling after ablation of one olfactory bulb [166], decrease after unilateral nostril occlusion [167]), acceleration by using growth hormones appears feasible. Intraperitoneal administration of transforming growth factor-alpha (TGA-alpha) resulted in enhanced cell proliferation not only in fetal but also in adult mice [168]. So far, no studies in humans have been performed.

4.3.6 Vitamin A

Vitamin A has been reported to normalize olfactory performance in malabsorption conditions or A-β-lipoproteinemia [169]. Moreover, Garrett-Laster et al. [170] reported a significant improvement of olfactory threshold for pyridine and taste threshold for bitter and salty substances in 37 patients with vitamin A deficiency due to alcoholic liver cirrhosis undergoing a 4-week therapy with oral vitamin A (10 mg/day). No additional data are available.

4.3.7 Zinc

Zinc sulfate (100 mg) did not have any significant effects in 106 patients participating in a double-blind study reported by Henkin et al. [171] (see also Quint et al. [134]). High doses of local intranasal zinc may even be olfactotoxic [172].

5. Introduction - Taste Disturbances

After biting into an apple, we identify the piece in the mouth as 'apple', based on its consistency, temperature, spiciness, retronasal olfactory sensation, and the slightly acidic taste. The combination of all perceptions is known as 'flavor', although the only genuine taste qualities defined are sweetness, acidity, saltiness, and bitterness.

5.1 Anatomy and Physiology

The site for taste perception has been identified as the taste buds located in the area of the tongue, soft palate, oropharyngeal mucosa, and also the epiglottis. The taste buds, approx. 4600 on average, consist of 20 to 50 cells arranged like slices of an orange exposing the taste pore in the center. The microvilli of neuroepithelial sensory cells extend into the taste pore [173]. The life span of taste buds ranges from about 10 to 20 days [174]. The majority of taste buds are located on taste papillae classified as vallate papillae, filiform papillae, and fungiform papillae [175], [176]. Basically, each type of papilla is sensitive to several, if not all, taste modalities [177]. Innervation takes place via the chorda tympani nerve, glossopharyngeal nerve, and vagus nerve. Excitatory transmission for acidic and salty tastes occurs directly via ions, while sweet and bitter tastes trigger secondary-messenger systems via membrane-specific receptors [178], [179].

6. Assessment of Gustatory Function

Gustatory function is assessed in terms of total or regional taste perception [180], [181]. Taste threshold is typically assessed with the 3-drop method using saccharose, citric acid, table salt, and quinidine hydrochloride solution [182], [183], or by using the so-called 'taste strips' [184]. Differences between the sides are assessed by electrogustometry that determines the electrical perception threshold [185]. Specialized ear, nose, and throat centers employ contact endoscopy to visualize the morphologic changes.

6.1 Classification and Epidemiology of Taste Disorders

Taste disorders are classified as quantitative and qualitative taste disorders. Quantitative disorders include hypogeusia and ageusia, while qualitative disorders are parageusia and phantogeusia. The classification as epithelial, neuronal, or central taste disturbance, depending on its cause, is in close agreement with the guidelines of the "Arbeitsgemeinschaft Olfaktologie/Gustologie der Deutschen Gesellschaft für HNO Heilkunde, Kopf- und Halschirurgie" [186]. Taste disturbances are less common than olfactory disorders, and qualitative changes are clearly more frequent than quantitative alterations.

7. Treatments

Because taste disorders are often coupled with a concomitant illness that can be diagnosed and treated, initial identification of the illness by means of detailed analysis of the medical history and clinical examination is of primary importance. The possible therapies of concomitant illnesses are not discussed here; for review see Bromley and Doty [187]. Below, some disorders and their possible treatments are discussed only as examples.

7.1 Taste Disorders after Radio-Chemotherapy

Radiotherapy leads to transient hypogeusia (especially for bitter and salty tastes) or even ageusia, which is most pronounced approx. 2 months after irradiation [188]. The taste disturbance can persist for 1 to 2 years after radiotherapy [189]. In a randomized clinical study, Ripamonti et al. [190] demonstrated faster recovery of taste function in patients receiving zinc sulfate (3 x 45 mg/day, given during radiotherapy and for 1 month afterwards) than in those receiving placebo. Similarly, zinc infusions had a positive effect on the electrogustometric threshold in chemotherapeutically treated patients [191]. Simultaneous application of amifostine during radiochemotherapy reduces xerostomia and dysgeusia [192].

7.2 Postoperative Taste Disorders

Taste disorders after tonsillectomy caused by pressure on the lingual branch of the glossopharyngeal nerve are rare (0.31%) and commonly disappear spontaneously [193]. Just et al. [194] studied 118 patients with a strained or severed chorda tympani nerve after various surgeries. The subjective complaints in these patients were highly variable and did not necessarily correlate with measured taste perception. Saito et al. [195] also demonstrated better long-term recovery of clinical (subjective) taste perception than of objective taste function measured by electrogustometry. After 2 years, only 2.7% of all patients (n=113) reported subjective taste impairment. This low rate was thought to be caused by the loss of central inhibition [196]. In patients with lingual nerve injuries excision of neurinomas and end-to-end suture resulted in improved postoperative taste perception in 40% of cases [197].

7.3 Drug-Induced Taste Disorders

Drug-induced dysgeusia, but also hypogeusia or ageusia, are common and especially associated with the ACE inhibitor captopril (20% dysgeusia) or the diuretic azetazolamide (100% dysgeusia) [150], [151]. In elderly patients, taste disturbances are often not the consequence of old age but may be associated with concomitant diseases or side effects of drugs taken [198]. Age-dependent impairment of taste varies considerably, and the debate of its clinical relevance is controversial [199].

7.4 Therapeutic Use of Zinc in Taste Disorders

Numerous studies document the favorable effect of zinc on taste perception. In an observational study, Stoll and Oepen reported improved taste perception in 5 psychiatric patients, but the authors failed to indicate their test method [200]. In an open study (n=119; idiopathic taste disturbance, n=45; drug-induced taste disturbance, n=38; zinc deficiency, n=36), taste improvement by 50% was achieved after 4 weeks and by 80% after 8 weeks of treatment with zinc sulfate (100 mg, three times daily) [201]. In a double-blind, placebo-controlled study (n=73; idiopathic taste disturbance, n=48; lowered zinc levels, n=25), treatment with zinc picolinate (30 mg, three times daily) for 3 months did not improve subjective taste assessment or taste performance in the entire mouth, although the group receiving zinc picolinate performed significantly better than the placebo group in the filter paper test [202]. However, both the double-blind study by Henkin et al. [171] and the double-blind study in 65 patients by Yoshida et al. [203] failed to confirm this difference. Nevertheless, if the patients with drug-induced taste disturbances were excluded and only the patients with idiopathic taste disturbances and zinc deficiency were analyzed, the result was significant [203]. A double-blind study in hemolized patients (n=22) with low zinc levels demonstrated a significant improvement in response to zinc (50 mg/day) given for 12 weeks [204]. Similarly, preliminary findings from a double-blind study with zinc gluconate by Heckmann et al. seemed promising in idiopathic dysgeusia [205], [206].

7.5 Experimental Drugs

Dysgeusia is the most frequent form of taste disturbance and is often idiopathic. A link between dysgeusia and depression has been established. In two thirds of cases, dysgeusia resolves spontaneously after about 10 months [207]. In an open observational study in 44 patients with burning mouth syndrome, treatment with alpha-lipoic acid (3 x 200 mg/day) for 2 months significantly improved taste function as measured by symptoms scores [208]. In cases of severe dysgeusia topical anesthetics, either as solution, spray or gel (lidocaine 2%, or lidocaine spray 10% or lidocaine gel) may be helpful [209].

7.6 Importance of Saliva in Taste Function

The entire oral surface, particularly the surface of the taste receptors, is covered with saliva whose quantitative excretion is controlled by the autonomic nervous system [210]. Saliva is produced by pairs of the major salivary glands (i.e., parotid, submandibular, and sublingual salivary glands) as well as the minor salivary glands (known as the Ebner glands) that secrete saliva into the crypts of the circumvallate and foliate papillae on the posterior of the tongue. Saliva secreted by the Ebner glands contains the Ebner gland protein [211] that was postulated to bind bitter, hydrophobic substances thus facilitating their recognition by the taste papillae. Meanwhile, it is established that this notion was incorrect; the protein is now thought to play a role in the management of inflammatory processes [212]. A further salivary protein, i.e., gustin [213], has meanwhile been identified as carbonic anhydrase VI [214]. In an open study in 14 patients with postviral taste and smell disorders and low levels of carbonic anhydrase VI, 4-month treatment with zinc sulfate (100 mg/day) clearly increased salivary levels of carbonic anhydrase VI and improved taste and olfactory functions in 10 patients [215].

7.6.1 Sjögren's Syndrome and Taste Disorders

This autoimmune disease is associated with decreased salivary secretion, which explains the taste disturbances often reported by Sjögren's patients. Henkin et al. demonstrated elevated taste thresholds in patients with Sjögren´s syndrome [216], but Weiffenbach et al. observed normal thresholds [217]. Reduced salivary volume can, but does not necessarily have to, lead to taste impairment [218]. Salivary secretion can be stimulated using parasympathomimetics, typically pilocarpine (5-10 mg/ 3-4x/d) [219], [220]. Interferon - α either systemically or as low dose lozenge (150 IU, 3x/d) has been shown to reduce xerostomia and increase salivary output [221],[222]. Moreover, artificial salivas, oral rinses and gels have been proposed to treat xerostomia, even though their effect is only transient and so far no effect on taste function has been shown. Specific dietary measures (e.g., consumption of raw vegetables or salty cookies, e.g., bretzels) may help to enhance salivary production. A similar method was already practiced by the redskin Indians who sucked pebbles to increase salivary output if no drinking water was available.

Acknowledgement

I wish to thank Prof. Dr. Rudolf Probst for his continuous support and challenging questions. Much constructive criticism and valuable recommendations by Prof. Dr. Thomas Hummel and Prof. Dr. Markus Wolfensberger have gone into this manuscript, for which I am most grateful to them. My thanks also go to PD. Dr. Daniel Simmen for his permission to use Figure 4 (Fig. 4).