Oral Diseases (2015) 21, 937–948 doi:10.1111/odi.12345 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd All rights reserved www.wiley.com

REVIEW ARTICLE

Pathophysiology of primary burning mouth syndrome with special focus on taste dysfunction: a review M Kolkka-Palomaa1, SK J€ a€ askel€ ainen2,3, MA Laine4, T Teerijoki-Oksa1, M Sandell5,6, H Forssell4 1

Department of Oral and Maxillofacial Diseases, Turku University Hospital, Turku; 2Department of Clinical Neurophysiology, Turku University Hospital, Turku; 3Department of Clinical Neurophysiology, University of Turku, Turku; 4Institute of Dentistry, University of Turku, Turku; 5Functional Foods Forum, University of Turku, Turku; 6Food Chemistry and Food Development, Department of Biochemistry, University of Turku, Turku, Finland

Primary burning mouth syndrome (BMS) is a chronic oral condition characterized by burning pain often accompanied with taste dysfunction and xerostomia. The most compelling evidence concerning BMS pathophysiology comes from studies on the somatosensory system using neurophysiologic or psychophysical methods such as blink reflex, thermal quantitative sensory testing, as well as functional brain imaging. They have provided convincing evidence for neuropathic involvement at several levels of the somatosensory system in BMS pain pathophysiology. The number of taste function studies trying to substantiate the subjective taste disturbances or studies on salivary factors in BMS is much more limited, and most of them suffer from definitional and methodological problems. This review aims to critically evaluate the existing literature on the pathophysiology of BMS, paying special attention to the correctness of case selection and the methodology used in published studies, and to summarize the current state of knowledge. Based on the recognition of several gaps in the current understanding of the pathophysiology of BMS especially as regards taste and pain system interactions, the review ends with future scenarios for research in this area. Oral Diseases (2015) 21, 937–948 Keywords: primary burning mouth syndrome; pathophysiology; taste dysfunction; saliva; taste

Introduction Burning mouth syndrome (BMS) is a chronic oral condition characterized by burning pain, often accompanied with taste dysfunction (dysgeusia, taste phantoms) or dry Correspondence: Marina Kolkka–Palomaa, Department of Oral and Maxillofacial Diseases, Turku University Hospital, Turku, Finland, Lemmink€aisenkatu 2, FI-20520 Turku, Finland. Tel: +358 2 3130881, Fax: +358-2-23338248, E-mail: marina.kolkka@tyks.fi Received 4 March 2015; revised 13 April 2015; accepted 19 April 2015

mouth sensation (xerostomia). Noticeable is that hyposalivation by itself can also induce burning sensation in the mouth without being true BMS. Burning mouth syndrome remained an enigma for a long time, but during the last years, knowledge of the pathophysiology of BMS has considerably increased. Research has particularly focused on the trigeminal somatosensory system to unravel the background of BMS pain, and various types of abnormalities have been found at several levels of the somatosensory system. Much less attention has been paid to the other aspects of the syndrome, taste disorders and xerostomia. The numbers of taste function studies trying to substantiate the subjective taste disturbances or studies on salivary factors are much more limited. The aim of this article was to review the existing literature on the pathophysiology of BMS, with special focus on studies on taste dysfunction and xerostomia in BMS.

BMS – clinical features Burning mouth syndrome is characterized by burning mucosal pain that is not due to any other local or systemic causes, and arises from a clinically normal, healthy mucosa (Bergdahl and Bergdahl, 1999; Woda and Pionchon, 1999; Zakrzewska and Hamlyn, 1999; Zakrzewska et al, 2005; Markman and Eliav, 2013). The International Classification of Headache Disorders defines BMS accordingly as ‘an intraoral burning or dysesthetic sensation, recurring daily for more than 2 h per day over more than 3 months, without clinically evident causative lesions’ (The International Classification of Headache Disorders, 2013). In addition to pain, BMS patients often complain of a feeling of oral dryness or taste disturbances justifying the use of the term ‘syndrome’ (Scala et al, 2003; Granot and Nagler, 2005; Zakrzewska et al, 2005). Burning mouth syndrome diagnosis is in practice based on the exclusion of local and/or systemic factors that could cause the oral burning or other sensory symptoms. Many studies, especially earlier ones, have not distinguished between BMS and oral burning symptoms, that is

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burning mucosal pain due to clinically identifiable aetiological factors (Zakrzewska, 1995; Scala et al, 2003). The factors causing oral sensory symptoms can be local, such as reduced saliva secretion, oral candidiasis, oral parafunctions, denture-related problems or allergic reactions. Also, some systemic factors such as nutrition (deficiency of vitamin B12, folic acid, or iron), hormonal disturbances and immunological abnormalities may give raise to burning oral mucosal pain. In the case of secondary oral burning symptoms, treatment of the underlying cause will alleviate the sensory symptoms. To highlight the importance of differentiating ‘true’ BMS from cases with similar but secondary symptoms induced by local or systemic causes, a clinical classification system was introduced where the former condition was called primary BMS and latter secondary BMS (Merskey and Bugduk, 1994; Zakrzewska, 1995). The clear differentiation between BMS and oral burning symptoms has been important to the progress made in the understanding of the pathophysiology of primary BMS. Due to the vagueness in diagnostic definitions of BMS, the findings of earlier studies should be interpreted with some caution (Zakrzewska, 1995). Obviously due to the loose diagnostic criteria, the reported prevalence figures of BMS have also varied and ranged from 0.7 to 15% (Zakrzewska and Hamlyn, 1999). According to an epidemiological study using strict diagnostic criteria, 3.7% of an adult population (5.5% of women and 1.6% of men) was found to suffer from BMS (Bergdahl and Bergdahl, 1999). According to the same study, the prevalence of BMS increased with age in both women and men, with the highest prevalence (12%) in women aged 60–69 years. Female predominance in BMS is obvious also when looking at clinical patient samples, the ratio varying between 7 and 10 women for one man (Woda et al, 2009). Burning pain of the oral mucosa is the cardinal feature of BMS (Scala et al, 2003; Braud et al, 2013). The intensity of pain varies from mild to severe (Grushka et al, 1987; Eli et al, 1994; Svensson and Kaaber, 1995; Bergdahl and Bergdahl, 1999; Forssell et al, 2012). It is most often experienced at more than one oral site, the anterior part of the tongue, the anterior hard palate and the lips being most frequently affected (Grushka, 1987; Svensson and Kaaber, 1995; Bogetto et al, 1998; Forssell et al, 2012). Pain is most often bilateral and symmetrical. It is important to note that the pain does not follow the anatomical distribution of peripheral sensory nerves. Neuroanatomically distinct or unilateral symptoms raise the possibility of organic disease (Barker and Savage, 2005). Most patients experience negligible symptoms on awakening, and symptoms build up over the day, being most intense in the evening, but the pain only seldom disturbs night sleep (Grushka, 1987; Forssell et al, 2012). Some patients, however, experience constant symptoms throughout the day (Eli et al, 1994; Bergdahl and Bergdahl, 1999; Forssell et al, 2012), while others only have intermittent symptoms (Svensson and Kaaber, 1995; Bergdahl and Bergdahl, 1999; Forssell et al, 2012). In more than half of the patients, the onset of pain is spontaneous, with no identifiable precipitating factors.

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One-third of the patients relate time of onset to dental treatment, recent illness or medication. Regardless of the onset of pain, it often persists for many years. Spontaneous partial remission has been reported to occur within 6– 7 years after onset in about one-half to two-thirds of the patients (Grushka et al, 1986). In one study, spontaneous complete remission occurred in approximately 4% of patients within 6 years (Sardella et al, 2006). Several studies have shown a high prevalence of psychiatric disorders or of psychological problems in BMS patients. In particular, depression, anxiety, somatization and personality disorders are reported to be frequent findings (Taiminen et al, 2011; Schiavone et al, 2012; de Souza et al, 2012). Psychological disorders can theoretically be associated with BMS by several mechanisms. However, BMS is usually no longer considered a psychological disorder per se (Woda et al, 2009), and psychiatric disorders are considered to represent comorbid or secondary conditions, not causally related to BMS pain (Taiminen et al, 2011).

Somatosensory system dysfunction in BMS Recent studies using several relevant, objective neurophysiologic or psychophysical methods such as blink reflex (BR) and thermal quantitative sensory testing (tQST), as well as neuropathological, neurobiological and functional brain imaging techniques, have provided convincing evidence for neuropathic involvement in the pathophysiology of primary BMS. Abnormalities have been found along the whole neuraxis from the peripheral trigeminal system to the central nervous system and top-down inhibitory control systems (J€a€askel€ainen, 2012). Peripheral neuropathic mechanisms in primary BMS BR recordings with stimulation of the distal branches of the third trigeminal division in primary BMS patients have revealed distinct abnormalities within the trigeminofacial large and small fibre systems and the trigeminal brainstem complex (J€a€askel€ainen et al, 1997; Forssell et al, 2002; Puhakka et al, 2010). In a large study with 52 primary BMS patients, the results of the BR studies indicated subclinical brainstem pathology or peripheral trigeminal neuropathy, mostly lingual or mandibular nerve lesions, in 20% of the patients (Forssell et al, 2002). In the same study, thermal quantitative sensory testing (tQST) within the lingual nerve distribution was performed in 46 of the BMS patients, and 76% of the patients showed abnormalities in one or more thermal detection threshold tests, mostly hypoesthesia indicative of either peripheral small fibre neuropathy or deafferentation of the central trigeminal thermal pathways. As a whole, a considerable overlap of abnormal findings in different tests was observed in that study, and only 10% of the patients showed normal findings. Other studies using tQST have demonstrated similar alterations in thermal sensory detection thresholds, most often negative sensory signs in small-fibre-mediated sensory modalities (thermal hypoesthesia or anaesthesia) (Svensson et al, 1993; Forssell et al, 2002; Ito et al, 2002; Granot and Nagler, 2005; Puhakka et al, 2010), but

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also positive sensory signs in the form of thermal allodynia or decreased heat pain tolerance have been detected in a minority of patients (Forssell et al, 2002; Granot and Nagler, 2005; Gremeau-Richard et al, 2010). In the study by Just et al (2010), the lingual nerve sensitivity was tested with capsaicin threshold tests. The results showed that BMS patients exhibited higher pain thresholds, which were negatively related to the duration of BMS symptoms; that is, patients were less sensitive to experimental pain with increasing duration of the pain symptoms. Similarly, hypoalgesia to noxious thermal stimuli has been observed in tQST studies as well (Forssell et al, 2002). These phenomena may be related to tonic activation of the conditioned pain modulation (CPM) systems (previously, diffuse noxious inhibitory control) in BMS patients suffering from chronic neuropathic pain. As regards the close connection between pain and taste disorders in BMS, it is interesting to note that according to some tQST studies, hypofunction within the Ad fibre class, that is the same fibre class that mediates cooling and first pain sensations as well as taste sensation, seems to be relatively more frequent than C-fibre hypofunction (Forssell et al, 2002; Puhakka et al, 2010). In addition to hypofunction of the focal small fibre system, the findings of several studies have indicated a more generalized disorder of the somatosensory system in BMS patients (Svensson et al, 1993; Lauritano et al, 1998; Lauria et al, 2005; Gremeau-Richard et al, 2010; Puhakka et al, 2010). In a recent study using extensive neurophysiologic and psychophysical examinations of the distal extremities in addition to the study of the trigeminal system, 90% of the BMS patients showed neurophysiologic or tQST signs of a more generalized nervous system disorder (Puhakka et al, 2010). In line with the tQST evidence for focal small fibre hypofunction, several small studies have demonstrated the loss of epithelial nerve fibres in tongue mucosal biopsies of BMS patients, giving further evidence for a peripheral neuropathic process affecting the small nerve fibres in BMS (Lauritano et al, 1998; Yilmaz et al, 2007; Forssell et al, 2008; Beneng et al, 2010; Penza et al, 2010; Puhakka et al, 2010). Most interestingly, detailed immunohistochemical analyses of the tongue mucosal biopsies from BMS patients have revealed significant overexpression of pro-nociceptive ion channels (TRPV1) and purinergic receptors (P2X3) in the spared subepithelial myelinated nerve fibres in the tongue mucosa of BMS patients (Yilmaz et al, 2007; Beneng et al, 2010). This phenomenon is compatible with altered phenotype of the remaining functional subepithelial large fibres and may offer another, peripheral explanation for the origin of pain in BMS patients. Despite the rather convincing evidence for the role of initial small fibre pathology in BMS, there are no systematic studies evaluating the possible causal factors of the focal or generalized small fibre neuropathy in BMS. However, as regards the aetiology of the focal peripheral neuropathy, one possible explanation could be repeated minor epithelial nerve fibre trauma caused by intraoral burn injuries experienced by virtually everybody every now and then when eating and drinking hot liquids. The common

burn injury sites, the anterior parts of the oral cavity, the tip of the tongue and the anterior palate, correspond well with the most frequent pain locations in BMS patients, although this connection has not been specifically investigated. In addition, minor injuries to the distal distributions of the trigeminal nerve, especially the lingual branch of the nerve, during common dental procedures can induce intraoral trigeminal neuropathic pain that may be clinically indistinguishable from primary BMS (J€a€askel€ainen et al, 2005; J€a€askelainen, 2012). It has also been suggested that BMS may in some cases be linked to another neuropathiclike oral pain condition, atypical odontalgia, which usually is induced by procedures that may cause nerve damage, such as endodontic treatment or tooth extraction (Grushka et al, 2003).

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Alterations in central nervous system function in primary BMS Signs of deficient habituation of the BR have been found in 20–36% of BMS patients (J€a€askel€ainen et al, 1997; Forssell et al, 2002). In line with these neurophysiologic signs of increased excitability within the trigeminal system in a subgroup of BMS patients, application of capsaicin on the hard palate in patients with BMS has been reported to evoke significantly higher pain ratings and more persistent pain compared to matched control subjects after 3min applications, suggesting a perturbed temporal summation of nociceptive afferent inputs or impairments in endogenous pain inhibitory systems (Svensson et al, 1993). Furthermore, the duration and intensity of poststimulus pain have been found to be higher in patients than in control subjects after painful heat, cold or mechanical stimulation (Ito et al, 2002). The finding of deficient habituation of the blink reflex (J€a€askel€ainen et al, 1997; Forssell et al, 2002) that is under striatal dopaminergic inhibitory control may reflect deficient dopamine-mediated inhibition of the trigeminal brainstem complex. The role of dopaminergic system in BMS has been directly investigated in two neurotransmitter positron emission tomography (PET) studies, which have demonstrated a decline in striatal endogenous dopamine levels in BMS with resulting defect in dopaminemediated top-down pain modulation (J€a€askel€ainen et al, 2001; Hagelberg et al, 2003). These dopamine system PET results in BMS are similar to those reported in early Parkinson’s disease (Heiss and Herholz, 2006), a condition that has been associated with increased incidence of central pain as well as BMS (Clifford et al, 1998) and that shows similarly deficient habituation of BR (Kimura, 2001). As there is overlap between abnormal habituation of the BR and hypoesthesia in tQST in primary BMS, it could be assumed that deficient inhibitory top-down modulation of pain experience via striatal dopamine loop may constitute a risk factor for the development of chronic neuropathic orofacial pain (J€a€askel€ainen et al, 2014). Siviero et al (2011) presented further evidence to support the notion that neural mechanisms are involved in the pathophysiology of BMS. In addition to higher tactile, thermal and taste detection thresholds, their BMS patients also showed higher olfactory thresholds. Based on these results, they proposed that central sensitization, probably Oral Diseases

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after peripheral deafferentation, may be involved in the pathophysiology of BMS. A brain functional magnetic resonance imaging (fMRI) study (Albuquerque et al, 2006) suggested that BMS patients process thermal painful stimuli both quantitatively and qualitatively differently from pain-free individuals; the anterior cingulate cortex and bilateral precuneus showed greater fractional signal change, whereas the thalamus showed decreased activation in BMS patients compared to controls. Furthermore, in quantitative volumetric analysis, BMS patients showed less activation throughout the entire brain compared to controls. The brain activation patterns in BMS patients thus resemble those of patients with other deafferentationrelated neuropathic pain conditions giving further evidence for the neuropathic nature of BMS (Baliki et al, 2014). In line, a recent study on cerebral reorganization demonstrated increased grey matter volumes in the hippocampus and decreased grey matter in the medial prefrontal cortex in BMS as well as increased functional connectivity from the prefrontal cortex to other pain-processing areas including the insula and the anterior singular cortex (Khan et al, 2014). To summarize, studies indicate that BMS may be a common clinical phenotype for variable dysfunctions affecting the peripheral and central nervous system. Neurophysiologically, BMS patients can be placed in three distinct subgroups. The first subgroup, 50–65%, is characterized by peripheral small-diameter fibre neuropathy of intraoral mucosa. The second subgroup, 20–25%, consists of patients with subclinical lingual, mandibular or trigeminal system pathology that can be found with careful neurophysiologic examination but is clinically indistinguishable from the two others. The third subgroup, 20–40%, fits the concept of central pain that may be related to hypofunction of dopaminergic neurons in the basal ganglia (J€a€askelainen, 2012). The relative involvement of peripheral vs central neurogenic mechanisms in BMS pain has important implications especially concerning the efficacy of different treatment approaches. A randomized, controlled (RCT) double-blind study has investigated the effects of peripheral lingual nerve block on spontaneous burning pain in BMS (Gremeau-Richard et al, 2010). In one-half of the patients, the lingual nerve block relieved the pain, suggesting predominantly peripheral mechanisms acting in this subgroup. In the other subgroup, lingual nerve anaesthesia had no effects or even increased the pain intensity indicating, in line with earlier neurophysiologic evidence, that central mechanisms predominate in the pathophysiology of pain in a subgroup of BMS patients. Topical clonazepam treatment, which has been proved to be effective in BMS in an earlier RCT (Gremeau-Richard et al, 2004), tends to be more effective in the peripheral type of BMS than that in the central subgroup (Gremeau-Richard et al, 2010). Interestingly, patients belonging to the central BMS subgroup had more comorbid psychiatric problems such as depression and anxiety (Gremeau-Richard et al, 2010). Another study utilizing structured psychiatric interviews (Taiminen et al, 2011) has also recently reported significant psychiatric comorbidity in BMS and atypical facial pain patients. While dopaminergic hypofunction has been shown to be

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prevalent in these patient groups (J€a€askel€ainen et al, 2001; Hagelberg et al, 2003, 2004), it raises the possibility of shared vulnerability to both chronic neuropathic pain and depression due to deficiencies in dopamine-mediated topdown control in various brain circuits (J€a€askelainen, 2012). To conclude, it seems that clinically identical primary BMS condition may arise from either peripheral or central alterations, or both, within the trigeminal system or even in the somatosensory system more generally. In individual patients, distinct patterns can be defined with neurophysiologic, psychophysical and brain imaging techniques. In future, this may enable tailored treatment according to individual pathophysiological profiles. Recently, an interesting theory has been presented to reconcile the findings of somatosensory dysfunction in BMS with the characteristic clinical features linked to the condition, that is the overrepresentation of older women sufferers and the high prevalence of psychological disorders reported in BMS (Woda et al, 2009). According to the hypothesis, changes in adrenal steroid levels in chronic anxiety and stress disorders together with the drastic fall in gonadal steroid levels at menopause could result in neurodegenerative changes in the peripheral or central nervous system leading to neuropathic pain and other sensory symptoms in BMS. To our knowledge, this hypothesis has so far not been confirmed in any further studies. Finally, supporting the general concept of BMS as a neuropathic pain condition, there is a hypothesis linking the prevalent taste symptoms with BMS pain. According to this hypothesis, there could be deafferentation hyperactivity of the somatosensory part of the trigeminal system following the loss of central inhibition due to taste fibre damage in the chorda tympani nerve, a branch of the facial nerve carrying the taste sensations of the anterior two-thirds of the tongue (Bartoshuk et al, 1996b, 2005; Grushka et al, 2003; Eliav et al, 2007). Some of the clinical features of BMS also support an association between BMS and taste dysfunction: BMS patients frequently report taste disturbances, and typically, BMS patients report reduced burning during eating. Furthermore, the anterior part of the tongue, the area most commonly affected by BMS, has a large number of taste buds.

Taste sensation process and taste–pain interactions The sense of taste is a chemical sensation and activated by different non-volatile molecules on the receptor level (Breslin, 2013). The chemical signals are converted into electrical signals by specific taste receptor cells and transducted to the central nervous system, where the information is perceived and recognized as a distinct taste sensation (Lindemann, 1996; Breslin, 2001; Breslin and Spector, 2008; Yarmolinsky et al, 2009; Chaudari and Roper, 2010). Sense of taste detects at least five taste modalities: sweet, salty, sour, bitter and umami, activated by various different ligands. Most of the different taste receptor cells are packed in taste buds and located at the outer parts of the papillae (foliate, fungiform, circumvallate) or in the other parts of the digestive tract mucosa such as the soft palate,

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larynx, pharynx and epiglottis (Breslin and Spector, 2008; Cowart, 2011). However, taste receptors may be found also in the gut or nasal epithelium (Rozengurt and Sternini, 2007; Finger and Kinnamon, 2011; Trivedi, 2012). It is estimated that there are around 5000 tasted buds in the human oral cavity (Chaudari and Roper, 2010), but the range can vary a lot. Four different types of taste receptors are located in taste buds (Housle et al, 2009). The taste sensations are mediated from taste receptors to the brain by the seventh, ninth and tenth cranial nerves (Housle et al, 2009). Facial nerve (VII) mediates the taste from the anterior part of the tongue, glossopharyngeal nerve (IX) from the posterior part of the tongue and vagal nerve (X) from the larynx. The nerve impulses are transmitted via nucleus of the tractus solitarius (NTS) and thalamus to insular cortex, where the taste sensation is recognized and interpreted in the primary and secondary taste centres. In 1901, H€anig described a theory of ‘tongue map’ based on heterogeneity of the receptor fields in the mouth. However, it is now known that taste receptors all around the tongue react to all kinds of different taste-active molecules (Breslin, 2001; Chandrashekar et al, 2006). Individual sensitivity to different tastes varies. Ageusia is usually specific for one taste, and seldom for combinations of tastes. Ability to taste bitter compounds such as phenylthiocarbamide (PTC) and its chemical relative propylthiouracil (PROP) shows a bimodal distribution that distinguishes two phenotypes in humans, sensitive and insensitive. The degree of human taste sensitivity for PTC, and partly also for PROP, has been shown to be explained from genetic perspective such as TAS2R38 taste receptor genotype (Kim et al, 2003; Kim and Drayna, 2005; Wooding et al, 2004; Bufe et al, 2005; Sandell and Breslin, 2006, 2010). Taste sensitivity may decrease with ageing, although the change may be smaller than that in the individual’s ability to smell (Cowart et al, 1997; Seiberling and Conley, 2004; Imoscopi et al, 2012). Ageing affects ability to taste bitter and sour more than sweet and salty (Methven et al, 2012). Injuries to NTS may result in taste disorders (Hendry et al, 2012), and head injury and radiation therapy may change the taste perception. Saliva has an important role in the taste perception process, and hyposalivation can cause altered taste sensation. Saliva protects the taste receptors, for example from drying. The main role of saliva in taste perception is to solve taste substances from non-liquid foods and to transport the dissolved taste substances to the taste receptors (Carpenter, 2013). Saliva is an electrolytic fluid; however, saliva has no taste as taste receptors usually adapt to the salivary environment (Matsuo, 2000). Some salivary constituents are able to modify taste perception; for example, increase in salivary bicarbonate can decrease the intensity of sour tastes (Matsuo, 2000). There is evidence that gustatory and trigeminal pathways interact. Anatomical studies have revealed trigeminal projections on gustatory neurons of the NST (Felizardo et al, 2009; Braud et al, 2012). Several studies have investigated trigeminal modulation of gustatory processing, showing that trigeminal somatosensory stimulation of the oral cavity can reduce gustatory transmission and the

perceived intensity of some tastants (Lawless and Stevens, 1984; Karrer and Bartoshuk, 1995; Wang et al, 1995; Simons et al, 2002; Boucher et al, 2003). Less is known about the effect of oral gustatory stimulus on trigeminal transmission (Boucher et al, 2014). Some early studies have reported on inhibitory interactions between oral sensorial and taste functions (Halpern and Nelson, 1965). Certain tastants, particularly sucrose, have been shown to reduce oral capsaicin-induced lingual pain sensations (Sch€obel et al, 2012). In line, it has been shown that sucrose reduces overall pain experience in infants (Miller et al, 1994; Blass and Watt, 1999; Anseloni et al, 2005). While taste disturbances frequently accompany pain in BMS, taste and pain interactions could potentially be involved in BMS pathophysiology.

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Taste dysfunction in BMS The prevalence of taste disturbances in the general adult population has been reported to vary from 0.6% to 11% (Thorstensson and Hugoson, 1996; Cowart et al, 1997; Hoffman et al, 1998; Bergdahl and Bergdahl, 2002; Cowart, 2011). Several clinical conditions or treatments such as otitis media, head and neck cancer, head trauma, middle ear surgery or tonsillectomy can cause taste nerve damage and taste dysfunction (Berteretche et al, 2008; Cowart, 2011; Bartoshuk et al, 2012). Taste disorders may also be a symptom of more widespread polyneuropathy (Heckmann et al, 2009). In one study, taste deficits were found to be related to dental nerve deafferentation: the greater the number of deafferented teeth, the higher the electrogustatometric thresholds (Boucher et al, 2006). Many patients with documented taste deficits fail to notice the loss of taste (Heckmann et al, 2009; Bartoshuk et al, 2012). Mild damage to one of the taste mediating nerves can lead to even intensification of both taste and tactile sensations, whereas damage to both chorda tympani and glossopharyngeal nerve leads to oral sensory loss (Bartoshuk et al, 2012). Prevalence of taste disturbances in BMS patients Taste disturbances, such as alteration (distortion) in taste perception and/or a persistently altered taste (dysgeusia) or phantom tastes, are often reported by BMS patients. Taste disturbances have been reported in 11–69% of the patients (Grushka, 1987; Bergdahl and Bergdahl, 1999; Forssell et al, 2012). From those patients, 67–88% report phantom tastes, and 59–67% report dysgeusia (Grushka, 1987; Grushka and Sessle, 1988). Phantom tastes reported include bitter, metallic or both (Grushka, 1987; Grushka and Sessle, 1988). Alterations in taste perception of salt, sweet, sour and bitter have also been found; sour and bitter can taste stronger, sweet weaker, and salt either stronger or weaker than before (Grushka, 1987). BMS and taste perception Psychophysical studies on taste detection thresholds and taste intensity scaling in BMS patients have corroborated the clinical results of subjective taste disturbance. In BMS, the detection thresholds for salty and bitter stimuli have been reported to be higher (Siviero et al, 2011) and Oral Diseases

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those for pure sweet stimulus significantly higher compared to control subjects (Grushka et al, 1986; Siviero et al, 2011). Difficulties in identification and recalling of taste quality have also been reported in BMS (Grushka and Sessle, 1988). In one study utilizing taste strips, patients with BMS were found to be significantly less sensitive than controls for different taste solutions such as sucrose, citric acid, sodium chloride and quinine hydrochloride in water (Just et al, 2010).

Hypotheses linking taste dysfunction and pain in BMS Chorda tympani hypofunction Bartoshuk et al (1996a) were the first to suggest a link between BMS and taste disorders and presented some evidence to support this. They showed that anaesthesia of the chorda tympani nerve intensified the burning pain evoked by capsaicin on the contralateral tongue (Tie et al, 1999), suggesting that taste input may normally inhibit trigeminal input centrally. The first argument presented to support this so-called chorda tympani hypothesis in BMS was the findings of the study by Formaker et al (1998) showing that topical anaesthesia of the mouth intensified the oral burn in about a third of the BMS patients; that is, topical anaesthesia may release peripheral inhibition of central sensory pathways in BMS. Dysgeusia symptoms were more likely to decrease after application of topical anaesthesia, suggesting that the origin of dysgeusia is due to the activity of peripheral gustatory afferents, or in the imbalance between somatosensory and gustatory afferent inputs. However, contradictory findings have been presented by Just et al (2007), who in their study on patients undergoing middle ear surgery showed that chorda tympani damage was associated with higher capsaicin thresholds; that is, pain sensitivity was reduced after injury of this nerve. Most likely cause of this hypoalgesia would be damage to small afferent nociceptive fibres travelling in the chorda tympani nerve. Indeed, in line with this, it has been shown that chorda tympani fibres respond not only to gustatory but also to thermal and mechanical stimuli (Robinson, 1988). If this is the case, it questions the original chorda tympani hypothesis on gustatory afferent inhibition of the trigeminal somatosensory system and its release after specific taste fibre damage. Instead, the trigeminal intraoral burning pain would result from thermal or nociceptive small fibre deafferentation also after chorda tympani or lingual nerve injuries, similar to neuropathic pain elsewhere in the body. Several studies using electrogustatometry (EGM) to measure the electrically elicited taste and somatosensory ‘tingling’ detection thresholds of the tongue have demonstrated taste system hypofunction in primary BMS, giving support to the hypothesis that BMS is related to taste and chorda tympani dysfunction. In the first of these studies, Eliav et al (2007) compared the electrical taste and tingling thresholds of BMS patients to those of patients having secondary burning mouth symptoms and healthy controls. The taste detection thresholds and the mean electrical taste/tingling thresholds ratio were both significantly higher in BMS patients compared to the other two groups. While the taste detection thresholds showed large intersubject variability, Oral Diseases

the authors recommended the use of electrical taste/tingling detection thresholds ratio as a sensitive clinical diagnostic tool. Their findings also suggested that unilateral chorda tympani hypofunction is sufficient to produce a bilateral burning sensation, probably due to central sensitization processes. Also in the study by Nasri-Heir et al (2011), the electric taste/tingling detection thresholds ratio was found to be significantly higher in BMS compared to controls, and the difference was even more significant in patients who had suffered from BMS for a longer time. Finally, Gremeau-Richard et al (2010) and Just et al (2010) found increased electric taste thresholds in BMS. In addition, the findings of the latter study suggested that also pain sensitivity is decreased in BMS, because the detection threshold for capsaicin irritation was elevated in BMS patients compared to controls. This supports the above-discussed focal, predominantly small fibre damage in BMS covering both Ar class nociceptors and cool afferents as well as Ar taste afferents and, to a lesser extent, also unmyelinated trigeminal C-fibres or large Ab afferents. The distinct profile of (small) fibre injury may have an effect on the generation of persistent pain after nerve damage, similarly as happens in thermal grill illusion due to non-physiological sensory input (Thunberg, 1896). In BMS, predominant loss of, for example, innocuous cool afferent input may thus result in distorted somatosensory perception that is interpreted in the brain as burning pain, analogously as has been suggested to occur in thermal grill illusion and central pain (Craig, 2002). A very recent study by Boucer et al (2014) questions the interactions between the gustatory and pain systems in BMS pathophysiology. In an animal model using rats, bilateral transection of chorda tympani did not enhance capsaicin avoidance, arguing against the hypotheses that gustatory nerve damage releases inhibition of trigeminal nociceptive pathways. Further studies are needed to ascertain whether the animal model used is a valid model for human BMS pain. At the moment, it seems that intraoral and intranasal (Siviero et al, 2011) small fibre afferents, regardless of their specific function, are damaged in the majority of BMS patients, and this peripheral small fibre neuropathy can lead to persistent neuropathic pain, in which both central sensitization and deficient top-down inhibition play a role. Density of fungiform papillae Bartoshuk et al (1996a) have suggested also other links between taste and pain sensations. They reported that the peak oral pain correlated with the density of fungiform papillae in BMS and further argued that most of the BMS patients are supertasters; that is, individuals with the highest density of fungiform papillae and along with this also have the largest density of pain innervation (Bartoshuk et al, 1999). According to them, individuals genetically endowed with a large number of fungiform papillae might be more disposed to develop BMS because of the greater potential of loss of inhibition in case of damage to the chorda tympani (Bartoshuk et al, 1994, 1996a). However, contrary to the hypotheses, no significant difference in the density of fungiform papillae between BMS patients and controls was found in another study (Nasri-Heir et al, 2011).

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Taste phantoms Anaesthesia or damage of chorda tympani has been shown to intensify tastes evoked from the contralateral rear of the tongue, the area innervated by the glossopharyngeal nerve (Kveton and Bartoshuk, 1994; Lehman et al, 1995) supporting the evidence for central inhibitory connections between the chorda tympani and glossopharyngeal nerves. It has been suggested that taste phantoms are the result of localized taste damage releasing the inhibition normally occurring between the central projection areas of different taste nerves, as about half of the subjects developed taste phantoms when the chorda tympani was anaestesized (Yanagisawa et al, 1998; Bartoshuk et al, 2005). Hormonal factors Bartoshuk et al (1996a) argued that the ability to taste bitter seems to be reduced following menopause (Weiffenbach et al, 2000) and also in BMS patients. This reduction could act like taste damage and result in central loss of inhibition to pain as well as produce the oral pain and other sensory symptoms in BMS owing to the loss of oestrogen (Grushka and Bartoshuk, 2000; Bartoshuk et al, 2005). However, the role of hormones in taste alteration in relation to BMS has not been directly studied, but taste alterations in general have been related to changes in women’s hormonal status. Postmenopausal women, for example, seem to have reduced perception of sucrose (Dangore-Khasbage et al, 2010). In a study using aged female rats as a model for human BMS condition (Boucer et al, 2014), ovariectomized rats exhibited a significant increase in capsaicin sensitivity, suggesting that a reduction in circulating gonadal hormones may contribute to the aetiology of BMS. Other factors Based on a retrospective analysis of 142 BMS patients with associated taste disturbance, Femiano et al (2008) reported that a majority of the patients used drugs or had pathologies with known interference with taste perception and proposed this to be the cause of taste deficits. The same study group has also suggested hypothyroidism to cause a reduction in taste perception in BMS due to the role of thyroid hormones in the maturation of fungiform papillae (Femiano et al, 2006).

Xerostomia, hyposalivation and salivary composition Much confusion has occurred in the use of the terms ‘xerostomia’ and ‘hyposalivation’. Xerostomia is defined as a sensation of dry mouth, whereas hyposalivation means a measurable decrease in amount of saliva. There is no clear relation between xerostomia and hyposalivation although the most common reason for xerostomia is hyposalivation. Hyposalivation and xerostomia Many studies have looked at possible differences in salivary flow rate in BMS patients compared to controls. Although many BMS patients complain the feeling of dry mouth, most of the studies have shown that the salivary

flow rate in BMS patients is the same as in controls (Hershkovich and Nagler, 2004; Granot and Nagler, 2005; de Moura et al, 2007). However, recently, in contrast to Boras et al (2010), Lee et al (2015) and Poon et al (2014) reported decreased unstimulated salivary flow rates in primary BMS patients compared to those of healthy controls, however, without any differences in stimulated salivary flow rates. The prevalence of ‘true’ xerostomia in BMS is not clear due the above-mentioned unclarity in the use of the terms and the subjective nature of the sensation. The prevalence figures have varied between 39 and 66% (Grushka, 1987; Gorsky et al, 1991; Bergdahl and Bergdahl, 1999). Due to sensory disturbances, BMS patients probably report more xerostomia not linked to hyposalivation than xerostomia patients in general.

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Salivary composition Altered salivary composition may play a role in the feeling of dry mouth. Tammiala-Salonen et al (1993) found lower total salivary protein concentration in BMS patients compared to controls; however, the definition of BMS in this study is not clear. Some attention has been paid to salivary gland mucins (MUCs), which are important secreted or membranebound glycoproteins. Secreted MUCs lubricate, cover and protect the oral mucosa, and therefore, they are considered as the first line of defence for epithelial tissues in the oral cavity. The main MUCs in saliva are MUC7 and MUC5b. Watery MUC7 mainly protects the tooth and mucosal surfaces from bacterial binding, whereas the gel-forming MUC5b mainly contributes to oral cavity hydration, lubrication and moistening. Membrane-bound MUC1 is in turn found on cell surfaces of salivary glands and oral epithelial cells. It has a protective role, for example, by participating in mucus gel formation. So far, the data concerning MUCs in BMS are scant. The only study on BMS patients’ oral mucosal epithelium showed increased MUC1 expression (Kho et al, 2013 ). Studies concerning other components of saliva in BMS patients have given conflicting results. One reason may be, for example, the variation in the definitions of BMS and differences in salivary collection methods. Some studies have reported changes in salivary composition, but it is not clear whether subjects included in their BMS group presented a group of primary BMS patients (Nagler and Herskovich, 2004; Hershkovich and Nagler, 2004; Granot and Nagler, 2005). The patients had increased the levels of salivary Na, total protein, albumin, IgA, IgG, IgM and lysozyme without any differences in salivary flow rates (Hershkovich and Nagler, 2004; Nagler and Herskovich, 2004). de Moura et al (2007) reported higher K, Cl and P concentrations and lower total protein concentrations in BMS patients compared to controls without any changes in salivary flow rate. As BMS may reflect a condition involving the peripheral and/or central nervous system, some attention has been paid to salivary neuropeptides. Calcitonin generelated peptide (CGRP) is a vasodilatator and has a role in the development of neurogenic inflammatory pain. Zidverc-Trajkovic et al (2009) reported decreased levels of Oral Diseases

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CGRP in BMS patients and suggested based on this that trigeminal nerve degeneration may be the underlying cause of BMS. Oral mucosa is exposed all the time to different irritants and prone to infections and inflammations as well as allergic reactions. Cytokines play a significant role in inflammatory and immune responses. Boras et al (2006, 2010) studied salivary cytokines and neuropeptides in saliva and serum of BMS patients. No significant differences were found in salivary IL-6, TNF-a, substance P, neurokinin A or CGRP between BMS patients and controls. However, significantly decreased serum neurokinin A was found, which according to the authors may reflect an inefficient dopaminergic system.

Conclusions and future scenarios Today, the most commonly used classification for research separates primary BMS from secondary burning intraoral sensation caused by specific local or systemic factors (Markman and Eliav, 2013). The use of this classification has been of paramount importance for the progress made in the understanding of the pathophysiology of primary BMS. However, the definition may be subject to changes when new information emerges. For example, the majority of primary BMS patients, carefully diagnosed according to the now-established clinical criteria, seem to suffer, in fact, from neuropathic pain arising from trigeminal system lesions at various levels along the neuraxis. As presented in the previous sections of this review, multiple neuropathic aetiologies for ‘primary’ BMS have been demonstrated by several accurate and sensitive diagnostic measures. Yet, the clinical examination of the carefully diagnosed patients has been normal despite clear subjective symptoms and laboratory confirmation of a neuropathic pain condition. Another source of confusion is how to adequately diagnose hyposalivation, which according to the definition excludes the diagnosis of primary BMS. Many studies have used the amount of stimulated saliva as a differential diagnostic measure. In some recent studies, however, primary BMS patients were reported to have a decreased unstimulated salivary flow rate without any differences in stimulated salivary flow rate. It is important to note that this finding gives new reason to consider the diagnosis of hyposalivation as exclusion criteria. Furthermore, all published studies do not necessarily comply with the current definition, or the study material has been insufficiently described and, thus, does not allow the reader to decide on the correctness of the inclusion criteria. All the above-mentioned make the interpretation of the current literature on BMS pathophysiology challenging. The present review sought to focus on studies with well-defined primary BMS patients and, in cases with uncertainty, to discuss this. For the progress of the research on BMS pathophysiology, it is of major importance that future studies define their study materials in detail. The most compelling evidence concerning BMS pathophysiology comes from studies on the somatosensory system in BMS which has been investigated using several relevant, objective, neurophysiologic and psychophysical methods, as well as neuropathological, neurobiological Oral Diseases

and functional brain imaging techniques, and been performed on well-defined primary BMS patients materials. These studies have provided convincing evidence for neuropathic involvement in the BMS pain pathophysiology and suggested that BMS is a subclinical trigeminal neuropathic pain that may arise from a minor, partial nerve trauma, pure peripheral or more generalized small fibre neuropathy, or a more central trigeminal system lesion including deficiencies in top-down pain modulation. Specific damage to thermal and gustatory Ad fibres of the oral mucosa or more universal focal small fibre neuropathy with an imbalance in the amount of Ad fibre damage in relation to C-fibre damage might give an explanation for the generation of spontaneous burning pain in BMS patients. It could be hypothesized that when the imbalanced small fibre information, whether due to Ad fibre damage within the intraoral somatosensory or gustatory system or both, arrives to the central nervous system, the brain could interpret this distorted information as pain, similarly as happens in the thermal grill illusion (Thunberg, 1896; Craig and Bushnell, 1994). tQST profiles of BMS patients support this hypothesis, but direct verification of the disproportionate involvement of different small fibre classes by means of specific immunohistochemical stainings, for example, for the many distinct transient receptor potential (TRP) ion channels from tongue mucosal biopsies is still missing. In particular, peripheral trigeminal mechanisms have been investigated in several studies, but in most cases using psychophysical methods such as tQST, which are subjective and rely on good patient co-operation. In future studies, the use of contact heat-evoked potentials (CHEP) or laser-evoked potentials (LEP) could offer more objective methods to study the small fibre function. Furthermore, only a few studies have focused on the central mechanisms of BMS pain, and the relative role of peripheral vs nervous system dysfunction in BMS pain pathophysiology is not yet fully understood. Studies on taste sensation in BMS are scarcer, even if the association between BMS and taste dysfunction has been documented in clinical studies for a long time. Older studies on taste dysfunction in BMS suffer from methodological problems, especially regarding diagnosis and classification of patients into primary and secondary BMS. Some of the studies have been published only as abstracts giving little or no information on the selection of patients and on the details of the methods used. There are only a few psychophysical studies on taste detection thresholds, although they consistently show deficiencies in taste perception and in taste intensity scaling. Most of these studies have used less precise whole mouth techniques; only one has used taste strips, and there are no studies comparing different methods as to their clinical utility, repeatability or reliability. The main hypotheses concerning the interaction between pain and taste in BMS suggest that gustatory nerve damage contributes to BMS pain by disinhibiting trigeminal nociceptive transmission. This hypothesis has received support from several studies on reliably defined BMS patient materials which have used electrogustatometry to measure the EMG thresholds for taste perception. These studies have consistently demonstrated hypofunction

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of chorda tympani. However, the method yields large intersubject variability both in somatosensory tingling detection and in taste detection thresholds, which may decrease the reliability and sensitivity of the electrogustatometric method, and complicates the interpretation of the results. Furthermore, the interaction between gustatory and pain systems has been questioned in a recently published study, and the soundness of the original chorda tympani hypotheses may also be questioned by the findings that chorda tympani nerve contains in addition to gustatory afferents also thermal and mechanosensitive sensory afferents. These contradictory findings give ground for new studies on whether somatosensory and gustatory interactions or their specific psychophysical and neurophysiologic profiles are critically involved in BMS pathophysiology. Only a few studies on salivary factors in BMS are published in which the criteria of primary BMS are fulfilled. Most of the earlier studies have not shown any differences in the salivary flow rate in BMS patients compared to that of controls. A reason for the sensation of dry mouth may be altered composition of saliva, for example salivary moisturizing properties that are mainly based on mucins secreted by minor salivary glands. As the role of minor glands in the perception of dry mouth is crucial, future studies should focus more on salivary composition, especially on unstimulated and minor salivary gland secretions. So far, only one study has investigated the pain perception within lingual nerve distribution together with gustatory sensitivity using capsaicin threshold testing and taste tests in a group of primary BMS patients (Just et al, 2010). The results of that study suggested that both peripheral trigeminal pain sensitivity and gustatory sensitivity are decreased in primary BMS, which indicates simultaneous damage to somatosensory and gustatory small fibres. We are not aware of any studies, in which all aspects of primary BMS, sensory and taste dysfunction as well as xerostomia would have been studied in the same patient material. These types of studies with detailed and extensive profiling of the intraoral dysfunction could provide crucial information on the relative importance of the different potentially pathogenetic factors in the pathophysiology and symptomatology of primary BMS. This kind of approach would also elucidate whether different profiles of disturbances will give rise to distinct clinical expressions or different treatment responses. In future, this may enable tailored treatment according to individual pathophysiological profiles. Acknowledgements This work was supported by the Academy of Finland (MA. Sandell 252005).

Author contributions H. Forssell led the review team. M. Kolkka-Palomaa reviewed the literature, wrote the first draft of the manuscript and co-ordinated the writing process. H. Forssell, M. Sandell, S. J€a€askel€ainen, T. Teerijoki-Oksa and M. Laine reviewed the literature, revised and reviewed the full manuscript and approved the submitted version.

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