Case Report Glossodynia from Candida-Associated Lesions, Burning Mouth Syndrome, or Mixed Causespme_

Pain Medicine 2010; 11: 856 860 Wiley Periodicals, Inc. PAIN & AGING SECTION Case Report Glossodynia from Candida-Associated Lesions, Burning Mouth Syndrome, or Mixed Causespme_861 856..860 Haruhiko Terai, DDS, PhD, and Masashi Shimahara, DDS, PhD Department of Oral Surgery, Osaka Medical College, Osaka, Japan Reprint requests to: Haruhiko Terai, DDS, PhD, Department of Oral Surgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-shi, Osaka, 5698686 Japan. Tel: 072-683-1221; Fax: 072 6813723; E-mail: ora007@poh.osaka-med.ac.jp. Abstract Objective. Candida-associated lesions (CALs) and burning mouth syndrome (BMS) may induce glossodynia without objective manifestations. We investigated patients with glossodynia to examine the relationship between CAL and BMS. Patients and Methods. A visual analog scale was used to divide 95 patients with glossodynia into three groups according to intensity of pain at rest and when eating. Group A was the functional pain group; group B was the nonfunctional pain group; and group C was a mixed pain group. Antifungal treatment was scheduled for patients with suspected Candida infection by clinical, mycological, or cytological criteria. Results. Culture tests and direct examination results indicated that group A had high Candida positivity (73.0% by culture and 59.5% by direct examination), and showed a good response to antifungal treatment (75.7%). Antifungal treatment was not useful in group B. This was supported by a low Candida infection rate, as determined by direct examination (3.1%). For group C, Candida positivity and antifungal treatment effectiveness were between groups A and B. Furthermore, six patients in group C showed complete remission of functional pain by antifungal treatment only. Favorable outcomes were obtained for 23 patients (10 in group B and 13 in group C), who received antidepressant treatment. Conclusion. These results suggested that glossodynia was Candida-associated in group A, and BMSinduced in group B, while group C contained patients with both CAL and BMS. Key Words. Glossodynia; Burning Mouth Syndrome; Candida-Associated Lesion Introduction Burning mouth syndrome (BMS) is characterized by burning and/or painful sensations in the mouth and an absence of mucosal lesions or any other clinical signs. It can occur at any site within or surrounding the oral cavity, with the tongue being the most frequently affected site. The condition is most prevalent in post-menopausal women, with up to 40% thought to be affected [1]. Conditions that have been reported to be associated with BMS include mechanical irritation, chronic anxiety or depression, nutritional deficiency, diabetes, changes in salivary function, dentures, candidal infection, parafunctional habits, and allergy [2 6]. Predisposing factors for candidiasis are almost identical to those for BMS, including nutritional deficiency, diabetes, and changes in salivary function. Therefore, the multifactoral etiologies of glossodynia are a topic of debate. The causes of glossodynia might be interrelated, and a differential diagnosis is difficult in cases without obvious clinical findings. Usually, glossodynia associated with BMS disappears or remits with eating [7,8]. We found, however, that Candida-associated lesions (CALs) can explain the high association of atrophic tongue with pain while eating, even when the atrophic change is slight and the tongue is almost normal appearance [9]. Previously, we reported the differential diagnosis of BMS and CALs using a visual analog scale (VAS) that assessed the intensity of tongue pain while eating and at rest [10]. We hypothesize that glossodynia associated with Candida is different from BMS, and for a variety of CALs, functional pain (i.e., pain during eating) is a sign of inflammation. Previously we found that patients with glossodynia could be divided by the VAS into three groups according to intensity of pain at rest and when eating: a functional pain group, a nonfunctional pain group, and a 856

Burning Mouth and Candida in Glossodynia mixed pain group. The results of mycological examinations and antifungal treatment suggested that in the functional pain group, glossodynia was Candida-associated, in the nonfunctional pain group it was BMS-induced, and in the mixed pain group, it was caused by mixed CAL and BMS conditions. These conclusions were based on the results of mycological examinations and antifungal treatment. This study includes additional cases and the results of antidepressant treatment as well as antifungal treatment. We particularly focused on glossodynia cases in which pain might be caused by BMS, and by both CAL and BMS, to test our previous hypothesis. Patients and Methods This study examined 95 patients who were referred to our department between April 2003 and March 2008 with a chief complaint of glossodynia. Patients with distinct atrophic tongue, ulceration or other objective changes of the tongue were excluded. Intensity of glossodynia was evaluated using a VAS ranging from 0 to 100 (no pain to extreme pain). The patients were divided into three groups according to VAS score at rest and while eating. Group A (functional pain group, n = 37) comprised subjects who experienced no pain at rest, or whose VAS score while eating was more than double that at rest. This group included 20 patients who experienced no tongue pain at rest. Group B (nonfunctional pain group, n = 32) comprised subjects who experienced no pain while eating, or whose VAS score at rest was more than double that while eating. This group included 19 patients who experienced no tongue pain while eating. Group C (n = 26) comprised subjects whose VAS scores were almost identical while eating and at rest (Table 1). Thus, group A contained patients whose tongue pain worsened while eating, group B contained subjects whose pain decreased while eating, and group C contained subjects whose pain level remained unchanged at rest and while eating. The following information was obtained for each patient: age at presentation, gender, duration of glossodynia, complete medical history, and prior treatment or medication for glossodynia. In addition, complete blood count, blood glucose, serum iron, vitamin B12, and folic acid levels were measured. Samples were collected for mycological examination by firmly swabbing the surface of the site where pain was experienced. Culture was performed on Sabouraud s agar medium at 35 C for 3 days. The same samples were subjected to direct cytological examination (Cyto Quick staining system, Mutou Pure Chemical Co. Tokyo), as described [9]. The presence of pseudohyphae in exfoliated epithelial cells constituted a positive cytological finding of candidiasis. An antifungal agent was administered to patients who were suspected of having a candidial infection on the basis of clinical, mycological, or cytological examination. All 37 patients in group A, 17 of 32 patients in group B, and 21 of 26 patients in group C were administered treatment. As the treatment, miconazol gel (25 mg; four times a day) was prescribed. Patients were instructed to drop the gel onto the tongue, spread over the entire inside of the mouth and hold as long as practicable, and then to swallow. Antifungal treatment was continued for at least 2 weeks. After antifungal treatment, improvement in glossodynia was evaluated based on VAS score while eating for patients in group A, VAS score at rest for subjects in group B, and a higher VAS score while eating and at rest for patients in group C. A total of 23 patients (10 in group B and 13 in group C) whose glossodynia failed to improve with antifungal treatment received treatment with the selective dopamine D2 antagonist sulpiride (150 mg/day) for 4 8 weeks. Results Clinical Features Table 1 Details of groups Group A (functional pain group): N = 37; 10 men and 27 women median age: 69 years; mean age:67.3 15.3 years; range: 29 82 years old, included 20 cases of no tongue pain at rest Group B (nonfunctional pain group): N = 32; 4 men and 28 women median age: 60 years; mean age:60.5 12.3 years; range: 43 82 years old included 19 cases of no tongue pain while eating Group C (mixed pain group): N = 26; 4 men and 22 women median age: 65 years; mean age: 64.2 15.5 years; range: 24 82 years old The sex and age distributions of the three groups were almost identical, with most patients being older women (Table 1). Disease duration was 4.2 5.3 months in group A, 7.1 8.1 months in group B, and 8.1 9.9 months in group C. Medical histories and laboratory tests revealed that 19 patients in group A (51.4%), 7 in group B (21.9%), and 8 in group C (30.8%) had predisposing factors for candidiasis, such as diabetes mellitus, systemic steroid treatment, or anemia. The remaining patients did not have these factors. Group A was significantly more likely to have predisposing factors than group B (P < 0.05, Fisher s exact test) (Table 2). Some patients had previously visited other clinics and were prescribed prior medication for glossodynia, including topical steroids (10 in group A, 10 in group B, and 6 in group C), or gargling with povidone iodine (eight in group A, five in group B, and two in group C). However, these treatments had failed to resolve their symptoms. 857

Terai and Shimahara Table 2 Clinical features Disease Duration (Months) Pre-Disposing Factors for Candidiasis* Group A 1 24 Diabetes mellitus: 4 Average: 4.2 5.3 Systemic steroids: 5 Antibiotics: 3 19 Anemia: 3 Others: 4 None: 18 Group B 1 36 Diabetes mellitus: 3 Average: 7.1 8.1 Antibiotics: 2 7 Anemia: 2 None: 25 Group C 1 36 Diabetes mellitus: 4 Average: 8.1 9.9 Systemic steroids: 3 8 Malignancy: 1 None: 18 * Significant difference in having rate of pre-disposing factors between Group A and B: P < 0.05 (Fisher s exact test). Culture Test and Direct Cytological Examination By culture test, Candida species were isolated from 27 (73.0%) samples from group A, 8 (25.0%) from group B, and 11 (42.3%) from group C. Candida albicans was isolated from almost all these samples (Table 3). By direct examination, fungal pseudohyphae were found in 22 (59.5%) samples from group A, 1 (3.1%) from group B, and 6 (23.1%) from group C with a significant difference between the results for group A and those of the other groups (Fisher s exact test) (Table 4). Antifungal Treatment Outcomes Table 3 Group A n = 27 B n = 8 C n = 11 Candidia species identified by culture Candidia spp C. albicans 21 C. albicans, C. glabrata 2 C. albicans, C. tropicalis 2 C. albicans, C. parapsilosis 1 C. glabrata 1 C. albicans 8 C. albicans 8 C. albicans, C. glabrata 1 C. glabrata 1 C. tropicalis 1 Two to four weeks after the start of antifungal treatment, patient improvement in group A (n = 37/37) was complete remission in 22 patients, marked improvement in six, improvement in four, and no improvement in five. Moreover, for 75.7% of patients in this group, glossodynia experienced while eating either disappeared or markedly improved. Glossodynia experienced at rest also improved in those patients who responded to treatment. In group B (n = 17/32), no improvement was observed in 15 patients, and benefit was seen in 2 patients. Thus, the antifungal treatment was not considered effective in this group. In group C (n = 21/26), complete remission of both functional and non-functional pain was seen in five patients, complete remission of functional pain only was observed in six, marked benefit was seen in one patient, benefit was seen in two patients, and seven patients experienced no improvement (Table 5). Table 4 Results of culture test and direct cytological examination Culture Test (Candida Species) Direct Cytological Exam. (Pseudohyphae) Group + - + - A 27 10 22 15 ** B 8 24 1 31 C 11 15 6 20 Significant difference: * P < 0.05; ** P < 0.01 (Fisher s exact test). ** * 858

Burning Mouth and Candida in Glossodynia Table 5 Outcome of antifungal treatment Improvement of VAS No Change <50% Benefit 50 80% Marked Benefit 80% Complete Remission 100% Group A (n = 37/37) 5 4 6 22 Group B (n = 17/32) 15 2 Group C (n = 21/26) 7 2 1 11 (6)* Group A: Improvement of VAS pain during eating. Group B: Improvement of VAS on pain at rest time. Seventeen were Candidia positive and/or reported pain during eating. Group C: Improvement of VAS on worse one among both values. Twenty-one were Candidia positive and/or reported greater pain during eating than at rest. * 6 patients experienced complete remission of pain only during eating. Antidepressant Treatment Outcomes Of the 15 patients in group B for whom antifungal treatment had no effect, 10 received sulpiride (150 mg/day). After 4 6 weeks of treatment, two were in complete remission, three showed marked benefit, and two showed benefit. In group C, 13 patients had no effect with antifungal treatment, or showed complete remission of glossodynia only while eating. These patients received antidepressant treatment, and after 4 6 weeks, six showed marked benefit, and three showed benefit, with favorable outcomes for nonfunctional, as well as functional pain (Table 6). Discussion Oral candidiasis is a relatively common and well-known infection; however, this disease is incompletely understood, and various classification systems have been proposed to describe the clinical forms of the lesion [11,12]. BMS is a multifactoral condition with the tongue being the most frequently affected site, and candidiasis has been reported as one of the etiologic factors [2 4]. Osaki et al. [6] reported that candidiasis in conjunction with hyposalivation may induce pain in the tongue without the manifestation of objective abnormalities. However, no criteria except the clinician s subjective analysis are available for the normal tongue. Indeed, mild atrophic cases may show an almost normal tongue on first examination. In several of these cases, we realized that the tongue had mild atrophic candidiasis only after comparing pre- and post-antifungal treatment photographs [9]. In a previous study [10], we suggested that glossodynia was Candida-associated in a functional pain group, and BMS-induced in a nonfunctional pain group. We suggested that a mixed pain group contained cases of both CAL and BNS. The aim of the present study was to confirm this model, and investigate antidepressant treatment in addition to antifungal treatment. The clinical features of the three groups in this study were similar, including age and sex distribution, disease duration and prior medication for tongue pain. However, the prevalence of pre-disposing factors for candidiasis differed in the functional and nonfunctional pain groups. Furthermore, the results of culture tests and direct examination indicated that the functional pain group had a higher prevalence of Candida infection than the other groups. Functional pain (pain during eating) is considered an important sign of inflammation. The favorable outcomes for antifungal treatment in the functional pain group supported glossodynia in this group were from Candida infection. In the nonfunctional pain group, the antifungal treatment was not effective, but about half of the patients showed Table 6 Outcome of sulpiride treatment* Improvement of VAS No Change <50% Benefit 50 80% Marked Benefit 80% Complete Remission 100% Group B (n = 10) 3 2 3 2 Group C (n = 13) 4 3 (2) 6 (4) * Patients administered sulpiride were either partial or complete nonresponders to antifungal treatment. All 10 patients were antifungal nonresponders. 2 of 3 patients were antifungal partial responders (i.e., pain remission only during eating). 4 of 6 patients were antifungal partial responders (i.e., pain remission only during eating). 859

Terai and Shimahara glossodynia improvement after additional treatment with sulpiride, a selective dopamine D-2 antagonist, with antipsychotic and antidepressant activity [13 15]. Our results suggest that the glossodynia in the nonfunctional pain group might be associated with BMS. In the mixed pain group, six patients experienced complete remission for functional pain only. However, favorable outcomes for nonfunctional pain were obtained after antidepressant treatment. Although these cases were few, some patients in group C might have glossodynia caused by both CALs and BMS. Mignogna et al. [16] reported an average delay of 34 months from the onset of symptoms to a definitive diagnosis of BMS, with an average of 3.1 medical and dental practitioners per patient over this period initially misdiagnosing BMS. Candidiasis and nonspecific stomatitis were the most frequent incorrect diagnoses. Glossodynia, however, may not be induced by only one etiology, as suggested by our results. For example, some patients with glossodynia caused by CAL may experience a period in which CAL is misdiagnosed as other lesions, and may subsequently suffer from BMS. In other cases, CALs may occur after BMS. Distinguishing between the two causes is difficult because the clinical features of these two disorders (e.g., appearance of lesions, sex and age prevalence, long disease duration, and lack of response to topical steroid treatment) are almost identical. Scala et al. [17] proposed that BMS be classified into two clinical forms: 1) primary BMS or essential/idiopathic BMS for which the organic, local, or systemic causes cannot be determined, and which is most likely to have a neuropathological cause; and 2) secondary BMS, which is a variant that results from local or systemic pathological conditions and is susceptible to etiology directed therapy. Our results suggest that glossodynia may be caused by both CAL and BMS, and practitioners should consider the similar patterns of these two lesions when diagnosing glossodynia. References 1 Wardrop RW, Hailes J, Burher H, Reade PC. Oral discomfort at menopause. Oral Surg 1989;67:535 40. 2 Gorsky M, Silverman S Jr., Chinn H. Clinical characteristics and management outcome in the burning mouth syndrome. Oral Surg Oral Med Oral Pathol 1991;72:192 5. 3 Rojo L, Silvestre FJ, Bagan JV, De Vicente T. Psychiatric morbidity in burning mouth syndrome. Oral Surg Oral Med Oral Pathol 1993;75:308 11. 4 Lamey P-J, Lamb AB. Prospective study of aetiological factors in burning mouth syndrome. Br Med J (Clin Res Ed) 1988;296:1243 6. 5 Eli I, Kleinhauz M, Baht R, Littner M. Antecedents of burning mouth syndrome (glossodynia) Recent life events vs psychopathologic aspects. J Dent Res 1994;73:567 72. 6 Osaki T, Yoneda K, Yamamoto T, Ueta E, Kimura T. Candidiasis may induce glossdynia without objective manifestation. Am J Med Sci 2000;319:100 5. 7 Zegarelli DJ. Burning mouth: An analysis of 57 patients. Oral Surg 1984;58:34 8. 8 Grushka M, Epstein JB, Gorsky M. Burning mouth syndrome: Differential diagnosis. Dermatol Ther 2002;15:287 91. 9 Terai H, Shimahara M. Atrophic tongue associated with Candida. J Oral Pathol Med 2005;34:397 400. 10 Terai H, Shimahara M. Tongue pain: Burning mouth syndrome vs Candida-associated lesion. Oral Dis 2007;13:440 2. 11 Lynch DP. Oral candidiasis. History, classification, and clinical presentation. Oral Surg Oral Med Oral Pathol 1994;78:189 93. 12 Samaranayake LP, Cheung LK, Samaranayake YH. Candidiasis and other fungal disease of the mouth. Dermatol Ther 2002;15:251 69. 13 Ferreri M, Gerard D, Martin P. Sulpiride in the treatment of pain disorder. Euro Psychiatry 1998;13(4):319. 14 Benelli A, De Pol A, Poggioli R, et al. L-sulpiride, at antidepressant dosage, prevents conditioned-fear stress-induced gastric lesions in rats. Pharmacol Res 2000;42:157 60. 15 Patton LL, Siegel MA, Benoliel R, De Laat A. Management of burning mouth syndrome: Systematic review and management recommendations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl 1):S39.e1 13. 16 Mignogna MD, Fedele S, Russo LL, Leuci S, Muzio LL. The diagnosis of burning mouth syndrome represents a challenge for clinicians. J Orofac Pain 2005;19:168 73. 17 Scala A, Checchi L, Montevecchi M, Marini I, Giamberardino MA. Update on burning mouth syndrome: Overview and patient management. Crit Rev Oral Biol Med 2003;14:275 91. 860