Burning Mouth Syndrome: An Evaluation of In Vivo Microcirculation Giuseppe Alessandro Scardina, Teresa Pisano, Francesco Carini, Vincenzo Valenza

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Burning mouth syndrome

An evaluation of in vivo microcirculation
Giuseppe Alessandro Scardina, DDS, PhD; Teresa Pisano, DDS; Francesco Carini, MD; Vincenzo Valenza, MD; Pietro Messina, MD

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urning mouth syndrome (BMS) is a painful syndrome of which the frequency in the Italian population is significant. The syndrome affects 3.7 percent of the Italian population, and is more common in women (5.5 percent) particularly after they experience menopausethan in men (1.6 percent).1 The prevalence of BMS in the world is about 8 percent.2 BMS often has an unknown etiopathogenesis and is associated with substantial clinical, diagnostic and therapeutic problems.3 It can be considered an atypical orofacial algesic syndrome owing to its clinical presentation.4,5 It is a clinical entity comprising various burning and dysesthetic conditions of the oral cavity that are not associated with visible alterations of the mucosa.6 Grushka and Sessle7 defined this condition as a burning sensation of the tongue and of other oral mucosa. Because of the absence of a clear clinical objective assessment for this disorder and the lack of a definite understanding of its etiopathogenesis, the clinical interpretation and treatment of BMS remain problematic.8 A burning sensation is the

ABSTRACT
Background. Burning mouth syndrome (BMS) is an atypical orofacial algesic syndrome. The aim of the authors research was to investigate the morphological characteristics of peripheral blood circulation in patients with BMS in comparison with those of the peripheral blood circulation in healthy people. Methods. The authors examined 28 subjects, of whom 14 (10 women and four men) had BMS and 14 (nine women and five men) were healthy control subjects. They performed videocapillaroscopic examination with a capillaroscope with a fiber-optic probe at a magnification of 200, which allowed them to examine the morphological characteristics within the capillaroscopic area accurately. Results. The capillaroscopic examination provided important diagnostic results regarding alterations of the local microcirculation in subjects with BMS when compared with healthy subjects. The results also showed a statistically significant increase in the diameter of the capillary ansae, afferent ansae and efferent ansae in subjects with BMS compared with subjects in the control group (P = .05). Conclusion and Clinical Implications. The results revealed a vascular involvement in BMS. This information could improve the understanding of etiopathogenetic factors and aid in the development of therapeutic strategies for treating this disorder. Key Words. Burning mouth syndrome; mouth diseases. JADA 2008;139(7):940-946.
Dr. Scardina is a researcher, University of Palermo, Department of Oral Sciences G. Messina, Via Del Vespro, 129-90127 Palermo, Italy, e-mail scardina@odonto.unipa.it. Address reprint requests to Dr. Scardina. Dr. Pisano is an internal dentist, Department of Oral Sciences, University of Palermo, Italy. Dr. Carini is a researcher, Department of Experimental Medicine, University of Palermo, Italy. Dr. Valenza is a professor, Department of Experimental Medicine, University of Palermo, Italy. Dr. Messina is a professor, Department of Oral Sciences, University of Palermo, Italy.

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pathognomonic symptom of BMS; it usually remains moderate but persists for long periods and therefore is difficult to tolerate. The pain is spontaneous and occurs without a triggering factor.1 The intensity of the pain varies among people, with patients reporting symptoms that range from mild to unbearable.9 Among the possible risk factors for BMS are numerous physiopathological situations in which the microcirculatory mechanisms are involved in pain generation. A local microcirculatory disturbance in the areas affected by BMS could contribute to the burning sensations described by patients. Some authors found that patients with BMS had parafunctional habits such as tooth grinding and clenching (bruxism) or tongue thrusting that could lead to changes in the intraoral blood flow.10,11 The aim of our research was to study the morphology of the microcirculation in the affected areas in patients with BMS and compare it with that in equivalent areas in healthy people.
SUBJECTS, MATERIALS AND METHODS

TABLE 1

Demographic characteristics of the recruited subjects.

CHARACTERISTIC SUBJECT GROUP With BMS* Sex (Male/Female) Age (Years) (Mean Standard Deviation) Age Range (Years) 4/10 60.71 12.25 Control 5/9 60.42 14.21

43-76

28-80

* BMS: Burning mouth syndrome.

We examined 28 subjects, 14 with BMS (10 women and four men, aged [mean standard deviation] 60.71 years 12.25) and 14 healthy people (nine women and five men, aged 60.42 years 14.21 [mean SD]), in our laboratory at the University of Palermo, Italy (Table 1). All patients signed a consent form as required by the Italian Ethical Committee. We excluded from the study smokers and subjects undergoing treatment with drugs that could alter microcirculation (such as antihypertensive, oral hypoglycemic or antiinflammatory agents). Neither the subjects with BMS nor the control subjects had any parafunctional habits that could alter microcirculation or produce inflammation in the oral mucosa. Subjects included in this study had a symptom typical of BMS: an extensive burning sensation in the oral cavity, particularly on the anterior one-third of the tongue.12 When diagnosing possible BMS, the clinician initially must exclude other pathologies that have similar symptoms.13-15 Therefore, we recommend that the clinician use oral swabs to obtain a fungal/bacterial microbiological culture, even if the painful areas of the oral mucosa have a normal appearance. Patients with BMS also may have allergies with or without oral manifestations (erythema). Thus, epicutaneous patch tests for both dental material and food allergens (such as nuts) are

particularly indicated for patients whose medical history reveals evidence of hypersensitivity.16-20 In our study, we carried out the following assessments in our laboratory: microbiological culture assay (to rule out fungal infections), cutaneous allergy patch tests (to rule out food allergies), complete blood cell count, seric ferritin tests, vitamin B12 tests, glucose tests and salivary flow tests. We did not test for autoimmune conditions and thyroid dysfunction because they can influence microcirculation.21,22 The subjects with BMS had healthy oral mucosa, with all tests yielding negative results, leading to the diagnosis of BMS. The subjects with BMS were not under treatment for the condition. We examined the subjects by using computerized videomicroscopic techniques and related software (Videocap 200, DS Medigroup, Milan, Italy). The optical probe videomicroscope is composed of a main unit, to which an optical probe with a video-optical terminal is connected, and a highresolution color monitor to permit viewing of the examined area. The main unit consists of a 100watt cold halogen light source with an incorporated electronic light intensity control and a processing unit for the high-definition video signal (420,000 pixels) with an incorporated color calibration device. The probe has a video-optical terminal containing a high-definition video sensor on which the user can apply different variable magnification optics from 10 to 1,000. One of the useful characteristics of the video-optical terminal is its ability to focus directly from the handpiece. Image digitization allows the user to analyze the fundamental parameters of the patients microcirculation (caliber and vessel length) and to calculate the number of capillaries per square milABBREVIATION KEY. BMS: Burning mouth syndrome.
IL: Interleukin.
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the examination); d3 = focusing difficult (occurring Evaluation of tortuosity and capillary after more than two minutes from ansae measurements in the lower lip. the beginning of the examination); ANSA MEASUREMENT d4 = focusing impossible. Consecutively, we performed a Length Diameter Efferent Afferent Tortuosity (mm*) (mm) Diameter Diameter (Score) morphofunctional evaluation of the (mm) (mm) microcirculation involving the fol0.182 0.030 0.013 0.012 1 1 lowing factors: 0.170 0.024 0.012 0.009 2 2 dlength of the capillary ansae; 0.185 0.025 0.011 0.007 2 3 ddiameter of the capillary ansae; 0.244 0.028 0.100 0.008 3 4 dafferent and efferent diameter; 0.228 0.048 0.013 0.010 2 5 dcapillary density (the number of ansae per mm2); 0.201 0.031 0.012 0.009 2 Mean dmorphology of the ansae. * mm: Millimeter. The authors gave each ansa a score from 0 to 3 on the basis of the number of crossings We examined and measured present: 0 = no crossings, 1 = one crossing, 2 = two or more crossings, 3 = distorted. three capillary ansae per image, choosing the ansae on which the limeter of the mucosa. We used a lens with 200 instrument could focus best (Table 2). magnification to identify the microangiotectonic We gave each ansa a tortuosity score from 0 to type and group; this lens allowed us to explore 3 on the basis of the number of crossings present: accurately all of the morphostructural character0 = no crossings, 1 = one crossing, 2 = two or more istics within the capillaroscopic area (a greater crossings, 3 = distorted. magnification does not allow proper focus on the Statistical analysis. We used the Manncapillary ansae). Whitney test for nonparametric data to analyze the One operator (G.A.S.) performed videocapildata gathered from the two groups (subjects with laroscopy on all subjects, who were in a seated BMS and control subjects) to highlight any potenposition, by using the same light source at a contially significant statistical differences. This is constant room temperature (23C) at the same time sidered to be one of the most efficient statistical tests, having 95 percent accuracy even when used of day (morning); the operator performed the proto analyze numerically irrelevant samples. cedure twice in each investigated area (according We used a software called PAST (Version 1.81) to a method used in other studies23-26). to perform the data analysis. PAST is a freeware For each subject in both the BMS group and developed by . Hammer, D.A.T. Harper and P.D. the control group, we observed the mucosa of the Ryan in 1995, last updated in April 2008. lower lip (frenulum), where the vascular bed is easily visible owing to the considerable thinness RESULTS of the mucosal lining; the gingiva (sextant II); and the ventral surface of the tongue. In patients with We focused our investigation on the mucosa of the BMS, all of the observed areas were affected by lower lip, the masticatory mucosa (gingivae) and the condition. the mucosa of the tongue. The capillaroscopy docOne of the most important morphological paraumented diversities in capillary location, shape meters was the visibility of the ansae, which indiand diameter, as well as in the microangioteccates the time taken by the instrument and its tonic type, which is the general spatial distribuassociated software to focus on the capillaries. In tion of the microcirculation, in the areas we some portions of the mouth (the palate, for observed. example), focusing on the vessels requires too In the mucosal lining of the lip, in subjects much time, making it difficult for the patient to with BMS as well as in control subjects, the archicomply with the examination.26,27 We evaluated tecture of the microcirculation was compatible this parameter according to the following criteria: with Curri28 classification type I, group B (capild1 = focusing easy (occurring within less than 30 laries located parallel to the mucosal surface, seconds from the beginning of the examination); with long capillary loops of even caliber and d2 = focusing relatively easy (occurring within hairpin shape). In some cases, it was similar to 30 seconds to two minutes from the beginning of Curri classification type III (upturned U or
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hairpin-shaped capillary TABLE 3 ansae that form the Differences between parameters in the labial mucosa of classic capillary comb). subjects with BMS* and control subjects. The capillary ansae of P PARAMETER SUBJECT GROUP SIGNIFICANCE the gingivae, on the VALUE (IN MILLIMETERS) (MEAN SD) other hand, had the typWith BMS Control ical characteristics of 28 0.194 0.054 0.186 0.044 .4434 NS Length Curri classification type II, group A: the 0.03558 0.00600 0.02448 0.00490 .0003 S Total Diameter architecture of the S Afferent Diameter 0.01088 0.00163 0.00688 0.00240 9.154 10-6 microcirculation of the .0004 S Efferent Diameter 0.01677 0.00444 0.00833 0.00170 marginal gingiva did not 19.04 14.88 18.42 6.66 .4772 NS Density show a constantly parallel orientation of the * BMS: Burning mouth syndrome. The authors evaluated the differences by means of the Mann-Whitney test for nonparametric data; capillary loops in relaP = .05 was considered to be significant. tion to the surface; only SD: Standard deviation. NS: Not significant. the apexes of the capil S: Significant. laries were visible; and the ansae had the aspect TABLE 4 of evenly distributed dots or commas, Results of the statistical analysis performed resulting from a loop course perpendicwith the Mann-Whitney test, regarding the ular to the surface. Therefore, in this area we could observe only the density masticatory mucosa alone.* of the ansae. Owing to the dimensions P CHARACTERISTIC SUBJECT GROUP SIGNIFICANCE of the probe, we did not examine the VALUE (MEAN SD) palate. With BMS Control We examined the morphology of the 27.44 5.96 19.25 6.68 .003 S Density ansae, which is one of the most impor* Only the apexes of the capillaries were visible, and only the density could be studied. tant morphological parameters in SD: Standard deviation. BMS: Burning mouth syndrome. BMS. Typically, the ansae were of a S: Significant (P < .05). hairpin or comma shape, but we also observed some that were particularly curved and branched. This parameter is imporof the symptoms. In particular, we observed an tant because it is characteristic of the disorder. It increase in the total diameter of the capillary is easy for an experienced observer to distinguish ansae, as well as a dilatation of the afferent and the morphology of ansae in patients with BMS efferent ansae in patients with BMS. These alterfrom that of ansae in healthy people; therefore, ations occured in both the lips and the tongue. In evaluation of this parameter could lead to a prethe gingival mucosa, we observed an increase in liminary diagnosis. (Such a diagnosis, however, the capillary density in subjects with BMS, always should be confirmed by further investigawhereas we did not find this parameters result tions.) In addition, we detected in subjects with altered in the other two areas we examined. BMS an altered capillary profile resulting from Tables 3, 4 and 5 show the results of the statisdilatations in the apical portion of the ansae. tical analysis. As Table 3 and Figures 1, 2, 3 The gravity and frequency of the morphofunc(page 945) and 4 (page 945) show, the differences tional alterations observed during the examibetween the two groups in terms of total, afferent nation with the capillaroscope suggest a borderand efferent ansae diameters are significant. line result characterized by a slight alteration in DISCUSSION the architecture of the microcirculation. We also As far as we are aware, this is the first scientific observed a significant difference between the two study that has involved the use of videocapilgroups in the diameter of the capillary ansae. laroscopy in the morphofunctional evaluation of Some of the observed parameters varied in microcirculation in subjects with BMS. The applipatients with BMS depending on the area under cation of capillaroscopy led to important diaginvestigation but not depending on the intensity
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nostic results regarding the alterations of the The differences between parameters in the tongues local microcirculation in of subjects with BMS* and control subjects. subjects with BMS when P PARAMETER SUBJECT GROUP (MEAN SD) SIGNIFICANCE compared with that in VALUE healthy subjects. With BMS Control Among the possible 0.222 0.032 0.198 0.031 .4566 NS Length risk factors for BMS are 0.03844 0.00210 0.02311 0.00330 .0004 S Total Diameter numerous physiopathoS Afferent Diameter 0.01022 0.00160 0.00664 0.00230 9.324 10-6 logic situations11,29-31 in .0005 S Efferent Diameter 0.01537 0.00423 0.00835 0.00180 which the circulatory 20.16 13.97 20.24 5.662 .4432 NS Density mechanisms are involved * BMS: Burning mouth syndrome. in pain generation. A The difference was evaluated with the Mann-Whitney test for nonparametric data; P = .05 was local circulatory disturconsidered significant. SD: Standard deviation. bance of the areas NS: Not significant. affected by BMS could S: Significant. contribute to the burning sensations patients describe. Heckmann and colleagues10 investigated the mucosal blood flow in areas typically affected in patients with BMS. Their most interesting observations included a relative increase in vasoreactivity after application of dry ice in patients with BMS compared with that in healthy subjects and notably stronger reactions on the hard palate in patients with BMS than in subjects in the control group. They found no significant differences in the other areas they examined (the vestibule and the tongue). The stimulation with dry ice significantly altered the heart rate in both groups, and partial pressure of carbon dioxide did not differ between the two Figure 1. Labial microvascular characteristics in a subject with burning mouth syndrome (magnification 200). groups. Therefore, we can exclude these parameters as causes of the altered blood flow; consequently, these changes seem to be linked to the symptoms of BMS and imply a disturbed vasoreactivity in patients with this disorder.13 Other authors described a lower tongue temperature in patients with BMS, which also could indicate alterations of the autonomic functions.32 Still other researchers found parafunctional habits in patients with BMS, such as teeth grinding (bruxism) or habitual pressing of the tongue against the teeth, both of which could lead to changes in the intraoral blood flow.32-34 Our results point out that a disturbed regulation of the mucosal blood circulation Figure 2. Labial microvascular characteristics in a healthy control subject (magnification 200). plays a part in the symptoms of BMS. In
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other words, it seems that BMS results from, or affects, the neurovascular microcirculatory unit (that is, microcirculatory control of the sensory and autonomic innervation). The capillaroscopic examination allowed us to detect a difference between subjects with BMS and healthy people in the diameters of the capillary, afferent and efferent ansae. In fact, the diameter of the ansae in subjects with BMS showed a statistically significant increase when compared with the diameter of the ansae in healthy mucosa (P = .05). Our research team has used capillaroscopy to investigate oral microcirculation in oral and systemic diseases; we observed oral microcirculatory alterFigure 3. Lingual microvascular characteristics in a subject with burning mouth syndrome (magnification 200). ations in patients with oral lichen planus or rheumatoid arthritis.35,36 In oral lichen planus, we found capillary density and diameters of the afferent and efferent ansae to be increased significantly.35,36 In patients who had rheumatoid arthritis, we observed a reduced caliber of the capillaries, as well as larger, elongated capillaries. These results point toward the presence of a disturbance in the mucosal circulation, probably due to local inflammation.35,36 The vascular inflammation develops mainly in correspondence with the microcirculation in the periphery of the blood circulation.36 This process can be described as a sequence of the following events: dvascular modifications of the microcirculation, in particular variations Figure 4. Lingual microvascular characteristics in a healthy control subject (magnifiin the vascular diameter and hematic cation 200). flow; dalterations of the blood-interstitial fluid by aggregation of the red blood cells) or both, or exchange that leads to the formation of exudate; the margination of the leukocytes that adhere to dmigration of leukocytes from the blood vessels the endothelial wall.37 toward the interstitial space. A study by Simci and colleagues38 showed an c These vascular modifications during vascular increase in the concentration of interleukin (IL)-6 inflammation determine an active hyperemia, and IL-2 in the saliva of subjects with BMS, which which is caused by an increase in the blood flow was correlated with the severity of their sympin the capillaries and is evident in the typical toms; the presence of these cytokines could symptoms of calor and rubor. Active hyperemia explain the role of the inflammatory response in can be brought on by different factors, such as an the etiopathogenesis of BMS. Pain is the principal increase in the size of the circulatory bed, an symptom of the inflammation caused by local bioincrease in blood viscosity levels (caused mainly chemical alterations. During the inflammatory
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process, important chemical mediators of plasmatic and cellular origin are produced; these have specific receptors, and a mediator can stimulate the release of other mediators by target cells with an amplifying, modulating or regulating effect. The mediators can act on one or many cellular types and have different effects depending on the type of tissue or cell; when they are produced or released, they have a short turnover. Inflammatory pain manifests as spontaneous pain and pain hypersensitivity. The spontaneous pain reflects the direct actions of specific receptors on free terminals of the nociceptors through inflammatory mediators.39
CONCLUSION

Although future research is necessary to enhance the findings of this study, the question remains whether the alterations we observed are a mere consequence of the symptoms of BMS or reflect a possible cause of the disorder. Furthermore, the presence of these alterations could be useful in establishing novel approaches to investigate therapeutic effects of drugs to combat this condition.26
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