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Figure.
Hypogeusia by Tastant
Hypogeusia by Tastant

Number of patients with hypogeusia by tastant (ie, sweet, salty, sour, and bitter).

Table 1.  
Participant Characteristics
Participant Characteristics
Table 2.  
Olfactory Results
Olfactory Results
Table 3.  
Taste Results
Taste Results
1.
Overberg  J, Hummel  T, Krude  H, Wiegand  S.  Differences in taste sensitivity between obese and non-obese children and adolescents.  Arch Dis Child. 2012;97(12):1048-1052.PubMedGoogle ScholarCrossref
2.
Simchen  U, Koebnick  C, Hoyer  S, Issanchou  S, Zunft  HJ.  Odour and taste sensitivity is associated with body weight and extent of misreporting of body weight.  Eur J Clin Nutr. 2006;60(6):698-705.PubMedGoogle ScholarCrossref
3.
Welge-Lüssen  A, Dörig  P, Wolfensberger  M, Krone  F, Hummel  T.  A study about the frequency of taste disorders.  J Neurol. 2011;258(3):386-392.PubMedGoogle ScholarCrossref
4.
James  CE, Laing  DG, Oram  N.  A comparison of the ability of 8-9-year-old children and adults to detect taste stimuli.  Physiol Behav. 1997;62(1):193-197.PubMedGoogle ScholarCrossref
5.
Obrebowski  A, Obrebowska-Karsznia  Z, Gawliński  M.  Smell and taste in children with simple obesity.  Int J Pediatr Otorhinolaryngol. 2000;55(3):191-196.PubMedGoogle ScholarCrossref
6.
Chandrashekar  J, Hoon  MA, Ryba  NJ, Zuker  CS.  The receptors and cells for mammalian taste.  Nature. 2006;444(7117):288-294.PubMedGoogle ScholarCrossref
7.
Bartoshuk  LM, Catalanotto  F, Hoffman  H, Logan  H, Snyder  DJ.  Taste damage (otitis media, tonsillectomy and head and neck cancer), oral sensations and BMI.  Physiol Behav. 2012;107(4):516-526.PubMedGoogle ScholarCrossref
8.
Barlow  SE; Expert Committee.  Expert Committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report.  Pediatrics. 2007;120(suppl 4):S164-S192.PubMedGoogle ScholarCrossref
9.
NIH Toolbox.  NIH Toolbox Odor Identification Test. http://www.nihtoolbox.org/WhatAndWhy/Sensation/Olfaction/Pages/NIH-Toolbox-Odor-Identification-Test.aspx. 2012. Accessed February 20, 2015.
10.
Dalton  P, Doty  RL, Murphy  C,  et al.  Olfactory assessment using the NIH Toolbox.  Neurology. 2013;80(11)(suppl 3):S32-S36.PubMedGoogle ScholarCrossref
11.
Mueller  C, Kallert  S, Renner  B,  et al.  Quantitative assessment of gustatory function in a clinical context using impregnated “taste strips.”  Rhinology. 2003;41(1):2-6.PubMedGoogle Scholar
12.
Torrey  TW.  The influence of nerve fibers upon taste buds during embryonic development.  Proc Natl Acad Sci U S A. 1940;26(11):627-634.PubMedGoogle ScholarCrossref
13.
Ichimori  Y, Ueda  K, Okada  H, Honma  S, Wakisaka  S.  Histochemical changes and apoptosis in degenerating taste buds of the rat circumvallate papilla.  Arch Histol Cytol. 2009;72(2):91-100.PubMedGoogle ScholarCrossref
14.
Laing  DG, Wilkes  FJ, Underwood  N, Tran  L.  Taste disorders in Australian Aboriginal and non-Aboriginal children.  Acta Paediatr. 2011;100(9):1267-1271.PubMedGoogle ScholarCrossref
15.
Ohnuki  M, Ueno  M, Zaitsu  T, Kawaguchi  Y.  Taste hyposensitivity in Japanese schoolchildren.  BMC Oral Health. 2014;14:36.PubMedGoogle ScholarCrossref
16.
Bhattacharyya  N, Kepnes  LJ.  Contemporary assessment of the prevalence of smell and taste problems in adults.  Laryngoscope. 2014;125(5):1102-1106.PubMedGoogle ScholarCrossref
17.
Jones-Smith  JC, Dieckmann  MG, Gottlieb  L, Chow  J, Fernald  LC.  Socioeconomic status and trajectory of overweight from birth to mid-childhood: the Early Childhood Longitudinal Study-Birth Cohort.  PLoS One. 2014;9(6):e100181.PubMedGoogle ScholarCrossref
18.
Mueller  CA, Khatib  S, Landis  BN, Temmel  AF, Hummel  T.  Gustatory function after tonsillectomy.  Arch Otolaryngol Head Neck Surg. 2007;133(7):668-671.PubMedGoogle ScholarCrossref
19.
Ohtsuka  K, Tomita  H, Murakami  G.  Anatomy of the tonsillar bed: topographical relationship between the palatine tonsil and the lingual branch of the glossopharyngeal nerve.  Acta Otolaryngol Suppl. 2002;(546):99-109.PubMedGoogle Scholar
Original Investigation
March 2016

Incidence of and Factors Associated With Hypogeusia in Healthy Children

Author Affiliations
  • 1Section of Otolaryngology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
  • 2Department of Anesthesiology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
 

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Otolaryngol Head Neck Surg. 2016;142(3):229-233. doi:10.1001/jamaoto.2015.3266
Abstract

Importance  There are currently no measures of isolated glossopharyngeal taste in healthy children, to our knowledge.

Objective  To define the taste characteristics of an otherwise healthy pediatric population that could serve as a control group for further investigations.

Design, Setting, and Participants  A prospective study of taste and smell was conducted from August 4 to 29, 2014, at a general pediatrics clinic in a tertiary care medical center in 80 healthy children aged 6 to 17 years who were receiving well-child examinations or vaccinations or in their healthy siblings.

Exposures  Testing of smell and taste.

Main Outcomes and Measures  Demographic data were gathered on age, sex, and body mass index as well as type of insurance. Smell testing was performed with the National Institutes of Health Toolbox Odor Identification Test, with scores based on national averages for age and sex. Validated Taste Strips were used for testing sweet, salty, sour, and bitter tastes. One strip at a time was placed on the midline of the tongue at the circumvallate papillae in random tastant order and in increasing concentrations. Correct identification of the tastant earned 1 point; of 16 possible points, a score of less than 9 signified hypogeusia. Fisher exact test was used for statistical analysis.

Results  The mean (SD) age of the 80 children in this study was 11.3 (3.2) years, and 43 were boys (54%). Hypogeusia was identified in 32 (40%) of the 80 children. Overweight or obesity was identified in 23 children (29%) (15 [31%] with a normal sense of taste and 8 [25%] with hypogeusia; P = .62), and 12 (15%) used public insurance (7 [15%] with a normal sense of taste and 5 [16%] with hypogeusia; P > .99). Age younger than 12 years (24 [50%] with a normal sense of taste and 19 [59%] with hypogeusia; P = .50), male sex (25 [52%] with a normal sense of taste and 18 [56%] with hypogeusia; P = .39), overweight or obesity (15 [31%] with a normal sense of taste and 8 [25%] with hypogeusia; P = .62), insurance type (P > .99), and olfaction less than the 50th percentile (29 [60%] with a normal sense of taste and 17 [53%] with hypogeusia; P = .65) or hyposmia (<10th percentile; P = .47) were not statistically significantly correlated with overall hypogeusia.

Conclusions and Relevance  A significant proportion of otherwise healthy children have hypogeusia according to previously published criteria. This study will provide baseline data from which future investigations studying taste disturbances in patients with chronic tonsillitis and after tonsillectomy can be compared.

Introduction

Taste is a complex human experience that relies on the integration of neural input from the taste receptors on the tongue supplied by glossopharyngeal and chorda tympani nerves as well as olfaction supplied by the olfactory nerve. In addition, intrinsic factors, such as age, sex, and body weight, modulate taste perception in humans. Young adults and middle-aged adults seem to have the best taste perception. Older children have better taste than do younger children, and taste ability decreases as adults age beyond 65 years.1,2 Females have better taste ability than males throughout childhood, adolescence, and adulthood.1-4 Overweight and obesity negatively affect taste perception in children and adults.1,2,5

There are 5 basic taste sensations: sweet, salty, sour, bitter, and umami (savory taste). It was once believed that there was a taste map on the tongue in which each taste had an area dedicated to its perception.6 According to this theory, the circumvallate papillae were thought to be most important for bitter perception, which would have restricted the glossopharyngeal perception primarily to this tastant. However, it is now accepted that all areas of the tongue possess the neural receptors for any tastant.6 This finding renews the importance of the glossopharyngeal nerve in taste.

Otolaryngologic diseases and interventions can affect the nerves that mediate taste. Even mild, unilateral, sensory nerve damage can affect whole-mouth sensation and palatability of foods.7 Despite the ubiquity of otolaryngologic diseases and treatment in children, there is a paucity of data on taste perception in healthy children, and there are no data specific to the region of the tongue innervated by the glossopharyngeal nerve. The objective of this study was to define the taste characteristics of an otherwise healthy pediatric population that could serve as a control group for further investigations.

Methods
Patient Population

From August 4 to 29, 2014, this prospective study recruited 80 developmentally normal, healthy, English-speaking children aged 6 to 17 years from the general pediatric clinic at Dartmouth Hitchcock Medical Center who were either patients seeking preventive care (ie, well-child examination or immunizations) or their healthy siblings. Children were excluded if they had a history of chronic tonsillitis or tonsillectomy, sleep-disordered breathing or obstructive sleep apnea, congenital anosmia, chronic middle ear infections, upper respiratory tract infection or uncontrolled sinus disease, allergy or gastroesophageal reflux, or ear surgery other than myringotomy and tube placement in their lifetime or adenoidectomy in the last year or were pregnant, were current or former nicotine users, or were taking medications known to alter taste. The Dartmouth Medical College Institutional Review Board approved this study. For all participants, written informed consent was obtained from the parent or guardian, and verbal informed assent was obtained from the children who were capable of understanding.

Data Collection

In addition to the results of smell and taste testing as described below, the following data were collected from each child: age, sex, and height and weight for body mass index (BMI) and BMI percentile calculation. Sociodemographic information pertaining to the child’s family, including insurance type and height and weight of an accompanying parent, was also obtained. Overweight was defined for children as being in the 85th percentile of BMI or greater, with the 95th percentile or greater meeting criteria for obesity.8

Smell Testing

The National Institutes of Health Toolbox Odor Identification Test was used to assess the child’s ability to identify various odors.9 Participants used scratch-and-sniff cards and, after scratching them one at a time, were asked to identify which of 4 pictures on a computer screen matched the odor they had just smelled. Participants aged 10 to 17 years were administered 9 odor cards, while those aged 6 to 9 years were administered 5 odor cards. Child participants (aged 6-9 years) were first asked to identify the 8 pictures that were used as answer choices to ensure they could complete the task. Having identified the pictures, they were asked if they had tasted or smelled the objects or foods depicted. Scores were calculated by simply summing the total number of correct items identified (score range for ages 3-9 years, 0-5; for ages ≥10 years, 0-9). Raw scores and normative score percentiles were recorded for each child. This testing has been validated in children.10 Hyposmia is accepted as olfactory ability that is less than the 10th percentile for a validated population. In this study, we identify hyposmia according to the validated national percentiles for age and sex that are specific to this test.

Taste Testing

Gustatory testing was carried out for the basic flavors of sweet, salty, sour, and bitter using Taste Strips (Berghart), which are paper strips impregnated with solutions of sucrose, sodium chloride, citric acid, and quinine hydrochloride, respectively. In accordance with previously published validated data, the following concentrations were used: 0.4, 0.2, 0.1, and 0.05 g/mL of sucrose; 0.25, 0.1, 0.04, and 0.016 g/mL of sodium chloride; 0.3, 0.165, 0.09, and 0.05 g/mL of citric acid; and 0.006, 0.0024, 0.0009, and 0.0004 g/mL of quinine hydrochloride.1,11 The strips were presented in increasing concentrations and in random flavor order. Each test strip was presented to the circumvallate papillae, which are supplied by the glossopharyngeal nerve. This association of the nerve to the papillae was demonstrated as early as 1940 by Torrey12 in developing rat embryos; Ichimori and colleagues13 in 2009 have shown that sectioning the glossopharyngeal nerves bilaterally in rats leads to decrease and loss of taste bud cells in the circumvallate papillae. After the strip was presented, the patient was asked to state the quality of the strip as no taste, sweet, salty, sour, or bitter. As needed, the patient was able to rinse his or her mouth with water. There were 4 strips for each flavor and 2 unflavored strips for control. Each correct answer earned 1 point for a possible total of 16 points; unflavored strips were not counted toward the total.

A score of 9 or greater for total taste was defined as normal; scores less than 9 signified hypogeusia, as these scores were less than the 10th percentile score from original validation of these Taste Strips.11 For sweet, sour, and salty, scores of 2 or greater out of 4 were considered normal; scores of 1 were considered hypogeusia.11 For bitter, a score of 1 or greater was defined as normal; thus, there was no parameter for hypogeusia for this tastant.11 Scores of 0 for any tastant with no report of taste sensation were considered ageusia. However, if the child sensed a taste but incorrectly identified the flavor for all 4 strips, a score of 0 was given for the tastant but was deemed a parageusia.

Statistical Analysis

Fisher exact test was used to calculate P values for correlations between hypogeusia and the following factors: age younger than 12 years, male sex, overweight or obesity, public insurance, olfactory ability less than 50th percentile, and hyposmia. P < .05 was considered statistically significant.

Results

The mean (SD) age of the children who participated was 11.3 (3.2) years (Table 1). There was a slight male predominance, with 43 boys (54%). Twenty-three children (29%) met criteria for being overweight or obese. Many children (68 [85%]) were covered by private insurance (Table 1).

For overall taste ability, 32 children (40%) were identified with hypogeusia, scoring fewer than 9 total points on the taste strip test. Sour tastant hypogeusia (n = 15) was found slightly more commonly than the other tastants; sweet hypogeusia was found in 12 patients, salty hypogeusia in 10, and bitter hypogeusia in 9 (Figure).

The majority of children had olfaction ability at the national 25th percentile or greater for their age and sex (Table 2). Hyposmia was uncommon, with 8 patients scoring less than the national 10th percentile. Children who scored at or above the national 50th percentile were not more likely to have hypogeusia than were their counterparts who scored below the 50th percentile (P = .65). Truly hyposmic patients also were not more likely to have hypogeusia than normosmic children (P = .47).

Demographic factors, such as male sex, age younger than 12 years, overweight or obesity, and public insurance, were investigated for correlation with taste disturbance in this pediatric population. None of these factors reached statistical significance (Table 3).

Discussion

The rate of hypogeusia in children aged 6 to 17 years was 40% in our otherwise healthy pediatric population. This rate exceeds previously published prevalence for children and adults; however, those studies tested whole-mouth taste sensation in contrast to our study, which focused on glossopharyngeal taste sensation alone. When whole-mouth testing was used, there was an approximate 8% and 12% prevalence of taste disorders (including parageusia and hypogeusia) in non-Aboriginal Australian and Aboriginal children, respectively.14 Ohnuki et al15 found that 6% of children had sweet hyposensitivity, 21% sour hyposensitivity, 6% bitter hyposensitivity, and 14% salty hyposensitivity; this group also used whole-mouth taste testing. In a study of 761 children and adults (approximately 75% were 20 years or older), the prevalence of hypogeusia was reported as approximately 5%.3 Subjectively, adults in the United States 40 years and older reported a 5.9% prevalence of taste disturbance.16

Our study found that age, sex, weight status, and olfactory ability did not correlate with hypogeusia, which does not support the findings from whole-mouth or anterior tongue testing that males, younger children, and obese or overweight children tend to have decreased taste ability. Female children and adolescents have better taste function than their male counterparts.1 In addition, it has been shown that boys aged 8 to 9 years have worse taste function than their female peers and adult men and women.4 Obese children have altered taste compared with nonobese children; they are less able to identify salty, bitter, and umami tastes compared with their counterparts.1 There is also evidence that obese children have decreased sense of smell and taste overall.5 There are contradictory reports of age-related changes in taste; however, it prevails that taste improves as a child grows older and that adults have better ability to taste than children.1,2 Olfaction is recognized as a key component of taste, and nearly half of US adults who report taste disorders also report olfactory disorder.16

In this study, insurance type was used as a proxy measure of socioeconomic status to capture environmental effects on taste. While this interaction is admittedly complex, it has been shown that socioeconomic status can affect weight status in children, particularly among white, Hispanic, and Asian children; weight status has been demonstrated to affect the ability to taste in children.17 We found that public insurance did not correlate with hypogeusia in this population.

Our determination of hypogeusia relied on the accepted definitions for the Taste Strips that were used for the test. In the original validation study in which only adults participated, the strips were placed 1.5 cm from the tip of the tongue.11 This study established the scores in a healthy adult population and defined hypogeusia as less than the 10th percentile score; higher scores were deemed normogeusia. These standards have been used in further adult and pediatric studies. However, Mueller and colleagues18 identified a significant difference between scores when the anterior and posterior tongue was tested, with lower glossopharyngeal scores than chorda tympani scores in adolescents and adults. We used these Taste Strips to test only the posterior tongue to isolate glossopharyngeal taste reception. While our findings could reflect a markedly high prevalence of hypogeusia in this pediatric population, it seems more plausible that they reflect this difference in posterior tongue taste ability.

These data for posterior tongue taste perception are important as tonsillitis and tonsillectomy could affect the lingual branch of the glossopharyngeal nerve. Anatomically, the palatine tonsils are positioned in close proximity to the lingual branch of the glossopharyngeal nerve. An adult cadaver study has demonstrated that in 21.5% of cadaver tonsillar fossae, the lingual branch was adherent to the tonsillar capsule.19 If this finding held true in vivo, there would be potential risk for damaging the nerve during standard tonsillectomy. Even mild, unilateral, sensory nerve damage can affect whole-mouth sensation and palatability of foods.7 These taste findings will serve as control data for future studies being undertaken by this group in an attempt to elucidate the effect of tonsillitis and tonsillectomy on taste and, subsequently, BMI.

Conclusions

Using normative values from previously validated taste testing data, a significant percentage of otherwise healthy children have hypogeusia in the region of the tongue innervated by the glossopharyngeal nerve. These data will serve as preliminary data for further studies of posterior tongue taste ability.

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Article Information

Submitted for Publication: May 11, 2015; final revision received October 2, 2015; accepted November 11, 2015.

Corresponding Author: Courtney A. Hill, MD, Section of Otolaryngology, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (courtney.a.hill@hitchcock.org).

Published Online: January 28, 2016. doi:10.1001/jamaoto.2015.3266.

Author Contributions: Dr Hill had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hill, Beach, Chen.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hill.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Hill, Beach.

Obtained funding: Hill.

Administrative, technical, or material support: Hill.

Study supervision: Smith, Chen.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by a Hitchcock Foundation Pilot grant.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: This study was presented at the 2015 American Society of Pediatric Otolaryngology Spring Meeting; April 25, 2015; Boston, Massachusetts.

References
1.
Overberg  J, Hummel  T, Krude  H, Wiegand  S.  Differences in taste sensitivity between obese and non-obese children and adolescents.  Arch Dis Child. 2012;97(12):1048-1052.PubMedGoogle ScholarCrossref
2.
Simchen  U, Koebnick  C, Hoyer  S, Issanchou  S, Zunft  HJ.  Odour and taste sensitivity is associated with body weight and extent of misreporting of body weight.  Eur J Clin Nutr. 2006;60(6):698-705.PubMedGoogle ScholarCrossref
3.
Welge-Lüssen  A, Dörig  P, Wolfensberger  M, Krone  F, Hummel  T.  A study about the frequency of taste disorders.  J Neurol. 2011;258(3):386-392.PubMedGoogle ScholarCrossref
4.
James  CE, Laing  DG, Oram  N.  A comparison of the ability of 8-9-year-old children and adults to detect taste stimuli.  Physiol Behav. 1997;62(1):193-197.PubMedGoogle ScholarCrossref
5.
Obrebowski  A, Obrebowska-Karsznia  Z, Gawliński  M.  Smell and taste in children with simple obesity.  Int J Pediatr Otorhinolaryngol. 2000;55(3):191-196.PubMedGoogle ScholarCrossref
6.
Chandrashekar  J, Hoon  MA, Ryba  NJ, Zuker  CS.  The receptors and cells for mammalian taste.  Nature. 2006;444(7117):288-294.PubMedGoogle ScholarCrossref
7.
Bartoshuk  LM, Catalanotto  F, Hoffman  H, Logan  H, Snyder  DJ.  Taste damage (otitis media, tonsillectomy and head and neck cancer), oral sensations and BMI.  Physiol Behav. 2012;107(4):516-526.PubMedGoogle ScholarCrossref
8.
Barlow  SE; Expert Committee.  Expert Committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report.  Pediatrics. 2007;120(suppl 4):S164-S192.PubMedGoogle ScholarCrossref
9.
NIH Toolbox.  NIH Toolbox Odor Identification Test. http://www.nihtoolbox.org/WhatAndWhy/Sensation/Olfaction/Pages/NIH-Toolbox-Odor-Identification-Test.aspx. 2012. Accessed February 20, 2015.
10.
Dalton  P, Doty  RL, Murphy  C,  et al.  Olfactory assessment using the NIH Toolbox.  Neurology. 2013;80(11)(suppl 3):S32-S36.PubMedGoogle ScholarCrossref
11.
Mueller  C, Kallert  S, Renner  B,  et al.  Quantitative assessment of gustatory function in a clinical context using impregnated “taste strips.”  Rhinology. 2003;41(1):2-6.PubMedGoogle Scholar
12.
Torrey  TW.  The influence of nerve fibers upon taste buds during embryonic development.  Proc Natl Acad Sci U S A. 1940;26(11):627-634.PubMedGoogle ScholarCrossref
13.
Ichimori  Y, Ueda  K, Okada  H, Honma  S, Wakisaka  S.  Histochemical changes and apoptosis in degenerating taste buds of the rat circumvallate papilla.  Arch Histol Cytol. 2009;72(2):91-100.PubMedGoogle ScholarCrossref
14.
Laing  DG, Wilkes  FJ, Underwood  N, Tran  L.  Taste disorders in Australian Aboriginal and non-Aboriginal children.  Acta Paediatr. 2011;100(9):1267-1271.PubMedGoogle ScholarCrossref
15.
Ohnuki  M, Ueno  M, Zaitsu  T, Kawaguchi  Y.  Taste hyposensitivity in Japanese schoolchildren.  BMC Oral Health. 2014;14:36.PubMedGoogle ScholarCrossref
16.
Bhattacharyya  N, Kepnes  LJ.  Contemporary assessment of the prevalence of smell and taste problems in adults.  Laryngoscope. 2014;125(5):1102-1106.PubMedGoogle ScholarCrossref
17.
Jones-Smith  JC, Dieckmann  MG, Gottlieb  L, Chow  J, Fernald  LC.  Socioeconomic status and trajectory of overweight from birth to mid-childhood: the Early Childhood Longitudinal Study-Birth Cohort.  PLoS One. 2014;9(6):e100181.PubMedGoogle ScholarCrossref
18.
Mueller  CA, Khatib  S, Landis  BN, Temmel  AF, Hummel  T.  Gustatory function after tonsillectomy.  Arch Otolaryngol Head Neck Surg. 2007;133(7):668-671.PubMedGoogle ScholarCrossref
19.
Ohtsuka  K, Tomita  H, Murakami  G.  Anatomy of the tonsillar bed: topographical relationship between the palatine tonsil and the lingual branch of the glossopharyngeal nerve.  Acta Otolaryngol Suppl. 2002;(546):99-109.PubMedGoogle Scholar
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