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Reversible Left Recurrent Laryngeal Nerve Palsy in Pediatric Graves’ Disease abstract Vocal cord paralysis associated with goiter usually indicates the presence of a malignancy. Pediatric patients retain significant thymic tissue that regresses only later in life. This thymic tissue can develop significant hyperplasia during an acute autoimmune process. We describe a case of a 17-year-old girl who presented with a goiter secondary to severe Graves’ disease and a 2-month history of hoarseness, choking on liquid intake, and small-volume vomiting especially after eating. She demonstrated a left vocal cord paralysis probably secondary to a unilateral left recurrent laryngeal nerve palsy. A marked enlargement of the thymus was discovered on thoracic imaging. Treatment was initiated with methimazole, with near complete remission of her vocal cord paralysis within 3 months. Given the immunomodulatory effects of methimazole, a potential mechanism of the left recurrent laryngeal nerve palsy was autoimmune hyperstimulation of the thymus and consequent hyperplasia, resulting in distension of the nerve. Attenuation of the hyperactive immune process with methimazole may have resulted in regression of the mass effect of the thymus and associated reduction of the nerve distension. This case illustrates the unique risk of left recurrent laryngeal nerve palsy in pediatric patients with an acute immune stimulation and hyperplasia of the thymus and the reversibility in the context of mitigation of the immune hyperactivity. Methimazole may be an optimal initial treatment choice in pediatric patients with Graves’ disease and left recurrent laryngeal nerve palsy. Pediatrics 2013;132:e1704–e1708 AUTHORS: Harvey K. Chiu, MD,a Daniel Ledbetter, MD,b Monica W. Richter, MD, PhD,b Ramesh S. Iyer, MD,b and Albert L. Merati, MDc aDavid Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; bSeattle Children’s Hospital, Seattle, Washington; and cUniversity of Washington Medical Center, Seattle, Washington KEY WORDS pediatric Graves’ disease, laryngeal nerve palsy, vocal cord paralysis, methimazole, reversible ABBREVIATIONS CT—computed tomography T3—triiodothyronine T4—thyroxine TSH—thyroid-stimulating hormone TSI—thyroid-stimulating immunoglobulin Dr Chiu provided the endocrinology consultation for the patient, conceptualized the significance of the case report, and drafted the initial manuscript; Dr Ledbetter provided the general surgery consultation for the patient and reviewed and revised the manuscript; Dr Richter provided the initial medical evaluation for the patient and reviewed and revised the manuscript; Dr Iyer contributed a radiology assessment of the patient’s imaging and reviewed and revised the manuscript; Dr Merati provided the otolaryngology consultation for the patient and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2013-0437 doi:10.1542/peds.2013-0437 Accepted for publication Jul 8, 2013 Address correspondence to Harvey K. Chiu, MD, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, MDCC 22-315, Los Angeles, CA 90095. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2013 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose. e1704 CHIU et al Downloaded from by guest on May 7, 2017 CASE REPORT Vocal cord paralysis associated with goiter usually indicates malignant thyroid disease. Rarely, nonmalignant causes are described. Most cases are secondary to a benign goiter or nodular thyroid.1,2 Postulated mechanisms include a compressive effect of the goiter on the recurrent laryngeal nerve or its blood supply, perinodular inflammation resulting in tiny arterial microemboli and consequent nerve fibrosis, or a direct effect of thyroiditis on the nerve.3,4 In such cases, surgical resection of the goiter, with consequent release of tension and reestablishment of blood supply to the recurrent laryngeal nerve, usually results in recovery of nerve function. Other very rare associations include subacute thyroiditis and a report of a 74year-old woman with Graves’ disease.2 This patient presented with a right vocal cord paresis. Three months after treatment with radioactive iodine ablation, symptomatically her voice had improved. To our knowledge, we describe the first case of a pediatric patient presenting with reversible laryngeal nerve palsy secondary to Graves’ disease, with a unique pathophysiologic mechanism. CASE A 17-year-old Asian girl presented with a 2-month history of voice changes. Antecedent facial pressure and rhinorrhea were treated with antibiotics for a presumptive sinusitis. Her voice progressively became more husky and deep, and she felt as if she did “not sound like a girl anymore.” Three weeks before presentation, she noted choking when swallowing solids and especially liquids. Periodic nausea, decreased appetite, difficulty swallowing saliva, infrequent small-volume postprandial vomiting, and a sensation of “thick phlegm” in her throat developed. Other symptoms included a remarkable unintentional weight loss, dyspnea limiting activity, fatigue, progressive weakness, and diarrhea. She denied any new rash,bruising,mucosalbleeding,orfever. Her past medical history was unremarkable. She took no medications. Her mother was diagnosed with Graves’ disease within the previous year. On physical examination, she appeared generally well but tachycardic (pulse 112–128 beats/minute) and hypertensive (blood pressure 130–153/97–98 mm Hg). Her weight was 69.7 kg (86.5th percentile), a significant decrease from a weight of 83.2 kg 3 months earlier, and her height was 166.0 cm (67.5th percentile) for a correlate BMI of 22.5 kg/m2 (65.1th percentile). She had a weak, raspy voice and a weak cough. Cranial nerves II to XII were intact except as noted later. Oral examination demonstrated 4+ tonsillary hypertrophy with thick mucoid postnasal drainage. The adenoids were small on mirror examination. No lymphadenopathy was appreciated. A diffuse symmetric goiter was present. On indirect laryngoscopy, she was noted to have left vocal cord paralysis with no mucosal lesions. Laboratory studies demonstrated a normal leukocyte count (7.2 K/mm3), a slight normocytic anemia (hemoglobin 11.5 g/dL), and normal platelets (162 K/mm3). Tumor markers were undetectable, specifically the b-human chorionic gonadotropin (,1 mIU/mL) and a-fetoprotein (,0.9 ng/mL). Her thyroid studies demonstrated marked hyperthyroidism, with an undetectably low thyroidstimulating hormone (TSH ,0.02 mIU/L) and exceedingly high levels of thyroxine (total T4 .24.9 mg/dL, free T4 .7.0 ng/dL) and triiodothyronine (T3 7.22 ng/mL [1.00–2.10]) (Table 1). A markedly elevated thyroid-stimulating immunoglobulin (TSI 5.8 [#1.3]) level confirmed a diagnosis of severe Graves’ disease. Neck and thoracic computed tomography (CT) imaging demonstrated borderline enlarged cervical lymph nodes but no other mediastinal or hilar adenopathy. A homogeneous soft tissue mass in the anterior mediastinum (Fig 1) extended from the manubrium to the right atrial appendage, measuring 9.4 cm transversely and 2.8 cm in the anterior– posterior diameter. No adjacent vascular invasion or other aggressive features were noted, and the structure was assessed to represent enlarged thymic hyperplasia. Mild asymmetric left laryngeal ventricular dilation and loss of the left subglottic arch supported the clinical diagnosis of left vocal cord paralysis (Fig 2). A swallowing and feeding evaluation revealed a weak laryngeal elevation and swallow for thin liquids, with a consistent concomitant cough. Oral nectar-thick liquids and regular solids were well tolerated. On a diagnosis of Graves’ disease, the patient was started on methimazole 10 mg every morning, 5 mg midday, and 10 mg every evening (0.4 mg/kg per day). TABLE 1 Summary of the Patient’s Course TSH (mIU/L) Baseline 9 wk 14 wk 20 wk 30 wk ,0.02 [0.50–4.50] 6.662 [0.360–5.800] 20.843 [0.450–5.100] 13.757 [0.450–5.100] 4.08 [0.50–4.50] T4 (mg/dL) .24.9 [4.5–10.0] 2.8 [5.1–10.0] 2.3 [4.7–11.3] 5.0 [4.7–11.3] 7.2 [5.5–10.9] T3 (ng/mL) TSI Methimazole Dose (mg/kg/day) 7.22 [1.00–2.10] 8.1 [8.1–20.0] 5.9 [#1.3] None 0.4 0.2 0.1 0.07 3.29 [,1.23] 1.25 [0.73–1.78] Brackets indicate the normal reference range of the performing laboratory. PEDIATRICS Volume 132, Number 6, December 2013 Downloaded from by guest on May 7, 2017 e1705 FIGURE 1 Contrast-enhanced CT imaging demonstrates marked thymic hyperplasia extending inferiorly to the level of the expected course of the left recurrent laryngeal nerve about the aortic arch. A 4-week course of nadolol 40 mg/day was provided for symptomatic treatment. After 9 weeks, her hoarseness was subjectively better, as noted by the patient and her friends, and she was able to yell. Laboratory studies demonstrated a slightly elevated TSH (6.662 mIU/L, reference range [0.360–5.800]), a low T4 (2.8 mg/dL, reference range [5.1–10.0]), and a normal T3 (8.1 ng/mL, reference range [8.0–20.0]). Her methimazole was reduced to 15 mg once daily (0.2 mg/kg per day). After 9 1/2 weeks, a videofluoroscopic swallowing study demonstrated intermittent mild supraglottic penetration without aspiration during the swallow of thin liquids and mild pharyngeal phase dysphagia. After 14 weeks, she was able to “gulp down” liquids without problems. Her initial choking sensations had resolved, although the goiter size was unchanged. Her “voice [was] back” as her hoarseness disappeared. With overt hypothyroidism (TSH 20.843 mIU/L [0.450–5.100], T4 2.3 mg/dL [4.7–11.3]), the methimazole was decreased to 7.5 mg once daily e1706 (0.1 mg/kg per day). By 17 weeks of therapy, under videostroboscopic flexible fiberoptic laryngoscope assessment, the left vocal cord was noted to have recovered to 90% of normal motion, with excellent closure and symmetric vibration. After 20 weeks, her TSI had decreased to 3.29 [,1.23]. DISCUSSION Graves’ disease is a prevalent condition, with a population frequency of 0.6%.5 Our patient presented with Graves’ disease, goiter, left vocal cord immobility, and an enlarged thymus. After treatment with methimazole for 3 months, her voice recovered. Her left vocal cord immobility was probably secondary to compromise of recurrent laryngeal nerve innervation.6 One mechanism may have been nerve compression by the goiter and the associated acute thyroiditis. With attenuation of the acute inflammation of the Graves’ disease, the compressive effects may have abated. However, given the extreme rarity of associated vocal cord paralysis1 with CHIU et al Downloaded from by guest on May 7, 2017 Graves’ disease and the fact that her goiter size did not appear to change with recovery of vocal cord function, additional explanations for this patient’s course seem necessary. Perhaps her markedly enlarged thymus and decreasing TSI provide a potential mechanism. The thymus is a large organ in the anterior thoracic cavity that grows until puberty and thereafter slowly regresses into 2 long fatty bodies. In the pediatric population, the thymus abounds with lymphocytes that have migrated from the bone marrow to generate T-cell receptors.7,8 Within the thymus, thymic stroma, antigen-presenting cells, and nurse cells develop T cells to recognize self-antigens for self-tolerance.9–11 Thyrotropin receptors are present in the thymus and, when stimulated by the anti–thyrotropin receptor antibodies present in Graves’ disease, may result in thymic hyperplasia,12 which has been described in pediatric Graves’ disease.13 In vivo data suggest an immunologic effect of antithyroid drugs such as methimazole. Use of an antithyroid drug CASE REPORT FIGURE 2 Coronal reformat of contrast-enhanced CT imaging demonstrates mild asymmetric left laryngeal ventricular dilation and loss of the left subglottic arch, consistent with left vocal cord paralysis. depletes intrathyroidal lymphocytes14 and decreases serologic levels of thyrotropin receptor antibodies,15,16 the immunomodulating intracellular adhesion molecule-1,17 cytokines such as interleukin-1b,18 and soluble interleukin2 and interleukin-6 receptors.19,20 Overall active T-cell numbers and helper T-cell21 and natural killer cell activity decrease.22 In vitro data suggest effective dosages of antithyroid drugs between 1024 and 1025 mol/L, but in vivo the intrathyroidal concentrations are unlikely to exceed 5 3 1025 mol/L.23,24 Thus, an extrathyroidal site of the immune modulation of antithyroid drugs is likely, and the central role of the thymus in autoimmunity suggests a site of action. Indeed, a significant decrease in thymic size has been demonstrated with antithyroid drug treatment.25,26 Interestingly, a case of a 34-year-old patient with Graves’ disease and thymic enlargement that did not decrease in size in response to antithyroid drug therapy has also been described.27 The differences in response to antithyroid drug intervention may reflect innate differences in thymic dynamics with younger age as compared with a more static thymus with older age,28,29 as suggested by studies that demonstrate a decreasing susceptibility to cytokine dynamics with increasing age.30 The left recurrent laryngeal nerve branches off of the left vagus in the superior mediastinum, passes inferior to the aortic arch, and then courses superiorly through the tracheal– esophageal groove to innervate the intrinsic left laryngeal muscles. Conversely, the right recurrent laryngeal nerve passes inferiorly around the right subclavian artery and then courses superiorly to innervate the intrinsic right laryngeal muscles, never entering the thoracic cavity. A mass effect in the thoracic cavity, such as from thymic enlargement secondary to severe Graves’ disease, could distend the lengthy left recurrent laryngeal nerve, with compromise of left vocal cord mobility, but leave the right recurrent laryngeal nerve unscathed. In this case, PEDIATRICS Volume 132, Number 6, December 2013 Downloaded from by guest on May 7, 2017 CT imaging demonstrated significant hyperplastic thymic extension inferiorly to the level of the aortic arch (Fig 1) that may have effected such nerve distension. The pediatric population may be especially susceptible given the large thymus. A therapeutic intervention on the thyroid that compromises the remaining intact right recurrent laryngeal nerve to cause bilateral vocal cord paralysis may have devastating consequences, such as airway compromise. Such a risk of injury to the recurrent laryngeal nerve is a wellrecognized risk of thyroid surgery27,31,32 but has been even described with radioiodine therapy.33 Thus the use of methimazole for Graves’ disease to modulate the immune stimulation of thymic hyperplasia becomes especially attractive in cases of recurrent laryngeal palsy as a primary intervention before other definitive therapies. CONCLUSIONS Our report describes a case of pediatric Graves’ disease that presented with reversible left recurrent laryngeal nerve e1707 palsy and thymic hyperplasia. Treatment with methimazole potentially ameliorated immune hyperstimulation of the thymus and resulted in remission of her left vocal cord palsy. Methimazole should be considered as an initial op- tion in pediatric patients presenting with Graves’ disease and vocal cord palsy. Pediatrics. 2010;125(2). Available at: www. pediatrics.org/cgi/content/full/125/2/e433 Beck JS, Young RJ, Simpson JG, et al. Lymphoid tissue in the thyroid gland and thymus of patients with primary thyrotoxicosis. Br J Surg. 1973;60(10):769–771 Hardisty CA, Fowles A, Munro DS. The effect of radioiodine and antithyroid drugs on serum long acting thyroid stimulator protector (IATS-P). A three year prospective study. Clin Endocrinol (Oxf). 1984;20(5):597– 605 McGregor AM, Petersen MM, McLachlan SM, Rooke P, Smith BR, Hall R. Carbimazole and the autoimmune response in Graves’ disease. N Engl J Med. 1980;303(6):302–307 Sonnet E, Massart C, Gibassier J, Allannic H, Maugendre D. Longitudinal study of soluble intercellular adhesion molecule-1 (ICAM-1) in sera of patients with Graves’ disease. 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Depressed natural killer activity in Graves’ disease and during antithyroid medication. Clin Endocrinol (Oxf). 1988;28 (2):205–214 Jansson R, Dahlberg PA, Johansson H, Lindström B. Intrathyroidal concentrations of methimazole in patients with Graves’ disease. J Clin Endocrinol Metab. 1983;57 (1):129–132 Okuno A, Yano K, Inyaku F, et al. Pharmacokinetics of methimazole in children and adolescents with Graves’ disease. Studies on plasma and intrathyroidal concentrations. Acta Endocrinol (Copenh). 1987;115(1): 112–118 Murakami M, Hosoi Y, Negishi T, et al. Thymic hyperplasia in patients with Graves’ disease. Identification of thyrotropin receptors in human thymus. J Clin Invest. 1996; 98(10):2228–2234 Desforges-Bullet V, Petit-Aubert G, ColletGaudillat C, et al. Thymic hyperplasia and Graves’ disease: a non-fortuitous association. Case report and review of literature. Ann Endocrinol (Paris). 2011;72(4):304–309 Yacoub A, Gaitonde DY, Wood JC. Thymic hyperplasia and Graves disease: management of anterior mediastinal masses in patients with Graves disease. Endocr Pract. 2009;15(6):534–539 Middleton G, Schoch EM. The prevalence and age distribution of human thymic B lymphoid follicles. Pathology. 1998;30(2):160–163 Simanovsky N, Hiller N, Loubashevsky N, Rozovsky K. Normal CT characteristics of the thymus in adults. Eur J Radiol. 2012;81 (11):3581–3586 Anthony DC, Bolton SJ, Fearn S, Perry VH. Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood–brain barrier permeability in rats. Brain. 1997;120(Pt 3):435–444 Friedrich T, Steinert M, Keitel R, Sattler B, Schönfelder M. [Incidence of damage to the recurrent laryngeal nerve in surgical therapy of various thyroid gland diseases: a retrospective study]. Zentralbl Chir. 1998; 123(1):25–29 Echeverri A, Flexon PB. 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Merati Pediatrics 2013;132;e1704; originally published online November 18, 2013; DOI: 10.1542/peds.2013-0437 Updated Information & Services including high resolution figures, can be found at: /content/132/6/e1704.full.html References This article cites 33 articles, 4 of which can be accessed free at: /content/132/6/e1704.full.html#ref-list-1 Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Endocrinology /cgi/collection/endocrinology_sub Metabolic Disorders /cgi/collection/metabolic_disorders_sub Pulmonology /cgi/collection/pulmonology_sub Respiratory Tract /cgi/collection/respiratory_tract_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: /site/misc/reprints.xhtml PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from by guest on May 7, 2017 Reversible Left Recurrent Laryngeal Nerve Palsy in Pediatric Graves' Disease Harvey K. Chiu, Daniel Ledbetter, Monica W. Richter, Ramesh S. Iyer and Albert L. Merati Pediatrics 2013;132;e1704; originally published online November 18, 2013; DOI: 10.1542/peds.2013-0437 The online version of this article, along with updated information and services, is located on the World Wide Web at: /content/132/6/e1704.full.html PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from by guest on May 7, 2017