Download Reversible Left Recurrent Laryngeal Nerve Palsy in

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.
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CHIU et al
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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
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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
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(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
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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
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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.
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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
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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