Retrospective Review of Pediatric Thyroid Eye Disease Cases Referred to Nicklaus Children ' s Hospital

Purpose: We evaluate presenting features of pediatric thyroid eye disease, and discuss the morbidity and clinical course of this condition in the pediatric population.  Methods: A retrospective chart review of 11 patients referred for evaluation of thyroid eye disease at a pediatric tertiary care facility in Miami, Florida.Results: The average age at presentation was 12.7 years. The most common ocular complaint was mild irritation. Patients tended to be positive for thyroid stimulating immunoglobulin and thyroid peroxidase antibody. The average displacement on Hertel exophthalmometry was 21mm for the right eye, and 21.45mm for the left eye. Lower scleral show was the most common eyelid finding. Conclusion: In contrast to thyroid eye disease in adults, the condition tends to present with mild ocular findings in children. Pediatric patients presenting with thyroid eye disease respond very well to medical therapy aimed at enhancing the altered ocular surface.


Introduction
2][3] As in adults, TED is most often associated with acquired hyperthyroidism, but may occur in hypothyroid and euthyroid states as well. 4One-third of children with Graves' disease develop ophthalmopathy, with a median time of one month from diagnosis of Graves' disease until development of TED, although 82% of children had ocular complaints prior to being diagnosis in a study by Jarusaitiene et al. 2,5 Two-thirds of children with TED are between the ages of 11 and 18 years, presumably due to an increased prevalence of smoking in this age group. 2 Although postpubertal children seem to experience more serious complications, signs of TED are generally mild and self-resolving, potentially delaying diagnosis. 1,4Common manifestations noted in the literature include upper eyelid retraction, proptosis, eyelid lag, pain, foreign body sensation, photosensitivity, tearing, and diplopia, while optic neuropathy and corneal breakdown are infrequent. 4n addition, myopia may accompany proptosis. 4In contrast to children, adults with Graves 'ophthalmopathy seem to experience more severe disease manifestations, with higher rates of exophthalmos, restrictive myopathy, and optic nerve dysfunction. 3

Methods
We performed a retrospective chart review of children with Graves' ophthalmopathy who had been referred for ophthalmic evaluation at Nicklaus Children's Hospital, a tertiary care center in Miami, Florida.We selected our patients based on diagnostic ICD-9 codes.Since the aim of the study was to further characterize the manifestations REVIEW REVIEW » Enghelberg M et al.Pediatric Thyroid Eye Disease of TED, patients whose ocular exams did not exhibit findings consistent with TED were excluded.Each patient's sex, age, systemic symptoms, thyroid autoantibody results, best corrected Motility (BCVA), visual field results, stereoacuity, Ishihara color plate results, motility, Hertel exophthalmometry measurements, external and biomicroscopy findings, ocular symptoms, treatment, and thyroid disorder were documented, and most of the results were averaged.

Results
We identified a total of 55 patients with Graves' disease who had been examined by the endocrinology team in the last decade.Of this cohort, 15 patients had ocular complaints that prompted referral to the pediatric ophthalmology service.Only 11 of these 15 patients exhibited signs of TED, and were included in this case series.The baseline ocular examination findings are displayed in Table 1.The average age of presentation in our series was 12.7 years.Most of the patients were females, constituting 90% of the study group.The most common systemic complaint was a fine tremor.Diarrhea, weight loss, anxiety, and tachycardia were also heavily present throughout the study population.One patient presented with suicidal ideation.The most common ocular complaint was itching and mild irritation, with over 30% of patients expressing these symptoms.The vast majority of patients did not complain of visual disturbances, and 82% had a BCVA of 20/20 in both eyes.Average refractive error by retinoscopy was +0.44 +0.70 x 88.33 OD and +0.41 +0.68 x 107.75 OS.
One child with exposure keratopathy had a BCVA of 20/50, while another child with intermittent exotropia had a BCVA of 20/50 in one eye and a BCVA of 20/20 in the fellow eye.All patients presented with lower scleral show Figure 1, with one patient developing exposure keratopathy.Superior eyelid retraction was present in 18% of patients, and another 27% presented with eyelid lag on downgaze.The average displacement on Hertel exophthalmometry was 21 mm for the right eye, and 21.45 mm for the left eye.In addition, 18% of patients presented with hyperemia over one of the extraocular muscles.A minority of cases, constituting 18% of the study cohort, presented with slight limitation of abduction.One patient presented with an unre-lated intermittent exotropia.
Available laboratory findings are displayed in Table 1.Of the seven patients who had thyroid autoantibody studies available, four (57%) were positive for thyroid peroxidase (TPO).Thyroid stimulating immunoglobulin (TSI) titers were also positive in 57% of patients.It is important to note that there was considerable overlap between antibody titers, with five of the seven patients (71%) being positive for two or more thyroid auto-antibodies.Approximately 90% of patients presented with low TSH.
Treatment plans for nine patients were available Table 1.Of these nine patients, 78% were treated with either methimazole or thiamazole.Three patients (33%) underwent thyroidectomy, while two patients (22%) actually received radioactive iodine.Four patients (44%) were also treated with beta blockers.All patients received topical lubricants since lower scleral show was such a prevalent finding, and all five patients who presented with complaints of itching and irritation experienced subjective improvement, as well as decreased punctate epithelial erosions after instillation of fluorescein.

Discussion
In Jankauskiene and Jarusaitiene's retrospective study of 18 children with TED second-ary to Graves' disease, the clinical activity score (CAS) based on inflammatory ocular symptoms was generally mild. 1 In their study, 72.3% of children had upper eyelid retraction, 66.7% had proptosis, and 44.4% had eyelid lag.Our results exhibited a comparable incidence of proptosis (54%) and eyelid abnormalities (100%), though lower scleral show secondary to proptosis or lower eyelid retraction was our most common adnexal finding.In comparison, Chan et al reported proptosis in only 12.0% of 83 children studied.3Similar to our study however, restrictive ex-traocular myopathy was an uncommon finding, exhibited in only 1.2% of children in their study, and they reported no cases of optic nerve dysfunction. 3Two children (18%) in our case series displayed mild ocular motility disturbances secondary to TED, and none displayed evidence of optic nerve dysfunction.In contrast to the typically mild findings of Graves' ophthalmopathy in children, proptosis can be found in up to 60.8% in adults, while restrictive myopathy and optic nerve dysfunction have been reported in 42.5% and 5.8% of adults, respectively. 3e most common ocular complaints in our study were itching and mild irritation, which we believe to be secondary to increased corneal exposure caused by inferior scleral show and mild proptosis.Mild and moderate ocular surface symptoms respond excellently to topical lubrication, as demonstrated by Goldstein et al in their study of the course of pediatric TED and its most common findings in 26 children. 8We found therapeutic results similar to those of Goldstein et al with resolution of these symptoms in all children who received topical lubrication.
Positive TSI titers, which have been shown to be associated with development of TED in adults, also correlated with the development of TED in children in a study of 49 patients with Graves' disease by Acuna et  al.6 Fifty-seven percent of our patients presented with positive TPO antibodies, while another 57% presented with positive TSI titers in our study.Shibayama et al found that TSI levels in children with TED were not significantly different from those without TED however, and instead found a strong correlation between TED and higher thyrotropinbinding inhibitory immunoglobulin (TBII) levels in their study of 35 serum samples from chil-dren with untreated active Grave's disease. 7We did not evaluate TBII titers in our cohort.Diagnosis of pediatric TED is based on ocular manifestations and evidence of thyroid autoimmunity.Even though the orbital fat tends to be more involved in this age group, orbital MRI may be helpful for detection of extraocular muscle inflammation. 4The typical treatment of Graves' disease in children is two years of antithyroid therapy, such as with methimazole, followed by re-evaluation and monitoring thereafter. 1 Radioiodine is a treatment option as well, but its use in children less than five years of age can increase risk of thyroid cancer; retrobulbar irradiation is also contraindicated due to risk of malignancy in children. 4 Thyroidectomy can generally improve ocular symptoms.Ocular manifestations typically resolve once a euthyroid state is established. 4With antithyroid treatment, 46.1-56.6% of Asian children are able to achieve remis-sion, compared to 12-33% of children in other studies. 1 Corticosteroids, somatostatin analogs, and immunomodulatory therapy may be necessary if symptoms do not improve even in the pres-ence of a euthyroid state. 4The majority of patients in our study were treated with an antithyroid drug, while 33 underwent thyroidectomy, and two patients, ages 8 and 11, were treated with radioactive iodine.

Conclusion
Compared to the adult disease course, pediatric TED demonstrates much more benign manifestations, and restrictive strabismic patterns and optic nerve dysfunction are much less common in pediatric TED than it is in adult TED.The most prevalent findings in our study of 11 children with pediatric TED were lower scleral show, mild to moderate ocular surface disturbances, and a small degree of proptosis.Symptoms of ocular exposure in children are amenable to lubrication and conservative medical measures.Treatment plans of most children in our study included antithyroid therapy.Children's symptoms tend to regress after an adequate thyroid status is achieved.

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Figure 1B.External color photograph of patient EL with lower scleral show and proptosis of the left eye.

Figure 1C .
Figure 1C.External color photograph of patient CP with lower scleral show bilaterally.

Figure 1A .
Figure 1A.External color photograph of patient JO demonstrating lower scleral show with a small degree of bilateral proptosis.