Orbit, 2014; 33(2): 96–103 ! Informa Healthcare USA, Inc. ISSN: 0167-6830 print / 1744-5108 online DOI: 10.3109/01676830.2013.851258
ORIGINAL ARTICLE
Pediatric Thyroid Eye Disease—The Singapore Experience Nigel Chen Siang Lim1, Shantha Amrith2, and Gangadhara Sundar2 1
Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore and 2Orbit & Oculofacial Surgery, Department of Ophthalmology, National University Health System, Singapore
ABSTRACT Purpose: To identify the demographics, risk factors, clinical manifestations and treatment methods of pediatric thyroid eye disease (TED) in a South-East Asian tertiary referral practice. Methods: Retrospective case series of all pediatric patients (aged 18 years and under) who presented to our TED clinic between Jan 2006 and Dec 2012. Results: Thirteen patients (26 eyes) were identified – 8 females (61.5%) and 5 males (38.5%), accounting for 6.2% of all TED patients in our practice. Median age was 10.0 years (range, 0.3–18.0). Positive family history was noted in 9 patients (69.2%) and there were no active/passive smokers. Mean follow-up duration was 1.81 years (range, 0–5.2). Common presenting signs included proptosis (92.3%), eyelid retraction (84.6%), acquired epiblepharon (69.2%), corneal erosion (53.8%), and lagophthalmos (53.8%). None had optic neuropathy or strabismus. Mean exophthalmometry was 17.8 mm (SD 3.6 mm, range 13.0–27.0). Ten patients (76.9%) had mild disease, 3 patients (23.1%) had moderate disease and none had severe disease. Clinically significant Active disease as defined in adults (VISA Inflammatory Score44/10), was not observed in any patient. The majority of the patients were treated conservatively. One patient underwent bilateral orbital decompression for severe proptosis, while two patients underwent bilateral lower epiblepharon correction with good outcomes. None required corticosteroids (oral/pulsed). Conclusion: Clinical manifestations in pediatric TED are relatively mild and respond well to conservative therapy. Orbital decompression is rarely required but may be considered in children with severe proptosis. Mean exophthalmometry values are lower in East-Asian pediatric TED as compared to Caucasians. Symptomatic acquired epiblepharon, usually associated with keratopathy, is commonly seen in East-Asian pediatric TED; thus, increased awareness among ophthalmologists and pediatricians should be emphasized.
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Keywords: Acquired epiblepharon, Graves’ ophthalmopathy, orbital decompression, pediatric, thyroid eye disease
INTRODUCTION
potentially result in visual loss due to exposure keratopathy or optic neuropathy. Another severe disabling feature is diplopia, either in primary gaze or within 30 degrees from primary gaze. Even when the vision is unaffected, the disfiguration from sequelae of the disease may have physical, aesthetic and psychological consequences in affected individuals. The incidence of TED among pediatric patients with Graves’ disease was previously reported as
Thyroid eye disease (TED) is an immune-mediated inflammatory orbital disease which poses a major clinical and therapeutic challenge. It commonly occurs in patients with autoimmune hyperthyroidism (Graves’ disease), and rarely in patients with Hashimoto’s thyroiditis or in euthyroid patients.1 Common signs of TED include: lid retraction, proptosis, chemosis and restrictive myopathy. It can
Received 17 June 2013; Revised 26 August 2013; Accepted 30 September 2013; Published online 7 November 2013 Correspondence: Gangadhara Sundar, Head & Senior Consultant, Orbit & Oculofacial Surgery, Department of Ophthalmology, National University Hospital, 1E, Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228. E-mail: [email protected]
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Pediatric Thyroid Eye Disease 17%,2 52%,3 and 63%.4 In comparison with adult TED, most studies agree that pediatric TED is associated with milder clinical manifestations and a lower frequency of sight-threatening complications such as optic neuropathy.5,6 However, there is a lack of literature highlighting the differences in clinical features of pediatric TED among various ethnicities. Therefore, the aims of this study were to: (i) identify the demographics, risk factors, clinical manifestations and treatment methods in East-Asian pediatric patients with TED; and (ii) compare these parameters with adults and other races in the same practice setting.
MATERIALS AND METHODS In this retrospective case series, we identified all pediatric patients (age 18 and under) who were diagnosed with TED at the Division of Orbit and Oculofacial Surgery, Department of Ophthalmology at the National University Hospital Singapore, between January 2006 and December 2012. The diagnosis of TED was based on the Bartley and Gorman criteria – eyelid retraction occurring in association with laboratory evidence of thyroid dysfunction, exophthalmos, optic nerve dysfunction or extraocular muscle involvement. If eyelid retraction is absent, then TED may be diagnosed only if exophthalmos, optic nerve involvement or restrictive myopathy is associated with thyroid dysfunction.7 The study was approved by the institution’s ethics committee (Domain Specific Review Board, National Healthcare Group, Singapore). Demographics, predisposing factors, clinical characteristics and treatment methods in pediatric TED were retrospectively reviewed from medical records. All patients had been evaluated using the International Thyroid Eye Disease Society (ITEDS) VISA first visit8 and follow-up9 forms. Risk factors reviewed included family history of thyroid disorders, presence of autoimmune comorbidities, and exposure to active/passive smoking. Features of ophthalmic examination that were reviewed included best corrected visual acuity (BCVA), ocular ductions, presence of strabismus, lagophthalmos, upper and lower eyelid retraction, lid lag, and keratopathy. Symptoms of diplopia were recorded based on the modified Bahn-Gorman grading10 – grade 0 (no diplopia), grade 1 (diplopia with horizontal or vertical gaze), grade 2 (intermittent diplopia in straight gaze) or grade 3 (constant diplopia in straight gaze). Ocular ductions were classified from 0 to 45 in all directions of gaze using the Hirschberg principle: the eye had rotated 15 if the light reflex was seen at the pupil edge, 30 if it was between the pupil edge and the limbus, and 45 if it was seen at the limbus.10 Restriction grade was therefore 0/3 if ductions was 445 , 1/3 if 30–45 , 2/3 if 15–30 , and 3/3 if 515 . !
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Upper eyelid retraction was noted when the upper eyelid was at or above the superior corneoscleral limbus in primary position without frontalis muscle contraction, while lower eyelid retraction was noted when the lower eyelid was below the inferior corneoscleral limbus in primary position.7 The degree of proptosis measured using Hertel exophthalmometer was also recorded. To our knowledge, there were no established guidelines for the normal exophthalmometry values in Singapore’s multi-racial pediatric population. Thus we selected a control group consisting of 20 healthy children, without any ocular disease, who were aged and ethnically matched with our patient group. The mean exophthalmometry value of the control group was obtained, and the upper normal limit (15.4 mm) was defined as 2 standard deviations above the mean. Proptosis was therefore present if measured exophthalmometry values were above 15.4 mm. Objective measures of optic neuropathy reviewed included: loss of central visual acuity, dyschromatopsia on Ishihara color test, relative afferent pupillary defect (RAPD), optic nerve congestion or pallor, and crowding of orbital apex on CT/MRI scans. Severity of inflammation and congestion were recorded using the VISA Inflammatory Score,10 which includes symptoms such as retro-orbital ache and diurnal variation, and signs such as conjunctival injection, chemosis, caruncular edema, lid redness and edema. Patients with a VISA score of 44/10 was defined as ‘‘clinically significant’’ active disease. These patients require more aggressive therapy such as corticosteroids, radiotherapy, and in refractory cases, immunosuppressive agents. We believe that patients with a VISA score of less than 4 out of 10 are possibly still active, but may not warrant aggressive/ immunosuppressive therapy based on the risk-benefit profile. Mild disease was defined as minimal eyelid swelling, lid retraction or proptosis with little or no extraocular muscle dysfunction.10 Severe disease was defined as the presence of optic neuropathy, corneal ulceration secondary to exposure keratopathy, or diplopia in primary gaze/within 30 degrees of primary gaze. Moderate disease referred to signs and symptoms in between ‘‘mild’’ and ‘‘severe.’’ Thyroid function tests and thyroid specific antibodies such as thyroid stimulating hormone antibodies (TRAb), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were assessed. For statistical analysis, SPSS version 21.0 for MS Windows (SPSS Inc., Chicago, IL, USA) software was used.
RESULTS Between January 2006 and December 2012, a total of 13 pediatric patients were included, and they
98 Lim et al. accounted for 6.2% of all 209 patients with TED in our practice. Mean age at diagnosis was 9.87 years (SD 5.74, range 0.3–18.0). There were 8 (61.5%) females and 5 (38.5%) males (female to male ratio of 1.6:1), and there were 12 Chinese (92.3%) and 1 (7.7%) Indian patient. Positive family history of thyroid disease was noted in 9 (69.2%) patients. There were 9 first-degree family members and 15 second-degree family members with Graves’ hyperthyroidism. None had any autoimmune comorbidity (myasthenia gravis, diabetes mellitus, thyroid dermopathy/acropachy) and there were no active or passive smokers. The mean follow-up duration for TED was 1.81 years (SD 1.88, range 0–5.2). Prior to presentation, all patients had been followed-up at the pediatric endocrine clinic for a mean duration of 12 months (SD 8.5, range 0–27). Onset of TED and systemic thyroid disease began simultaneously in 9 patients (69.2%), while onset of TED was on average 9.1 months after systemic thyroid disease in the remaining 4 patients (30.8%). The most common presenting complaint was prominent eyes (92.3%); followed by ocular irritation (n = 5, 38.5%), lid swelling (n = 3, 23.1%) and epiphora (n = 3, 23.1%). Subjective diplopia with horizontal gaze (modified Bahn–Gorman grade 1) was present in 1 patient (7.7%) only. None complained of blurring of vision or color desaturation at presentation or during follow-up (Table 1). The commonest sign on ophthalmic examination was proptosis (n = 12, 92.3%), followed by lid retraction (n = 11, 84.6%). Lower lid retraction (10 eyes) was more common than upper lid retraction (6 eyes). Interestingly, there were 9 (69.2%) patients who had bilateral epiblepharon, of which both upper and lower lid involvement was noted in 3 patients, and single lid involvement was noted in 6 patients (upper lid = 2, lower lid = 4) (Table 2). This was followed by punctate epithelial erosions (n = 7, 53.8%), lagophthalmos (n = 7, 53.8%), conjunctival injection (n = 6, 46.2%), and lid lag (n = 6, 46.2%). Four (30.8%) patients had limited ocular motility, all of which were restriction grade 1/3. None had corneal ulcer or superior limbic keratoconjunctivitis. None had optic neuropathy, as evidenced by the absence of acquired dyschromatopsia, RAPD and optic disc pallor/edema. The mean Hertel exophthalmometry reading was 17.8 mm (SD 3.60, range 13.0–27.0). Mild and moderate disease was noted in 10 (76.9%) and 3 (23.1%) patients, respectively. The VISA Inflammatory Score was less than 4/10 in all patients, thus none had clinically significant active disease. At the time of referral to oculoplastics, all patients were euthyroid secondary to medication. However, prior to presentation, 11 patients were diagnosed with hyperthyroidism (Graves’ disease), while 1 patient had congenital hypothyroidism, and 1 patient was
euthyroid. 9 patients underwent thyroid autoantibody testing, of which TRAb was positive in 12 patients (92.3%), and TPOAb and TgAb positivity was noted in 6 patients (46.2%), respectively. Only two patients underwent computed tomography scans of the orbits. Both patients had an increase in intra-orbital fat and mild proptosis. However, no hypertrophy of the extraocular muscles or orbital apex crowding was noted. All patients were treated conservatively. Management for systemic thyroid disease included: anti-thyroid medication alone (n = 10, 76.9%), betablockers (n = 2, 15.4%), block and replace regime (n = 1, 7.7%) and thyroxine (n = 1, 7.7%). Two patients (15.4%) underwent bilateral lower eyelid epiblepharon correction, as they had persistent symptoms despite conservative management with lubricants. Post-operative outcome was good (Figure 1). One patient with severe proptosis (26 mm and 28 mm in the right (OD) and left eye (OS) respectively) underwent bilateral orbital decompression (bony and fat) with mullerectomy. Her post-operative Hertel exophthalmometry readings improved significantly to 18 mm (OD) and 17 mm (OS) with no eyelid retraction (Figure 2). None required corticosteroids (oral/pulsed), orbital radiotherapy, radioactive iodine, or thyroidectomy.
DISCUSSION The incidence of adult Graves’ disease was reported by Barker et al. to be between 15–20 per 100,000 per year,11 which is relatively higher than the incidence of pediatric Graves’ disease in Denmark12 and New Zealand13 (0.8 and 1 per 100,000 children, respectively). Interestingly, a study from Hong Kong reported a higher annual incidence of pediatric Graves’ disease (6.5/100,000/year), which may be attributable to genetic and environmental factors.14 These differences among age groups and ethnicities not only exist in Graves’ disease, but also in the context of TED. Many studies2,4,5,6 have shown that the clinical features of pediatric TED are milder than adult TED. Chng et al. suggested that while Asians suffer less severe features of TED compared to Caucasians, their orbital anatomy may predispose them to optic neuropathy more readily.15 Tsai et al. observed that the mean exophthalmometry values for adult Chinese Graves’ disease patients in Taiwan (18.32 mm) tend to be lower than those of Caucasians and Black-American people, but are close to those of Korean, Japanese, Iranian, Indian, and Asian-American people.16 However, there is a lack of literature that looks specifically at ethnic differences in pediatric TED. Hence our study aimed to investigate the demographics, risk factors, clinical features and treatment methods in East-Asian Orbit
Pediatric Thyroid Eye Disease TABLE 1. Demographics, risk factors, clinical features, and treatment methods in pediatric TED. n Sex Male Female Mean age Race/ethnicity Chinese Indian Risk factors Family history of thyroid disease History of autoimmune disease Smoking Follow-up duration (mean) TED clinic Endocrine clinic (prior to presentation) Presenting complaint Prominent eyes Ocular irritation Lid swelling Epiphora Retrobulbar ache Diplopia Light sensitivity Blurring of vision Color desaturation Signs Proptosis Mean exophthalmometry Lid retraction Acquired epiblepharon Punctate epithelial erosions Lagophthalmos Conjunctival injection Lid lag Limited ocular motility Lid edema Caruncular edema Lid redness Chemosis RAPD Optic disc edema/pallor Dyschromatopsia Disease activity Active Quiescent Disease severity Mild Moderate Severe Treatment (medical) Anti-thyroid medication only Beta-blockers Block and replace regime Thyroxine replacement Corticosteroids Radioactive iodine Orbital radiotherapy Treatment (surgical) Epiblepharon correction (modified Hotz procedure) Orbital decompression Thyroidectomy
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5 38.5 8 61.5 9.87 years (SD 5.74, range 0.3–18.0) 12 1
92.3 7.7
9 0 0
69.2 0.0 0.0
1.81 years (SD 1.88, range 0–5.2) 12 months (SD 8.5, range 0–27) 12 5 3 3 1 1 1 0 0
92.3 38.5 23.1 23.1 7.7 7.7 7.7 0.0 0.0
12 92.3 17.8 mm (SD 3.60, range 13.0–27.0) 11 84.6 9 69.2 7 53.8 7 53.8 6 46.2 6 46.2 4 30.8 3 23.1 1 7.7 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 13
0.0 100.0
10 3 0
76.9 23.1 0.0
10 2 1 1 0 0 0
76.9 15.4 7.7 7.7 0.0 0.0 0.0
2 1 0
15.4 7.7 0.0
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Mild Mild Mild Moderate Mild Mild Mild Mild Mild Mild Mild Moderate Moderate 0/10 0/10 0/10 3/10 0/10 1/10 0/10 1/10 3/10 1/10 1/10 0/10 3/10 Present Present Present Present Present Nil Nil Present Nil Present Nil Nil Nil Not done 14, 14 17, 17 17, 17 17, 17 18, 18 17, 17 17, 18 13, 12 21, 21 16, 18 26, 28 19, 19 Present (bilateral lower lid) Present (bilateral lower lid) Present (bilateral upper lid) Present (bilateral lower lid) Present (bilateral upper and lower lid) Nil Nil Present (bilateral upper and lower lid) Nil Present (bilateral lower lid) Present (bilateral lower lid) Present (bilateral lower lid) Nil 0/3 0/3 1/3 1/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 1/3 1/3 Hypothyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Euthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Nil Positive Positive Positive Positive Nil Nil Positive Positive Positive Nil Positive Positive
Gender
Female Male Female Female Male Male Male Female Female Female Male Female Female 1 2 3 4 5 6 7 8 9 10 11 12 13
0.3 1 5 6 8 9 10 11 13 14 16 17 18
Thyroid status Family history of thyroid disorder Age (years) Case no.
TABLE 2. Clinical data of 13 pediatric TED patients.
Restriction grade
Epiblepharon
Exophthalmometry (OD, OS) (mm)
Punctate epithelial erosions
VISA Inflammatory Score
Severity
100 Lim et al. pediatric TED, and to compare these parameters with existing studies of different ethnicities. The female-to-male ratio of pediatric TED in our study was 1.6:1, while studies in European6 and American3 children had ratios ranging from 2.7:1 to 7:1. Although female predominance was a common feature, the predominance of females over males in our study of Asian children with TED was relatively lower. In our study, the mean age at diagnosis of ophthalmopathy was 9.89 years (range 0.3–18), with more than half (53.8%) of our patients age 10 and under. In contrast, a study of 35 pediatric patients with TED done by Durairaj et al.17 reported a mean age at diagnosis of TED of 15 years. Furthermore, a European questionnaire study by Krassas et al. revealed that out of the 654 pediatric TED cases seen in Europe over the past 10 years, one-third were 10 years, and two-thirds were between 11–18 years.18 Therefore, it is evident that majority of our pediatric patients tend to present with TED at an earlier age compared to Caucasians. This may represent an ethnic variation, or it may be attributed to the nature of our referral practice and the existence of a pediatric endocrinology service at our institution. Smoking has been reported to be the strongest risk factor for development of severe TED and optic neuropathy among Korean adult patients.19 Because there were no active or passive smokers in our study, this may explain the relatively milder nature of TED in our pediatric patients compared to adults. Krassas et al. suggested that the prevalence of pediatric TED is higher in countries with a higher prevalence of smoking among teenagers.18 In Singapore, a study conducted in 1987 among adolescents found that 2% of the school-aged population smoke at least one cigarette a week, with 13% having experimented with smoking.20 Other local studies have reported an alarming 33% increase in the prevalence of smoking in the 18–29 age group, from 12.3% in 2004 to 16.3% in 2010. Furthermore, the mean age at which smokers aged between 18–24 years established their smoking habit was 16 years.21 Therefore, there has been an increasing trend in the number of Singaporean youths picking up smoking at a younger age. From a medical standpoint, this is worrying as severe TED may set in earlier, resulting in devastating visual dysfunction. Thus it is imperative to formulate effective antismoking campaigns to target the adolescent population where such initiation of smoking originates. TED has also been known to co-exist with other autoimmune diseases such as vitiligo, diabetes mellitus, rheumatoid arthritis and myasthenia gravis,22 resulting in a major diagnostic and therapeutic challenge. Although the senior author has diagnosed and managed several children with Graves orbitopathy and ocular myasthenia gravis during his regional teaching missions, none were encountered in this study. Orbit
Pediatric Thyroid Eye Disease 101
FIGURE 1. Bilateral lower eyelid epiblepharon treated by modified Hotz procedure: (A) Preoperatively; (B) Postoperatively.
FIGURE 2. Bilateral orbital decompression in a patient with severe proptosis: (A) Preoperatively; (B) Postoperatively.
Not surprisingly, the majority (76.9%) of the pediatric TED patients in our study had mild disease, and VISA inflammatory score was less than 4/10 in all patients. The commonest sign was proptosis (92.3%) and lid retraction (84.6%), and there were no signs and symptoms of optic neuropathy such as decreased visual acuity, dyschromatopsia, RAPD or optic disc pallor/edema. Limited ocular motility and diplopia on extreme gaze was noted in 30.8% and 7.7%, respectively. The absence of optic neuropathy and low frequency of limited ocular motility in our study is consistent with previous studies.2,4,6 It can be attributed to several reasons: (1) the degree of extraocular muscle infiltration/ enlargement with subsequent fibrosis may be less in children than adults, thus restrictive myopathy is less common; (2) due to continuous growth, expansion and remodeling of the orbit in children, compression of the optic nerve is less likely; (3) enlargement of orbital fat rather than extraocular muscles tends to occur in children,23 thus proptosis occurs more readily than strabismus or compressive neuropathy; (4) imaging studies have shown that the prevalence of extraocular muscle involvement in Asians is lower than Caucasians15; (5) as mentioned previously, the lack of exposure to cigarette smoke in our patients may decrease the risk of dysthyroid optic neuropathy. Interestingly, our study had a high frequency of acquired epiblepharon (9 patients, 69.2%). !
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Epiblepharon is defined as a horizontal fold of skin that stretches across the margin of the eyelid due to overriding of the anterior lamella over the posterior lamella.24 This results in eyelashes brushing against the ocular surface, subsequently leading to keratopathy and conjunctivopathy. Epiblepharon is a common condition among East Asians. In a local study, Tan et al. reported a 9.5% prevalence of epiblepharon in Singapore25; while a Japanese study found that the prevalence among Japanese children aged 3 months to 18 years was 10%.26 Park et al. found a 8.5% prevalence of acquired lower lid epiblepharon among Korean TED patients,27 while Chang et al. described a retrospective case series of 9 patients with acquired epiblepharon secondary to TED, of which 6 were Asians.28 To our knowledge, none of these studies looked specifically at acquired epiblepharon in the pediatric TED population. In our study, we believe that the high frequency of epiblepharon was acquired rather than developmental in nature, and this could be due to the following mechanisms. Increased intraorbital pressure in TED may lead to fat prolapse, predisposing to overriding of anterior lamella over the posterior lamella.24 Lower lid retraction in TED may be involved in the pathogenesis of acquired epiblepharon,29 as it was seen in 7 out of 8 patients with epiblepharon (87.5%). Lower lid retraction may occur secondary to fibrosis and shortening of the posterior lamella, and since the anterior lamella remains in its normal position, this results in anterior lamella overriding and the subsequent development of an acquired epiblepharon.
102 Lim et al. A high frequency of corneal erosions (63.6%) was also noted in our study, and this may be secondary to epiblepharon (72.7%) and lagophthalmos (54.5%). None of our patients had superior limbic keratoconjunctivitis (SLK), which is a prognostic marker for severe TED.30 Given the high prevalence of acquired epiblepharon associated with keratopathy among Singaporean children with TED, increased awareness should be emphasized among all ophthalmologists and pediatricians. The mean Hertel exophthalmometry reading in our study was 17.8 mm (SD 3.60, range 13.0–27.0). This is consistent with a Lithuanian study,31 which reported mean exophthalmometry values of 15.94 and 17.28 for children (under 14 years) and teenagers (14–18 years), respectively. In contrast, a German study by Eha et al.6 reported a mean of 21.6 mm, with 6 out of 11 patients with exophthalmometry values 422 mm; while a study in USA17 revealed that 74.3% of their pediatric TED patients had exophthalmometry values of 20 mm. Therefore, ethnic variations in exophthalmometry values exist among pediatric patients with TED, hence adjustment of normal and abnormal values according to ethnicity is required in the management of pediatric TED. At our institution, we follow the European Group on Graves’ Orbitopathy (EUGOGO) guidelines for the treatment of pediatric TED, which highlight the importance of achieving euthyroidism and reducing exposure to active/passive smoking.32 Due to growth restriction, corticosteroids are not recommended unless optic neuropathy is present, or if VISA inflammatory score was 44/10. Orbital radiotherapy, which has been proven beneficial in adults, is contraindicated in children due to the risk of tumor induction.33 In our study, the majority of the patients were treated conservatively and none required corticosteroids, orbital radiotherapy, radioactive iodine, or thyroidectomy. Two patients (18.2%) underwent bilateral lower lid epiblepharon correction (modified Hotz procedure) with good post-operative outcome (Figure 1). Due to the mild nature of pediatric TED, orbital decompression is rarely required. However, it has been performed in previous studies2,17 for cases of severe proptosis and exposure keratopathy. In our series, bilateral orbital decompression was carried out in a 17-year-old female with inactive moderate TED. She had features of severe proptosis (26 mm OD, 28 mm OS) associated with bilateral upper and lower eyelid retraction (Figure 2). Post-operatively, her exophthalmometry readings improved significantly to 18 mm (OD) and 17 mm (OS) with no eyelid retraction. Orbital decompression in pediatric TED patients may therefore be considered if features of severe proptosis (with or without exposure keratopathy) are present in the inactive phase of the disease. The procedure should ideally be
performed in older children, as cessation of orbital growth would have occurred. The strengths of our study include the high frequency of acquired epiblepharon, and adherence to the ITEDS VISA classification system, which contains a detailed list of relevant clinical features. Limitations include its retrospective design and small sample size, thus a larger prospective randomized study is recommended. As patients were reviewed by different members of the oculoplastics team, subjective measurements such as Hertel exophthalmometry values were prone to interobserver variability. Finally, even though we tried to obtain a baseline exophthalmometry value in healthy Chinese children to define the upper limit of normal exophthalmometry, it may not be representative of the entire pediatric population in Singapore. In conclusion, pediatric TED is an infrequent and under-recognized clinical entity that may occur in hyperthyroid, hypothyroid and euthyroid patients. Clinical manifestations of pediatric TED are milder as compared to adult TED, with less morbidity and residual deformities. While conservative management is sufficient in most cases, orbital decompression may be considered in older children with inactive TED and severe proptosis. Ethnic variations in pediatric TED exist – in particular, acquired epiblepharon is unique among East Asians and increased awareness should be emphasized due to its high prevalence. Mean exophthalmometry values vary among different ethnicities, hence adjustment of normal and abnormal values based on ethnicity should be conducted.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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21. Epidemiology and Disease Control Division, Ministry of Health, Singapore. National Health Survey, 2010. Available at: http://www.moh.gov.sg/content/moh_ web/home/Publications/Reports/2011/national_health_ survey2010.html. Assessed March 1, 2013. 22. Cruz AA, Akaishi PM, Vargas MA, de Paula SA. Association between thyroid autoimmune dysfunction and non-thyroid autoimmune diseases. Ophthal Plast Reconstr Surg 2007;23:104–108. 23. Antoniazzi F, Zamboni G, Cerini R, et al. Graves’ ophthalmopathy evolution studied by MRI during childhood and adolescence. J Pediatr 2004;144:527–531. 24. Sundar G, Young SM, Tara S, et al. Epiblepharon in East Asian patients: the Singapore experience. Ophthalmology 2010;117:184–189. 25. Tan MC, Young S, Amrith S, Sundar G. Epidemiology of oculoplastics conditions: the Singapore experience. Orbit 2012;31:107–113. 26. Noda S, Hayasaka S, Setogawa T. Epiblepharon with inverted eyelashes in Japanese children. I. Incidence and symptoms. Br J Ophthalmol 1989;73:126–127. 27. Park SW, Khwarg SI, Kim N, et al. Acquired lower eyelid epiblepharon in thyroid-associated ophthalmopathy of Koreans. Ophthalmology 2012;119:390–395. 28. Chang EL, Hayes J, Hatton M, Rubin PA. Acquired lower eyelid epiblepharon in patients with thyroid eye disease. Ophthal Plast Reconstr Surg 2005; 21:192–196. 29. Sung MS, Lee MJ, Choung HK, et al. Lower eyelid epiblepharon associated with lower eyelid retraction. Korean J Ophthalmol 2010;24:4–9. 30. Kadrmas EF, Bartley GB. Superior limbic keratoconjunctivitis. A prognostic sign for severe Graves’ ophthalmopathy. Ophthalmology 1995;102:1472–1475. 31. Jankauskiene J, Jarusaitiene D. Assessment of visual acuity, refraction changes, and proptosis in different ages of patients with thyroid diseases. Int J Endocrinol 2012;2012: 643275. 32. Bartalena L, Baldeschi L, Dickinson AJ, et al. Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 2008;18:333–346. 33. Gogakos AI, Boboridis K, Krassas GE. Pediatric aspects in Graves’ orbitopathy. Pediatr Endocrinol Rev 2010;7: 234–244.
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ORIGINAL ARTICLE
Pediatric Thyroid Eye Disease—The Singapore Experience Nigel Chen Siang Lim1, Shantha Amrith2, and Gangadhara Sundar2 1
Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore and 2Orbit & Oculofacial Surgery, Department of Ophthalmology, National University Health System, Singapore
ABSTRACT Purpose: To identify the demographics, risk factors, clinical manifestations and treatment methods of pediatric thyroid eye disease (TED) in a South-East Asian tertiary referral practice. Methods: Retrospective case series of all pediatric patients (aged 18 years and under) who presented to our TED clinic between Jan 2006 and Dec 2012. Results: Thirteen patients (26 eyes) were identified – 8 females (61.5%) and 5 males (38.5%), accounting for 6.2% of all TED patients in our practice. Median age was 10.0 years (range, 0.3–18.0). Positive family history was noted in 9 patients (69.2%) and there were no active/passive smokers. Mean follow-up duration was 1.81 years (range, 0–5.2). Common presenting signs included proptosis (92.3%), eyelid retraction (84.6%), acquired epiblepharon (69.2%), corneal erosion (53.8%), and lagophthalmos (53.8%). None had optic neuropathy or strabismus. Mean exophthalmometry was 17.8 mm (SD 3.6 mm, range 13.0–27.0). Ten patients (76.9%) had mild disease, 3 patients (23.1%) had moderate disease and none had severe disease. Clinically significant Active disease as defined in adults (VISA Inflammatory Score44/10), was not observed in any patient. The majority of the patients were treated conservatively. One patient underwent bilateral orbital decompression for severe proptosis, while two patients underwent bilateral lower epiblepharon correction with good outcomes. None required corticosteroids (oral/pulsed). Conclusion: Clinical manifestations in pediatric TED are relatively mild and respond well to conservative therapy. Orbital decompression is rarely required but may be considered in children with severe proptosis. Mean exophthalmometry values are lower in East-Asian pediatric TED as compared to Caucasians. Symptomatic acquired epiblepharon, usually associated with keratopathy, is commonly seen in East-Asian pediatric TED; thus, increased awareness among ophthalmologists and pediatricians should be emphasized.
20 14
Keywords: Acquired epiblepharon, Graves’ ophthalmopathy, orbital decompression, pediatric, thyroid eye disease
INTRODUCTION
potentially result in visual loss due to exposure keratopathy or optic neuropathy. Another severe disabling feature is diplopia, either in primary gaze or within 30 degrees from primary gaze. Even when the vision is unaffected, the disfiguration from sequelae of the disease may have physical, aesthetic and psychological consequences in affected individuals. The incidence of TED among pediatric patients with Graves’ disease was previously reported as
Thyroid eye disease (TED) is an immune-mediated inflammatory orbital disease which poses a major clinical and therapeutic challenge. It commonly occurs in patients with autoimmune hyperthyroidism (Graves’ disease), and rarely in patients with Hashimoto’s thyroiditis or in euthyroid patients.1 Common signs of TED include: lid retraction, proptosis, chemosis and restrictive myopathy. It can
Received 17 June 2013; Revised 26 August 2013; Accepted 30 September 2013; Published online 7 November 2013 Correspondence: Gangadhara Sundar, Head & Senior Consultant, Orbit & Oculofacial Surgery, Department of Ophthalmology, National University Hospital, 1E, Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228. E-mail: [email protected]
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Pediatric Thyroid Eye Disease 17%,2 52%,3 and 63%.4 In comparison with adult TED, most studies agree that pediatric TED is associated with milder clinical manifestations and a lower frequency of sight-threatening complications such as optic neuropathy.5,6 However, there is a lack of literature highlighting the differences in clinical features of pediatric TED among various ethnicities. Therefore, the aims of this study were to: (i) identify the demographics, risk factors, clinical manifestations and treatment methods in East-Asian pediatric patients with TED; and (ii) compare these parameters with adults and other races in the same practice setting.
MATERIALS AND METHODS In this retrospective case series, we identified all pediatric patients (age 18 and under) who were diagnosed with TED at the Division of Orbit and Oculofacial Surgery, Department of Ophthalmology at the National University Hospital Singapore, between January 2006 and December 2012. The diagnosis of TED was based on the Bartley and Gorman criteria – eyelid retraction occurring in association with laboratory evidence of thyroid dysfunction, exophthalmos, optic nerve dysfunction or extraocular muscle involvement. If eyelid retraction is absent, then TED may be diagnosed only if exophthalmos, optic nerve involvement or restrictive myopathy is associated with thyroid dysfunction.7 The study was approved by the institution’s ethics committee (Domain Specific Review Board, National Healthcare Group, Singapore). Demographics, predisposing factors, clinical characteristics and treatment methods in pediatric TED were retrospectively reviewed from medical records. All patients had been evaluated using the International Thyroid Eye Disease Society (ITEDS) VISA first visit8 and follow-up9 forms. Risk factors reviewed included family history of thyroid disorders, presence of autoimmune comorbidities, and exposure to active/passive smoking. Features of ophthalmic examination that were reviewed included best corrected visual acuity (BCVA), ocular ductions, presence of strabismus, lagophthalmos, upper and lower eyelid retraction, lid lag, and keratopathy. Symptoms of diplopia were recorded based on the modified Bahn-Gorman grading10 – grade 0 (no diplopia), grade 1 (diplopia with horizontal or vertical gaze), grade 2 (intermittent diplopia in straight gaze) or grade 3 (constant diplopia in straight gaze). Ocular ductions were classified from 0 to 45 in all directions of gaze using the Hirschberg principle: the eye had rotated 15 if the light reflex was seen at the pupil edge, 30 if it was between the pupil edge and the limbus, and 45 if it was seen at the limbus.10 Restriction grade was therefore 0/3 if ductions was 445 , 1/3 if 30–45 , 2/3 if 15–30 , and 3/3 if 515 . !
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Upper eyelid retraction was noted when the upper eyelid was at or above the superior corneoscleral limbus in primary position without frontalis muscle contraction, while lower eyelid retraction was noted when the lower eyelid was below the inferior corneoscleral limbus in primary position.7 The degree of proptosis measured using Hertel exophthalmometer was also recorded. To our knowledge, there were no established guidelines for the normal exophthalmometry values in Singapore’s multi-racial pediatric population. Thus we selected a control group consisting of 20 healthy children, without any ocular disease, who were aged and ethnically matched with our patient group. The mean exophthalmometry value of the control group was obtained, and the upper normal limit (15.4 mm) was defined as 2 standard deviations above the mean. Proptosis was therefore present if measured exophthalmometry values were above 15.4 mm. Objective measures of optic neuropathy reviewed included: loss of central visual acuity, dyschromatopsia on Ishihara color test, relative afferent pupillary defect (RAPD), optic nerve congestion or pallor, and crowding of orbital apex on CT/MRI scans. Severity of inflammation and congestion were recorded using the VISA Inflammatory Score,10 which includes symptoms such as retro-orbital ache and diurnal variation, and signs such as conjunctival injection, chemosis, caruncular edema, lid redness and edema. Patients with a VISA score of 44/10 was defined as ‘‘clinically significant’’ active disease. These patients require more aggressive therapy such as corticosteroids, radiotherapy, and in refractory cases, immunosuppressive agents. We believe that patients with a VISA score of less than 4 out of 10 are possibly still active, but may not warrant aggressive/ immunosuppressive therapy based on the risk-benefit profile. Mild disease was defined as minimal eyelid swelling, lid retraction or proptosis with little or no extraocular muscle dysfunction.10 Severe disease was defined as the presence of optic neuropathy, corneal ulceration secondary to exposure keratopathy, or diplopia in primary gaze/within 30 degrees of primary gaze. Moderate disease referred to signs and symptoms in between ‘‘mild’’ and ‘‘severe.’’ Thyroid function tests and thyroid specific antibodies such as thyroid stimulating hormone antibodies (TRAb), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were assessed. For statistical analysis, SPSS version 21.0 for MS Windows (SPSS Inc., Chicago, IL, USA) software was used.
RESULTS Between January 2006 and December 2012, a total of 13 pediatric patients were included, and they
98 Lim et al. accounted for 6.2% of all 209 patients with TED in our practice. Mean age at diagnosis was 9.87 years (SD 5.74, range 0.3–18.0). There were 8 (61.5%) females and 5 (38.5%) males (female to male ratio of 1.6:1), and there were 12 Chinese (92.3%) and 1 (7.7%) Indian patient. Positive family history of thyroid disease was noted in 9 (69.2%) patients. There were 9 first-degree family members and 15 second-degree family members with Graves’ hyperthyroidism. None had any autoimmune comorbidity (myasthenia gravis, diabetes mellitus, thyroid dermopathy/acropachy) and there were no active or passive smokers. The mean follow-up duration for TED was 1.81 years (SD 1.88, range 0–5.2). Prior to presentation, all patients had been followed-up at the pediatric endocrine clinic for a mean duration of 12 months (SD 8.5, range 0–27). Onset of TED and systemic thyroid disease began simultaneously in 9 patients (69.2%), while onset of TED was on average 9.1 months after systemic thyroid disease in the remaining 4 patients (30.8%). The most common presenting complaint was prominent eyes (92.3%); followed by ocular irritation (n = 5, 38.5%), lid swelling (n = 3, 23.1%) and epiphora (n = 3, 23.1%). Subjective diplopia with horizontal gaze (modified Bahn–Gorman grade 1) was present in 1 patient (7.7%) only. None complained of blurring of vision or color desaturation at presentation or during follow-up (Table 1). The commonest sign on ophthalmic examination was proptosis (n = 12, 92.3%), followed by lid retraction (n = 11, 84.6%). Lower lid retraction (10 eyes) was more common than upper lid retraction (6 eyes). Interestingly, there were 9 (69.2%) patients who had bilateral epiblepharon, of which both upper and lower lid involvement was noted in 3 patients, and single lid involvement was noted in 6 patients (upper lid = 2, lower lid = 4) (Table 2). This was followed by punctate epithelial erosions (n = 7, 53.8%), lagophthalmos (n = 7, 53.8%), conjunctival injection (n = 6, 46.2%), and lid lag (n = 6, 46.2%). Four (30.8%) patients had limited ocular motility, all of which were restriction grade 1/3. None had corneal ulcer or superior limbic keratoconjunctivitis. None had optic neuropathy, as evidenced by the absence of acquired dyschromatopsia, RAPD and optic disc pallor/edema. The mean Hertel exophthalmometry reading was 17.8 mm (SD 3.60, range 13.0–27.0). Mild and moderate disease was noted in 10 (76.9%) and 3 (23.1%) patients, respectively. The VISA Inflammatory Score was less than 4/10 in all patients, thus none had clinically significant active disease. At the time of referral to oculoplastics, all patients were euthyroid secondary to medication. However, prior to presentation, 11 patients were diagnosed with hyperthyroidism (Graves’ disease), while 1 patient had congenital hypothyroidism, and 1 patient was
euthyroid. 9 patients underwent thyroid autoantibody testing, of which TRAb was positive in 12 patients (92.3%), and TPOAb and TgAb positivity was noted in 6 patients (46.2%), respectively. Only two patients underwent computed tomography scans of the orbits. Both patients had an increase in intra-orbital fat and mild proptosis. However, no hypertrophy of the extraocular muscles or orbital apex crowding was noted. All patients were treated conservatively. Management for systemic thyroid disease included: anti-thyroid medication alone (n = 10, 76.9%), betablockers (n = 2, 15.4%), block and replace regime (n = 1, 7.7%) and thyroxine (n = 1, 7.7%). Two patients (15.4%) underwent bilateral lower eyelid epiblepharon correction, as they had persistent symptoms despite conservative management with lubricants. Post-operative outcome was good (Figure 1). One patient with severe proptosis (26 mm and 28 mm in the right (OD) and left eye (OS) respectively) underwent bilateral orbital decompression (bony and fat) with mullerectomy. Her post-operative Hertel exophthalmometry readings improved significantly to 18 mm (OD) and 17 mm (OS) with no eyelid retraction (Figure 2). None required corticosteroids (oral/pulsed), orbital radiotherapy, radioactive iodine, or thyroidectomy.
DISCUSSION The incidence of adult Graves’ disease was reported by Barker et al. to be between 15–20 per 100,000 per year,11 which is relatively higher than the incidence of pediatric Graves’ disease in Denmark12 and New Zealand13 (0.8 and 1 per 100,000 children, respectively). Interestingly, a study from Hong Kong reported a higher annual incidence of pediatric Graves’ disease (6.5/100,000/year), which may be attributable to genetic and environmental factors.14 These differences among age groups and ethnicities not only exist in Graves’ disease, but also in the context of TED. Many studies2,4,5,6 have shown that the clinical features of pediatric TED are milder than adult TED. Chng et al. suggested that while Asians suffer less severe features of TED compared to Caucasians, their orbital anatomy may predispose them to optic neuropathy more readily.15 Tsai et al. observed that the mean exophthalmometry values for adult Chinese Graves’ disease patients in Taiwan (18.32 mm) tend to be lower than those of Caucasians and Black-American people, but are close to those of Korean, Japanese, Iranian, Indian, and Asian-American people.16 However, there is a lack of literature that looks specifically at ethnic differences in pediatric TED. Hence our study aimed to investigate the demographics, risk factors, clinical features and treatment methods in East-Asian Orbit
Pediatric Thyroid Eye Disease TABLE 1. Demographics, risk factors, clinical features, and treatment methods in pediatric TED. n Sex Male Female Mean age Race/ethnicity Chinese Indian Risk factors Family history of thyroid disease History of autoimmune disease Smoking Follow-up duration (mean) TED clinic Endocrine clinic (prior to presentation) Presenting complaint Prominent eyes Ocular irritation Lid swelling Epiphora Retrobulbar ache Diplopia Light sensitivity Blurring of vision Color desaturation Signs Proptosis Mean exophthalmometry Lid retraction Acquired epiblepharon Punctate epithelial erosions Lagophthalmos Conjunctival injection Lid lag Limited ocular motility Lid edema Caruncular edema Lid redness Chemosis RAPD Optic disc edema/pallor Dyschromatopsia Disease activity Active Quiescent Disease severity Mild Moderate Severe Treatment (medical) Anti-thyroid medication only Beta-blockers Block and replace regime Thyroxine replacement Corticosteroids Radioactive iodine Orbital radiotherapy Treatment (surgical) Epiblepharon correction (modified Hotz procedure) Orbital decompression Thyroidectomy
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5 38.5 8 61.5 9.87 years (SD 5.74, range 0.3–18.0) 12 1
92.3 7.7
9 0 0
69.2 0.0 0.0
1.81 years (SD 1.88, range 0–5.2) 12 months (SD 8.5, range 0–27) 12 5 3 3 1 1 1 0 0
92.3 38.5 23.1 23.1 7.7 7.7 7.7 0.0 0.0
12 92.3 17.8 mm (SD 3.60, range 13.0–27.0) 11 84.6 9 69.2 7 53.8 7 53.8 6 46.2 6 46.2 4 30.8 3 23.1 1 7.7 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 13
0.0 100.0
10 3 0
76.9 23.1 0.0
10 2 1 1 0 0 0
76.9 15.4 7.7 7.7 0.0 0.0 0.0
2 1 0
15.4 7.7 0.0
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Mild Mild Mild Moderate Mild Mild Mild Mild Mild Mild Mild Moderate Moderate 0/10 0/10 0/10 3/10 0/10 1/10 0/10 1/10 3/10 1/10 1/10 0/10 3/10 Present Present Present Present Present Nil Nil Present Nil Present Nil Nil Nil Not done 14, 14 17, 17 17, 17 17, 17 18, 18 17, 17 17, 18 13, 12 21, 21 16, 18 26, 28 19, 19 Present (bilateral lower lid) Present (bilateral lower lid) Present (bilateral upper lid) Present (bilateral lower lid) Present (bilateral upper and lower lid) Nil Nil Present (bilateral upper and lower lid) Nil Present (bilateral lower lid) Present (bilateral lower lid) Present (bilateral lower lid) Nil 0/3 0/3 1/3 1/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 1/3 1/3 Hypothyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Euthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Hyperthyroid Nil Positive Positive Positive Positive Nil Nil Positive Positive Positive Nil Positive Positive
Gender
Female Male Female Female Male Male Male Female Female Female Male Female Female 1 2 3 4 5 6 7 8 9 10 11 12 13
0.3 1 5 6 8 9 10 11 13 14 16 17 18
Thyroid status Family history of thyroid disorder Age (years) Case no.
TABLE 2. Clinical data of 13 pediatric TED patients.
Restriction grade
Epiblepharon
Exophthalmometry (OD, OS) (mm)
Punctate epithelial erosions
VISA Inflammatory Score
Severity
100 Lim et al. pediatric TED, and to compare these parameters with existing studies of different ethnicities. The female-to-male ratio of pediatric TED in our study was 1.6:1, while studies in European6 and American3 children had ratios ranging from 2.7:1 to 7:1. Although female predominance was a common feature, the predominance of females over males in our study of Asian children with TED was relatively lower. In our study, the mean age at diagnosis of ophthalmopathy was 9.89 years (range 0.3–18), with more than half (53.8%) of our patients age 10 and under. In contrast, a study of 35 pediatric patients with TED done by Durairaj et al.17 reported a mean age at diagnosis of TED of 15 years. Furthermore, a European questionnaire study by Krassas et al. revealed that out of the 654 pediatric TED cases seen in Europe over the past 10 years, one-third were 10 years, and two-thirds were between 11–18 years.18 Therefore, it is evident that majority of our pediatric patients tend to present with TED at an earlier age compared to Caucasians. This may represent an ethnic variation, or it may be attributed to the nature of our referral practice and the existence of a pediatric endocrinology service at our institution. Smoking has been reported to be the strongest risk factor for development of severe TED and optic neuropathy among Korean adult patients.19 Because there were no active or passive smokers in our study, this may explain the relatively milder nature of TED in our pediatric patients compared to adults. Krassas et al. suggested that the prevalence of pediatric TED is higher in countries with a higher prevalence of smoking among teenagers.18 In Singapore, a study conducted in 1987 among adolescents found that 2% of the school-aged population smoke at least one cigarette a week, with 13% having experimented with smoking.20 Other local studies have reported an alarming 33% increase in the prevalence of smoking in the 18–29 age group, from 12.3% in 2004 to 16.3% in 2010. Furthermore, the mean age at which smokers aged between 18–24 years established their smoking habit was 16 years.21 Therefore, there has been an increasing trend in the number of Singaporean youths picking up smoking at a younger age. From a medical standpoint, this is worrying as severe TED may set in earlier, resulting in devastating visual dysfunction. Thus it is imperative to formulate effective antismoking campaigns to target the adolescent population where such initiation of smoking originates. TED has also been known to co-exist with other autoimmune diseases such as vitiligo, diabetes mellitus, rheumatoid arthritis and myasthenia gravis,22 resulting in a major diagnostic and therapeutic challenge. Although the senior author has diagnosed and managed several children with Graves orbitopathy and ocular myasthenia gravis during his regional teaching missions, none were encountered in this study. Orbit
Pediatric Thyroid Eye Disease 101
FIGURE 1. Bilateral lower eyelid epiblepharon treated by modified Hotz procedure: (A) Preoperatively; (B) Postoperatively.
FIGURE 2. Bilateral orbital decompression in a patient with severe proptosis: (A) Preoperatively; (B) Postoperatively.
Not surprisingly, the majority (76.9%) of the pediatric TED patients in our study had mild disease, and VISA inflammatory score was less than 4/10 in all patients. The commonest sign was proptosis (92.3%) and lid retraction (84.6%), and there were no signs and symptoms of optic neuropathy such as decreased visual acuity, dyschromatopsia, RAPD or optic disc pallor/edema. Limited ocular motility and diplopia on extreme gaze was noted in 30.8% and 7.7%, respectively. The absence of optic neuropathy and low frequency of limited ocular motility in our study is consistent with previous studies.2,4,6 It can be attributed to several reasons: (1) the degree of extraocular muscle infiltration/ enlargement with subsequent fibrosis may be less in children than adults, thus restrictive myopathy is less common; (2) due to continuous growth, expansion and remodeling of the orbit in children, compression of the optic nerve is less likely; (3) enlargement of orbital fat rather than extraocular muscles tends to occur in children,23 thus proptosis occurs more readily than strabismus or compressive neuropathy; (4) imaging studies have shown that the prevalence of extraocular muscle involvement in Asians is lower than Caucasians15; (5) as mentioned previously, the lack of exposure to cigarette smoke in our patients may decrease the risk of dysthyroid optic neuropathy. Interestingly, our study had a high frequency of acquired epiblepharon (9 patients, 69.2%). !
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Epiblepharon is defined as a horizontal fold of skin that stretches across the margin of the eyelid due to overriding of the anterior lamella over the posterior lamella.24 This results in eyelashes brushing against the ocular surface, subsequently leading to keratopathy and conjunctivopathy. Epiblepharon is a common condition among East Asians. In a local study, Tan et al. reported a 9.5% prevalence of epiblepharon in Singapore25; while a Japanese study found that the prevalence among Japanese children aged 3 months to 18 years was 10%.26 Park et al. found a 8.5% prevalence of acquired lower lid epiblepharon among Korean TED patients,27 while Chang et al. described a retrospective case series of 9 patients with acquired epiblepharon secondary to TED, of which 6 were Asians.28 To our knowledge, none of these studies looked specifically at acquired epiblepharon in the pediatric TED population. In our study, we believe that the high frequency of epiblepharon was acquired rather than developmental in nature, and this could be due to the following mechanisms. Increased intraorbital pressure in TED may lead to fat prolapse, predisposing to overriding of anterior lamella over the posterior lamella.24 Lower lid retraction in TED may be involved in the pathogenesis of acquired epiblepharon,29 as it was seen in 7 out of 8 patients with epiblepharon (87.5%). Lower lid retraction may occur secondary to fibrosis and shortening of the posterior lamella, and since the anterior lamella remains in its normal position, this results in anterior lamella overriding and the subsequent development of an acquired epiblepharon.
102 Lim et al. A high frequency of corneal erosions (63.6%) was also noted in our study, and this may be secondary to epiblepharon (72.7%) and lagophthalmos (54.5%). None of our patients had superior limbic keratoconjunctivitis (SLK), which is a prognostic marker for severe TED.30 Given the high prevalence of acquired epiblepharon associated with keratopathy among Singaporean children with TED, increased awareness should be emphasized among all ophthalmologists and pediatricians. The mean Hertel exophthalmometry reading in our study was 17.8 mm (SD 3.60, range 13.0–27.0). This is consistent with a Lithuanian study,31 which reported mean exophthalmometry values of 15.94 and 17.28 for children (under 14 years) and teenagers (14–18 years), respectively. In contrast, a German study by Eha et al.6 reported a mean of 21.6 mm, with 6 out of 11 patients with exophthalmometry values 422 mm; while a study in USA17 revealed that 74.3% of their pediatric TED patients had exophthalmometry values of 20 mm. Therefore, ethnic variations in exophthalmometry values exist among pediatric patients with TED, hence adjustment of normal and abnormal values according to ethnicity is required in the management of pediatric TED. At our institution, we follow the European Group on Graves’ Orbitopathy (EUGOGO) guidelines for the treatment of pediatric TED, which highlight the importance of achieving euthyroidism and reducing exposure to active/passive smoking.32 Due to growth restriction, corticosteroids are not recommended unless optic neuropathy is present, or if VISA inflammatory score was 44/10. Orbital radiotherapy, which has been proven beneficial in adults, is contraindicated in children due to the risk of tumor induction.33 In our study, the majority of the patients were treated conservatively and none required corticosteroids, orbital radiotherapy, radioactive iodine, or thyroidectomy. Two patients (18.2%) underwent bilateral lower lid epiblepharon correction (modified Hotz procedure) with good post-operative outcome (Figure 1). Due to the mild nature of pediatric TED, orbital decompression is rarely required. However, it has been performed in previous studies2,17 for cases of severe proptosis and exposure keratopathy. In our series, bilateral orbital decompression was carried out in a 17-year-old female with inactive moderate TED. She had features of severe proptosis (26 mm OD, 28 mm OS) associated with bilateral upper and lower eyelid retraction (Figure 2). Post-operatively, her exophthalmometry readings improved significantly to 18 mm (OD) and 17 mm (OS) with no eyelid retraction. Orbital decompression in pediatric TED patients may therefore be considered if features of severe proptosis (with or without exposure keratopathy) are present in the inactive phase of the disease. The procedure should ideally be
performed in older children, as cessation of orbital growth would have occurred. The strengths of our study include the high frequency of acquired epiblepharon, and adherence to the ITEDS VISA classification system, which contains a detailed list of relevant clinical features. Limitations include its retrospective design and small sample size, thus a larger prospective randomized study is recommended. As patients were reviewed by different members of the oculoplastics team, subjective measurements such as Hertel exophthalmometry values were prone to interobserver variability. Finally, even though we tried to obtain a baseline exophthalmometry value in healthy Chinese children to define the upper limit of normal exophthalmometry, it may not be representative of the entire pediatric population in Singapore. In conclusion, pediatric TED is an infrequent and under-recognized clinical entity that may occur in hyperthyroid, hypothyroid and euthyroid patients. Clinical manifestations of pediatric TED are milder as compared to adult TED, with less morbidity and residual deformities. While conservative management is sufficient in most cases, orbital decompression may be considered in older children with inactive TED and severe proptosis. Ethnic variations in pediatric TED exist – in particular, acquired epiblepharon is unique among East Asians and increased awareness should be emphasized due to its high prevalence. Mean exophthalmometry values vary among different ethnicities, hence adjustment of normal and abnormal values based on ethnicity should be conducted.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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