Influence of prior carbimazole on the outcome of radioiodine therapy in pediatric and adolescent Graves disease

1. Original article Influence of prior carbimazole on the outcome of radioiodine therapy in pediatric and adolescent Graves’ disease Sanjana Ballal, Ramya Soundararajan, Harmandeep Singh, Aayushi Garg, Saurav Chopra and Chandrasekhar Bal Results The cure rate was 70% in group 1 and 83% in group 2 with a single dose of radioiodine (P=0.299). The success rate achieved at the end of 1-year follow-up in group 1 and group 2 was 81 and 87%, respectively (P=0.401). No independent predictor was associated with success or failure of treatment. At the median follow-up of 75 months (range: 12–216 months), 76% of patients were hypothyroid on replacement doses of levothyroxine and 24% still continued to be euthyroid. Objective of the study Therapeutic options for pediatric Graves’ disease (PGD) include antithyroid drug therapy (ATD) as the first line and radioiodine (I-131) therapy as the second line of treatment. To date, controversies persist regarding the true effect of prior ATD in the outcome of I-131 therapy in PGD. This study evaluated the effect of prior carbimazole treatment on the outcome of I-131 therapy in PGD. Methods This is a retrospective study covering the years 1995–2012, with a median follow-up of 75 months. Records of 114 children (84 girls and 30 boys, age range: 5–20 years, mean 24-h radioiodine uptake, 58%) who had clinically and biochemically proven Graves’ disease irrespective of prior ATD therapy were included. All patients were treated with fixed doses of 5 mCi (185MBq) I-131 for Graves’ disease; 74 had undergone prior carbimazole treatment (group 1) and 40 were drug naive (group 2). The endpoint of follow-up was stable euthyroid or hypothyroid in patients. The effect of prior carbimazole treatment on the outcome of I-131 therapy in PGD patients was evaluated. The success of radioiodine therapy was defined as the cure of hyperthyroidism. Variables were analyzed to identify the potential predictive factors for euthyroidism/ hypothyroidism after treatment. Conclusion Prior carbimazole treatment does not alter the outcome of radioiodine therapy in PGD. Nucl Med Commun 36:566–572 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Nuclear Medicine Communications 2015, 36:566–572 Keywords: antithyroid drug therapy, pediatric Graves’ disease, radioiodine therapy Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India Correspondence to Chandrasekhar Bal, MD, DNB, Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India- Tel: +91 986 839 7182; fax: +91 112 658 8663; e-mail: drcsbal@gmail.com Received 17 October 2014 Revised 7 January 2015 Accepted 22 January 2015 Introduction Graves’ disease (GD) is the most common cause of hyperthyroidism in pediatric and adolescent populations, with a strong female-to-male predominance of 3.5–6.1 :1 [1]. Current treatment approaches involve antithyroid drugs (ATD), thyroidectomy, and radioablation using radioiodine (I-131; RAI). However, the optimal treatment in children is still controversial [2]. Although medical therapy is commonly used as the first-line treatment, only 20–30% of pubertal and 15% of prepubertal children treated medically for 1–2 years experience long-term remission [3–5]. Pediatric patients with GD who do not achieve remission after 1–2 years of methimazole therapy are usually considered for treatment with I-131 or thyr- oidectomy. Thus, either surgery or RAI therapy is nee- ded as definitive treatment in a large proportion of such cases [6]. I-131 was introduced for the treatment of pediatric GD more than five decades ago [7] using var- ious calculated and fixed-dose regimens of RAI [3,5,8,9]. Treatment with RAI is associated with the fear of potential carcinogenic and teratogenic risks. However, follow-up studies have not revealed an increase in the rates of thyroid cancer or genetic abnormalities in chil- dren or in the offspring of such children treated with moderate or high doses of RAI [10]. These observations, coupled with the disappointing results associated with medical therapy for most patients, have led to the use of RAI as first-line therapy for treating GD in children [5]. Although several data on the effect of ATD therapy in adults exist [11,12], it is still unclear whether prior ATD therapy has any effect on the outcome of RAI in pediatric GD. The purpose of this retrospective cohort study was to evaluate the effect of prior carbimazole therapy on the outcome of RAI in pediatric and adolescent GD from a single institution with uniform treatment policy followed over the last two decades. Subjects and methods Although I-131 therapy for hyperthyroidism started in the 1960s, at our institute pediatric endocrinologists started referring GD patients for I-131 therapy only from 1990. It is our institutional policy to treat all children and 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MNM.0000000000000291 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

2. Effect of prior ATD on I-131 therapy Ballal et al. 567 adolescents suffering from GD with 185 MBq of I-131, as a lower dose of RAI can be used to achieve euthyroidism in a larger proportion of patients. Records of 114 children and adolescents who received I-131 for the treatment of GD at the Department of Nuclear Medicine, All India Institute of Medical Sciences, Thyroid Clinic, during the period 1995–2012 were reviewed. Those patients who were less than 20 years of age at the time of RAI treat- ment with a minimum follow-up period of 12 months after RAI therapy were included in the study. were provided to the parents/guardians. Patients were advised not to have close contact with younger siblings and other children, and to avoid close contact with pregnant women for 1 week. Outcome endpoints Patients were followed up and reassessed quarterly at our clinic. They were considered to be responders to initial I-131 therapy if, at the 3-month follow-up, they showed biochemical evidence of a euthyroid or hypothyroid state and normal or decreased RAIU values. Persistence of a biochemical hyperthyroid state along with raised 24-h RAIU values at 3-month follow-up was considered as treatment failure. Patients with persistent disease were administered subsequent fixed low doses of 5mCi I-131 therapy until they reached a biochemical euthyroid or stable hypothyroid state. On follow-up, patients were exclusively assessed for the side effects of I-131 therapy, such as pain, redness or swelling in the neck region, ageusia, sialadenitis, radiation-induced thyroiditis, thyr- oid crisis, and aggravation of opthalmopathy. Methodology All patients underwent detailed clinical and biochemical evaluation. GD was diagnosed on the basis of compatible symptoms, suppressed thyroid-stimulating (TSH) levels, elevated serum thyroid hormones (total T4 and/or total T3), elevated radioiodine uptake (RAIU), and diffuse gland enlargement (clinically or on imaging when performed). hormone Hormone assays Hormone assays were performed before RAI and subse- quently every 3 months until 12 months. If the patient was euthyroid he or she was followed up every 6 months until hypothyroidism was reached. The laboratory refer- ence ranges were as follows: serum TSH, 0.17–4.0mIU/l; total T4, 4.5–12.5μg/dl; and total T3, 70–200ng/dl (Immunotech, Glendale, California, USA). The tests were assayed by means of classic radioimmunossay techniques. Protocols and patient groups A total of 84 girls and 30 boys (female/male ratio 2.8 :1), of a mean age of 17 years (range: 5–20 years) and a mean 24 h RAIU of 58.5±17.9%, were included in our study. The thyroid gland was not palpable in 38 patients, and moderate to severe thyromegaly was noted in the rest of the patients. No patient had low RAIU values that would otherwise contraindicate RAI therapy. No patient had features of Graves’ opthalmopathy before ATD therapy and RAI therapy. A fixed dose of 185 MBq of I-131 was given to all patients irrespective of their gland size or RAIU values. The 114 patients were thus divided into two groups: group 1 with 74 (65%) children (25 boys and 49 girls; age range 5–20 years) who were pretreated with ATD and needed radioactive iodine as definitive ther- apy; and group 2 with 40 (35%) children (five boys and 35 girls; age range 12–20 years) who were drug naive and received RAI as first-line treatment as they had symp- toms of mild to moderate thyrotoxicosis and/or were agoiterous. In group 1, patients had undergone ATD therapy with a median treatment period of 12 months and were subsequently treated with RAI because of the absence of remission after medical therapy in 32 patients (63%), because of noncompliance in 31 patients (27%), and because of the development of adverse effects in 11 patients (10%). There was no significant difference in the clinical and biochemical baseline parameters and in the median follow-up time between the two groups, except for mean serum T4 levels, which were higher in patients who were not pretreated with ATD [P=0.004, 95% confidence interval (CI): 15.564–21.402] (Table 1). Radioiodine uptake Liquid RAI I-131was procured from BRIT (Board of Radiation and Isotope Technology, Mumbai, India). All GD patients who were referred for RAI therapy under- went RAIU both before I-131 therapy and at 3-month follow-up. I-131 [185 kBq (5 μCi)] was administered orally. Atomlab 950 (Biodex Medical Systems, Shirley, New York, USA) thyroid uptake probe was used for RAIU estimation at 2 and 24 h, with pulse height analy- zer setting such that the window width was set at 309–420 keV and the photopeak was set at 364 keV. The uptake probe was placed at a distance of 25 cm in front of the neck such that the entire thyroid gland was included within the isocentric field of the probe. Counts were taken from the background, from the standard sample placed in the neck phantom, and from the patient’s neck and thigh for 1min each. The percentage RAIU values at the specific time intervals were calculated using the fol- lowing formula: RAIU=(neck counts per minute−thigh counts per minute)/(standard counts per minute−back- ground counts per minute)×100%. The normal 2 and 24 h RAIU reference values were 5–15% and 15–35%, respectively. Radioiodine therapy All patients were administered a fixed dose of 5mCi (185MBq) I-131 on an outpatient basis. Safety precautions Statistical analysis The Kolmogorov–Smirnov test was applied to assess normality of data. Comparison of continuous variables Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

3. Nuclear Medicine Communications 568 2015, Vol 36 No 6 Comparison of baseline data of groups Table 1 Total patients (N=114) Group 1 (with medication) (N=74) Group 2 (without medication) (N=40) Significance level (P-value) Variable 16.99±3.07 260.54±183.3 21.33±34.1 0.943±3.2 58.48±17.92 8.0±6.08 20.9±17.7 25.7±25.2 16.79±3.7 272±184.7 18.9±32.4 0.954±335 57.937±17.85 8.4±7.1 23.88±18.51 27.4±27.1 17.35±2.14 252.5±184 26.17±37.4 0.924±3.02 59.47±18.24 7.24±3.1 14.7±14.28 22.5±21.2 Age (years) T3 (ng/dl) T4 (μg/dl) TSH (mIU/l) RAIU 24 h (%) Total dose (mCi) Gap between Dx and Tx (months) Follow-up time (months) 0.935 0.838 0.567 0.972 0.905 0.083 0.438 0.324 All data are presented as mean±SD. Dx, diagnosis; RAIU, radioactive iodine uptake; T3, tri-iodothyronine; T4, tetra-iodothyroxine; TSH, thyroid-stimulating hormone; Tx, therapy. P<0.05 was considered significant. between those who responded to initial therapy (n=85) and those who did not (n=29). Patients on previous ATD therapy showed a poor response to first-dose RAI therapy with an odds ratio 0.538–8.455). However, there was no statistically sig- nificant difference in outcome between the drug naive and ATD group (P=0.280). Outcome was also not sig- nificantly related to factors like age at presentation of disease, sex, baseline T3, T4, and TSH, and 24 h RAIU (Table 2). was done using the Student t-test. In variables in which the distribution of data was not normal the Mann– Whitney test was used. The χ2-test was used to test the association between categorical variables. Kaplan–Meier survival curves were generated to predict the various factors associated with the time to reach euthyroidism/ hypothyroidism. P values less than or equal to 0.05 were considered significant. Stata 11.2 (StataCorp., College Station, Texas, USA) was used for analysis. of 2.134 (95% CI: Results Success after I-131 therapy was defined as a sustained biochemical euthyroid or hypothyroid status for at least 6 months. At initial follow-up, after the first dose of RAI therapy, the proportion of children with hypothroidism, euthyroidisim, and hyperthyroidism was 28% (n=21), 42% (n=31), and 30% (n=22) in group 1 and 45% (n=18), 37.5% (n=15), and 17.5% (n=7) in group 2, respectively (P=0.154). The success rate achieved by single-dose RAI therapy was 70% in group 1 and 83% in group 2 (P=0.228). The success rate achieved at 1-year follow-up in group 1 and group 2 was 81 and 87% (P=0.401), respectively, the difference not being statis- tically significant. Of 29 children who remained hyper- thyroid at first follow-up, 22 had a history of prior carbimazole therapy and seven were drug naive; these patients were treated with successive I-131 therapy (range 2–5 doses) with the cumulative I-131 therapy dose ranging from 10 to 25 mCi (370–925 MBq). Even after subsequent I-131 therapy, seven of 29 patients remained hyperthyroid at last follow-up, and further management was accordingly continued. Four patients who responded to the first dose of I-131 therapy relapsed with hyper- thyroid symptoms at the end of follow-up. Therefore, at the end of follow-up, of 114 patients, 11 remained hyperthyroid. All patients who became hypothyroid were started on thyroxine replacement and titrated subse- quently to maintain serum TSH range between 1 and 3 μIU/ml. To assess the temporal relationship of the effect of I-131 therapy, various predictive factors – namely, age, sex, prior therapy with ATD, thyroid size, duration of ATD, and 24 h RAIU - were analyzed in all 114 patients (Table 3). Among these factors, male sex showed the highest hazard ratio of 1.431 (P=0.042, 95% CI: 0.950–2.152). No significant relationship could be established with respect to any other predictive factors (Fig. 1a–f). Discussion The three major forms of treatment of GD include ATDs, RAI therapy, and thyroidectomy [2]. ATDs are actively transported into the thyroid gland and act on the gland by inhibiting thyroid peroxidase-mediated iodide oxidation, iodine organification, and iodotyrosine cou- pling. The main goal of ATD therapy is to bring patients to a euthyroid condition rather than to a hypothyroid state [13]. Many pediatric endocrinologists still prefer ATD as the first choice of treatment as it is nonablative and Analysis of predictive factors among responders and Table 2 nonresponders in the outcome of first dose of radioiodine Significance level (P-value) Predictive factor Age T3 T4 TSH 24 h RAIU (%) Sex ATD 0.717 0.569 0.243 0.534 0.793 0.247 0.152 Predictive factors To assess the outcome of the first dose of I-131 therapy, various clinical and biochemical variables were analyzed in all 114 patients and the results were compared ATD, antithyroid drug therapy; RAIU, radioactive iodine uptake; T3, tri-iodothyr- onine; T4, tetra-iodothyroxine; TSH, thyroid-stimulating hormone. P<0.05 was considered significant. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

4. Effect of prior ATD on I-131 therapy Ballal et al. 569 as first line therapy for GD in children [14,18–20]. Unlike ATDs, the goal of I-131 therapy for GD is to induce hypothyroidism rather than euthyroidism [6]. Although the desirable endpoint of RAI therapy is to achieve hypothyroidism in GD patients, in our institute I-131 therapy in pediatric GD was aimed at achieving a euthyroid state by administering a fixed low dose of RAI in most patients. It is well known that a very high dose of RAI leads to most patients becoming hypothyroid within a short period of time [21]. In this regard, the dose of RAI administered by us was considered small enough not to cause total ablation of the gland. Thus, 5mCi (185 MBq) of I-131 was administered in the present study. Among 74 patients who had undergone prior ATD therapy before RAI treatment, 70% were cured, of whom 28% became hypothyroid and 42% became euthyroid at initial follow-up. Forty-three percent of the patients became hypothyroid in group 1 and 45% in group 2 at a median follow-up of 15 months. Pinto et al. [9] have reported their experience with RAI treatment in 22 pediatric patients who did not remit with medical therapy. They achieved a 73% success rate with a calculated dose of 3.7 MBq/g of thyroid tissue and all patients turned hypothyroid within a mean period of 2.96±1.05 months. In another study, Allahabadia et al. [22] obtained a suc- cess rate of 66.6% in adult patients using fixed 185 MBq of I-131 activity, which is lower compared with the suc- cess rate in our study but not statistically significant. Analysis of time to reach biochemically euthyroid/ Table 3 hypothyroid state after I-131 therapy and its relation with various predictive factors Median time for euthyroidism/ hypothyroidism (months) Statistical significance (P-value) Predictive factor Hazard ratio 95% CI Sex Male (n=30) Female (n=84) ATD taken previously Yes (n=74) No (n=40) Thyroid enlargment Mild (n=36) Moderate (n=70) Severe (n=8) Duration of ATD (months) <3 (n=54) 3–6 (n=12) >6 (n=48) 24 h RAIU (%) ≤50 >50 5 (2–60) 0.0427 1.431 0.950–2.152 3.5 (2–26) 3 (2–60) 4 (2–24) 0.558 1.104 0.7313–1.665 4 (3–30) 4 (2–60) 0.447 − − 4 (2–5) 4 (2–24) 6 (3–30) 3 (3–60) 0.281 − − 3 (2–17) 4 (2–6) 0.329 1.194 0.753–1.894 Kaplan–Meier analysis was carried out to analyze the various predictive factors associated with the time to reach euthyroidism/hypothyroidism. ATD, antithyroid drugs; CI, confidence interval; RAIU, radioactive iodine uptake. P<0.05 was considered significant. results in subsequent cure, albeit in a small number of pediatric patients [3,14]. However, it must be noted that remission is definitely achieved only in about 20–30% of pubertal children after the course of ATD [3–5]. Also, ATDs are associated with adverse side effects and also have high relapse rates, particularly in children [3–7,15, 16]. Published data show that 20–30% children usually develop complications of drug therapy [7,15]. Serious and fatal side effects of ATDs, such as liver toxicity leading to organ failure, have also been observed [16]. Several factors have been considered to influence the outcome of RAI treatment. Studies in adults have shown that ATD confers a degree of radio-resistance but the results have been conflicting, with some [23,24] but not all [11,12,25] reporting a reduction in response rates to RAI in patients pretreated with ATD. Similarly, a meta- analysis report of 14 randomized controlled trials on adults with a total of 1306 participants by Walter et al. [26] suggested that ATD were associated with increased treatment failures when given before, with, or after RAI. These studies advocate the radioprotective effect of ATD, which was observed in the adult population. Similarly in our study, in the pediatric population there was a trend toward lower success rate in group 1 com- pared with drug-naive group 2; however, it was not sta- tistically significant, perhaps because of the smaller number of patients studied. A recent retrospective study by Cury et al. analyzed the effect of prior ATD therapy on the outcome of RAI therapy in GD among children. Among a total of 65 patients, 61 children were on prior ATD therapy. Consistent with our results, pretreatment with ATD did not alter the efficacy of RAI therapy [27]. Moreover, our study found no difference in the median time to attain hypothyroidism/euthyroidism between the two groups (Table 3). The high failure rate of I-131 with prior treatment with ATD has been attributed to a decrease in RAIU by the thyroid [24]. Although calcu- lated dose regimens adapted to I-131 uptake possibly Subtotal thyroidectomy earlier and total thyroidectomy in current time are the choice surgical procedures in GD patients. However, it is associated with complications such as hypocalcemia, laryngeal nerve injury, hematoma, and hypoparathyroidism. Hence, in children this may not be considered a choice of treatment. Dötsch et al. [17] reported the success rate of surgery as 97%, but with severe adverse effects occurring in ∼4% of patients. Alternatively, administration of RAI to GD patients is associated with reasonably high success rates. Although RAI therapy for GD was introduced more than 60 years ago, its application in children became widespread only after the 1990s, when sufficient supporting data on its efficacy in children and their long-term follow-up were published [3,5,8–10]. Traditionally, RAI has been advised in children if major side effects are experienced or if hyperthyroidism did not remit after prolonged medical treatment or compliance issues. However, the use of RAI in hyperthyroidism is increasing, particularly Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

5. Nuclear Medicine Communications 570 2015, Vol 36 No 6 Fig. 1 (a) (b) 100 100 100 − probability remission (%) 80 80 60 60 40 40 ≤ 16 years > 16 years Group 1 Group 2 20 20 0 0 20 30 40 50 60 0 10 20 30 40 50 60 0 10 (c) (d) 100 100 100 − probability remission (%) 80 80 60 60 40 40 ≤ 50% > 50% 20 20 Male Female 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 (e) (f) 100 100 100 − probability remission (%) 80 80 60 60 40 40 < 3 months 3 − 6 months 20 20 Palpable Nonpalpable > 6 months 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Time (months) Time (months) Kaplan–Meier analysis of various predictive factors associated with time to reach euthyroidism/hypothyroidism. (a) Prior ATD therapy group (group 1) versus drug naive group (group 2). (b) Age ≤15 versus >15 years. (c) Male patients versus female patients. (d) 24h-RAIU: ≤50 versus >50%. (e) Palpable versus nonpalpable gland size. (f) Duration of ATD taken before radioiodine therapy. Male sex showed the highest hazard ratio of 1.431 (P=0.042, 95% CI: 0.950–2.152). ATD, antithyroid drug therapy; CI, confidence interval; RAIU, radioiodine uptake. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

6. Effect of prior ATD on I-131 therapy Ballal et al. 571 compensate for this effect, this modification does not alter the cure rates [26,28]. Therefore, the inhibition of thyroid-peroxidase-catalyzed synthesis of free radicals that mainly mediate cell damage in RAI treatment is a more suitable explanation for the radioprotective effect of ATD. previously analyzed in the adult population, our study merits attention as the first to report no effect of ATD therapy in a large population of pediatric patients. However, as all patients in group 1 were only on prior carbimazole therapy, the influence of propylthiouracil on the outcome of RAI therapy could not be assessed. The outcome of the various predictive factors in pediatric GD patients with RAI has been studied on a large scale in the Western world; however, no similar study has been reported from the Indian subcontinent to the best of our knowledge. In addition, being a retrospective analysis there is the risk of bias. Therefore, more prospective randomized control trials should be carried out for sys- tematic and unbiased results. Allahabadia et al. [22] reported in adults that male GD patients had a significantly lower success rate after a single dose of RAI compared with women. In dis- cordance with their results in adults, no significant dif- ference was observed in single-dose success rates between male and female children in our population (P=0.247). However, 79% of boys achieved remission compared with 91% of girls at 1-year follow-up. Because of the difference in achieving remission at various time points, a significant difference was observed in the time to reach euthyroidism/hypothyroidism in boys when compared with girls (P=0.042; 95% CI: 0.950–2.152). Most dosimetric methods incorporate the size of the thyroid and RAIU, because these two parameters have been considered as important predictive factors for the success of RAI therapy by many authors [9,21]. However, there is evidence from various studies that calculated doses of RAI do not have any benefit over fixed doses in improving the success rates of pediatric GD patients [29]. In our study, we did not find RAIU to be significantly related to the success rate in the pediatric patients. To conclude, prior carbimazole treatment did not influ- ence the outcome of I-131 therapy in the pediatric and adolescent population with GD. Although there was a trend toward lower success rates in children and adoles- cents treated with carbimazole before I-131 therapy, it was not statistically significant. The present study also proved I-131 therapy to be safe, effective, and associated with high success rates irrespective of whether carbima- zole therapy was given. Acknowledgements Conflicts of interest There are no conflicts of interest. Clark et al. [8] reported the acute side effects of RAI treatment, which included transient vomiting, radiation- induced thyroiditis, and the development of thyroid nodules in the long run. Unlike their study, our patients did not experience any significant side effects. I-131, being radioactive, possesses the theoretical risk of indu- cing neoplastic changes leading to the development of malignancies. Read et al. [30], in a retrospective analysis of 116 young patients, did not find an increase in the risk for cancer when followed up for 36 years. Also, a number of studies have failed to show any causal relationship between RAI therapy and subsequent development of leukemia or other malignancies [2,3,8,10]. The duration of follow-up in these studies ranged from less than 5 years to 20 years. Studies of the offspring born to patients who received RAI for childhood GD revealed a 3% incidence of congenital anomaly, similar to the gen- eral population [31]. Furthermore, there are no reports of increase in miscarriage rates or fetal losses because of genetic abnormalities in patients treated with RAI [32]. In our study, four children were followed up to 18 years and no malignant transformation has been observed yet. Therefore, RAI should be considered a safe and effective therapy for pediatric GD [10,20,31]. Hence, the main goal of RAI treatment for GD in children should be to achieve cure by hyperthyroidism in the shortest possible time with the highest possible euthyroid rates. This is a single institutional experience. Although the effect of ATD therapy on the outcome of RAI therapy has been References 1 Kraiem Z, Newfield RS. Graves’ disease in childhood. J Pediatr Endocrinol Metab 2001; 14:229–243. 2 Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin North Am 1998; 27:109–126. 3 Hamburger JI. Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab 1985; 60:1019–1024. 4 Lazar L, Kalter-Leibovici O, Pertzelan A, Weintrob N, Josefsberg Z, Phillip M. Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab 2000; 85:3678–3682. 5 Rivkees SA, Sklar C, Freemark M. Clinical review 99: the management of Graves’ disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab 1998; 83:3767–3776. 6 Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, et al. Hyperthyroidism and other causes of thyrotoxicosis management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011; 21:593–646. 7 Chapman EM. History of the discovery and early use of radioactive iodine. JAMA 1983; 250:2042–2044. 8 Clark JD, Gelfand MJ, Elgazzar AH. Iodine-131 therapy of hyperthyroidism in pediatric patients. J Nucl Med 1995; 36:442–445. 9 Pinto T, Cummings EA, Barnes D, Salisbury S. Clinical course of pediatric and adolescent Graves’ disease treated with radioactive iodine. J Pediatr Endocrinol Metab 2007; 20:973–980. 10 Ron E, Doody MM, Becker DV, Brill AB, Curtis RE, Goldman MB, et al. Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group. JAMA 1998; 280:347–355. 11 Andrade VA, Gross JL, Maia AL. The effect of methimazole pretreatment on the efficacy of radioactive iodine therapy in Graves’ hyperthyroidism: one- year follow-up of a prospective, randomized study. J Clin Endocrinol Metab 2001; 86:3488–3493. 12 Braga M, Walpert N, Burch HB, Solomon BL, Cooper DS. The effect of methimazole on cure rates after radioiodine treatment for Graves’ hyperthyroidism: a randomized clinical trial. Thyroid 2002; 12:135–139. 13 Cooper DS. Treatment of thyrotoxicosis. In: Braverman LE, Cooper SD, editors. Werner & Ingbars’s the thyroid a fundamental and clinical text, 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. pp. 492–516. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

7. Nuclear Medicine Communications 572 2015, Vol 36 No 6 Marcocci C, Gianchecchi D, Masini I, Golia F, Ceccarelli C, Bracci E, et al. A reappraisal of the role of methimazole and other factors on the efficacy and outcome of radioiodine therapy of Graves’ hyperthyroidism. J Endocrinol Invest 1990; 13:513–520. Walter MA, Briel M, Christ-Crain M, Bonnema SJ, Connell J, Cooper DS, et al. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ 2007; 334:514. Cury AN, Meira VT, Monte O, Marone M, Scalissi NM, Kochi C, et al. Clinical experience with radioactive iodine in the treatment of childhood and adolescent Graves’ disease. Endocr Connect 2013; 2:32–37. Imseis RE, Vanmiddlesworth L, Massie JD, Bush AJ, Vanmiddlesworth NR. Pretreatment with propylthiouracil but not methimazole reduces the therapeutic efficacy of iodine-131 in hyperthyroidism. J Clin Endocrinol Metab 1998; 83:685–687. Peters H, Fischer C, Bogner U, Reiners C, Schleusener H. Radioiodine therapy of Graves’ hyperthyroidism: standard vs. calculated 131-iodine activity. Results from a prospective, randomized, multicentre study. Eur J Clin Invest 1995; 25:186–193. Read CH Jr, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves’ patients. J Clin Endocrinol Metab 2004; 89:4229–4233. Ma C, Kuang A, Xie J, Liu G. Radioiodine treatment for pediatric Graves’ disease. Cochrane Database Syst Rev 2008; 16:1–29. Gruters A. Treatment of Graves’ disease in children and adolescents. Horm Res 1998; 49:255–257. 25 14 Leu SW, Chi CS, Shu SG. Outcome of antithyroid medication and radioiodine therapy in pediatric Graves’ disease. Acta Paediatr Taiwan 2003; 44:220–226. Vaidya VA, Bongiovanni AM, Parks JS, Tenore A, Kirkland RT. Twenty-two years’ experience in the medical management of juvenile thyrotoxicosis. Pediatrics 1974; 54:565–570. Chawla M, Bal CS. Four cases of coexistent thyrotoxicosis and jaundice: results of radioiodine treatment and a brief review. Thyroid 2008; 18:289–292. Dötsch J, Rascher W, Dörr HG. Graves disease in childhood: a review of the options for diagnosis and treatment. Paediatr Drugs 2003; 5:95–102. Rivkees S. Radioactive iodine use in childhood Graves’ disease: time to wake up and smell the I-131. J Clin Endocrinol Metab 2004; 89:4227–4228. Rivkees SA. The treatment of Graves’ disease in children. J Pediatr Endocrinol Metab 2006; 19:1095–1111. Rivkees SA, Dinauer C. An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab 2007; 92:797–800. Rivkees SA, Cornelius EA. Influence of iodine-131 dose on the outcome of hyperthyroidism in children. Pediatrics 2003; 111 (Pt 1):745–749. Allahabadia A, Daykin J, Sheppard MC, Gough SC, Franklyn JA. Radioiodine treatment of hyperthyroidism–prognostic factors for outcome. J Clin Endocrinol Metab 2001; 86:3611–3617. Koroscil TM. Thionamides alter the efficacy of radioiodine treatment in patients with Graves’ disease. South Med J 1995; 88:831–836. Sabri O, Zimny M, Schulz G, Schreckenberger M, Reinartz P, Willmes K, Buell U. Success rate of radioiodine therapy in Graves’ disease: the influence of thyrostatic medication. J Clin Endocrinol Metab 1999; 84:1229–1233. 15 26 16 27 17 18 28 19 20 29 21 22 30 23 31 24 32 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.