antithyroid drugs ( atd ) have been proposed as a first - line treatment for children with graves disease ( gd ) 
 ( 1,2,3 ) . because recent reports have documented that propylthiouracil ( ptu ) is associated with 
 severe side effects , methimazole ( mmi ) although the initial dose of mmi for pediatric gd is generally 0.51.0 mg / kg / d given once or twice daily ( 5 ) , the most appropriate dose at the start of therapy is controversial . for 
 adults with gd , mmi 15 mg / d is recommended for patients with mild and moderate disease , as this dosage was 
 demonstrated to induce euthyroidism as effectively as 30 mg / d of mmi but with a significantly lower frequency of 
 adverse events ( 6 , 7 ) . for adults 
 with severe gd , 30 mg / d of mmi can induce euthyroidism quickly ( within 3 mo ) and is thus the recommended dosage 
 ( 6 , 7 ) . we retrospectively compared high and low doses of 
 mmi in children to determine the most appropriate dosing for this age group . newly diagnosed patients with gd who were treated with mmi were included in the retrospective analysis . gd 
 was diagnosed by clinical findings and the determination of serum t3 , t4 , free t4 ( ft4 ) , free t3 ( ft3 ) , 
 thyroid stimulating hormone ( tsh ) , tsh receptor antibody ( trab ) and i- or tc 
 uptake . patients who were older than 17 yr of age , who had severe complications , such as heart failure , or who 
 were receiving glucocorticoid steroids or drugs that might influence thyroid function were excluded from the 
 study . this retrospective study was conducted at four medical institutions in japan : yaizu city hospital in yaizu , 
 west hamamatsu medical center in hamamatsu , fujieda city hospital in fujieda and hamamatsu university school 
 of medicine in hamamatsu , japan . the ethical committees of hamamatsu university school of medicine and each 
 hospital involved in the study approved the protocol . all eligible patients with untreated gd were seen at one 
 of the four participating medical institutions from october 1991 to march 2009 and were treated with mmi . they 
 were registered for the trial after informed consent was obtained from the patients legal guardians . the 
 patients were divided into the high - dose mmi group ( hd ; mmi0.7 mg / kg / d ) or low - dose mmi group ( ld ; mmi<0.7 
 mg / kg / d ) based on hospital records . a total of 35 patients with untreated gd were initially recruited for the 
 study ; 8 patients were excluded from the final analysis for the following reasons : could not be follow up 
 ( n=1 ) , change in drug regimen or lack of efficacy ( n=5 ) and drug dose was reduced before ft4 reached normal 
 levels of 1.6 ng / dl ( n=2 ) . the reasons for changing the drug regimen included side effects in 2 patients ( 1 
 patient started on an mmi dose of 0.31 mg / kg / d and experienced a mild decrease in white blood cell count , mild 
 liver function abnormalities and drug fever , and 1 patient started on a mmi dose of 0.50 mg / kg / d and 
 experienced drug eruption ) and lack of efficacy in 2 patients ( 1 patient s dose was increased to 1.2 mg / kg / d 
 ( 45 mg / d ) , and 1 patient s dose was increased to 1.8 mg / kg / d ( 60 mg / d ) ; the reason was unknown in 1 patient . 
 ultimately , 27 patients were evaluated ( fig . characteristics of the patients are shown in table 1table 
 1  characteristics and clinical data of the patients . we compared the duration between the start of 
 mmi start and normalization of thyroid function between the groups . normalization of thyroid function was 
 defined as ft4 levels of 0.81.6 ng / dl or t4 levels of 512 g / dl ( 2 patients were followed by t4 ) . after the 
 serum ft4 level decreased to within the normal range , the mmi dosage was reduced to match the condition of 
 each patient . because ft3 and tsh levels require more time to reach normal levels than the ft4 level , it is 
 difficult to analyze the results for ft3 and tsh , and therefore we used only the ft4 levels to define 
 normalization of thyroid function . remission was defined as a continuous euthyroid state for more than 1 yr 
 without drugs . the dose of mmi was lessened over time , but it was not reduced before the ft4 or t4 levels 
 reached normal ranges . after the ft4 or t4 levels reached normal ranges , the patients were given suitable 
 doses of mmi to maintain normal thyroid hormone ( th ) concentrations . although some patients received treatment 
 with l - thyroxine , which influenced the ft4 levels , no patient received this medication before the ft4 or t4 
 levels were normalized . we also analyzed the time it took for the ft3 and tsh levels to normalize . serum ft4 , ft3 and tsh were measured using a roche eclusys kit ( roche , basel , switzerland ) . normal values and 
 measurable ranges are as follows : ft4 , 0.81.6 ng / dl ( measurable range up to 7 ng / dl ) ; t4 , 512 g / dl ; and 
 ft3 , 3.14.9 pg / ml ( measurable range up to 30 pg / ml ) . trab ( normal range 010% ) was assayed with trab - ct 
 ( cosmic corporation , tokyo , japan ) . normal ranges for the thyroid scan and uptake are as follows : 0.43.0% 
 for tc , 13% for i ( we used the 6-h uptake after oral administration , and patients 
 had restricted intake of iodine - containing food for a week prior to the scan ) . newly diagnosed patients with gd who were treated with mmi were included in the retrospective analysis . gd 
 was diagnosed by clinical findings and the determination of serum t3 , t4 , free t4 ( ft4 ) , free t3 ( ft3 ) , 
 thyroid stimulating hormone ( tsh ) , tsh receptor antibody ( trab ) and i- or tc 
 uptake . patients who were older than 17 yr of age , who had severe complications , such as heart failure , or who 
 were receiving glucocorticoid steroids or drugs that might influence thyroid function were excluded from the 
 study . this retrospective study was conducted at four medical institutions in japan : yaizu city hospital in yaizu , 
 west hamamatsu medical center in hamamatsu , fujieda city hospital in fujieda and hamamatsu university school 
 of medicine in hamamatsu , japan . the ethical committees of hamamatsu university school of medicine and each 
 hospital involved in the study approved the protocol . all eligible patients with untreated gd were seen at one 
 of the four participating medical institutions from october 1991 to march 2009 and were treated with mmi . they 
 were registered for the trial after informed consent was obtained from the patients legal guardians . the 
 patients were divided into the high - dose mmi group ( hd ; mmi0.7 mg / kg / d ) or low - dose mmi group ( ld ; mmi<0.7 
 mg / kg / d ) based on hospital records . a total of 35 patients with untreated gd were initially recruited for the 
 study ; 8 patients were excluded from the final analysis for the following reasons : could not be follow up 
 ( n=1 ) , change in drug regimen or lack of efficacy ( n=5 ) and drug dose was reduced before ft4 reached normal 
 levels of 1.6 ng / dl ( n=2 ) . the reasons for changing the drug regimen included side effects in 2 patients ( 1 
 patient started on an mmi dose of 0.31 mg / kg / d and experienced a mild decrease in white blood cell count , mild 
 liver function abnormalities and drug fever , and 1 patient started on a mmi dose of 0.50 mg / kg / d and 
 experienced drug eruption ) and lack of efficacy in 2 patients ( 1 patient s dose was increased to 1.2 mg / kg / d 
 ( 45 mg / d ) , and 1 patient s dose was increased to 1.8 mg / kg / d ( 60 mg / d ) ; the reason was unknown in 1 patient . 
 ultimately , 27 patients were evaluated ( fig . characteristics of the patients are shown in table 1table 
 1  characteristics and clinical data of the patients . we compared the duration between the start of 
 mmi start and normalization of thyroid function between the groups . normalization of thyroid function was 
 defined as ft4 levels of 0.81.6 ng / dl or t4 levels of 512 g / dl ( 2 patients were followed by t4 ) . after the 
 serum ft4 level decreased to within the normal range , the mmi dosage was reduced to match the condition of 
 each patient . because ft3 and tsh levels require more time to reach normal levels than the ft4 level , it is 
 difficult to analyze the results for ft3 and tsh , and therefore we used only the ft4 levels to define 
 normalization of thyroid function . remission was defined as a continuous euthyroid state for more than 1 yr 
 without drugs . the dose of mmi was lessened over time , but it was not reduced before the ft4 or t4 levels 
 reached normal ranges . after the ft4 or t4 levels reached normal ranges , the patients were given suitable 
 doses of mmi to maintain normal thyroid hormone ( th ) concentrations . although some patients received treatment 
 with l - thyroxine , which influenced the ft4 levels , no patient received this medication before the ft4 or t4 
 levels were normalized . we also analyzed the time it took for the ft3 and tsh levels to normalize . serum ft4 , ft3 and tsh were measured using a roche eclusys kit ( roche , basel , switzerland ) . normal values and 
 measurable ranges are as follows : ft4 , 0.81.6 ng / dl ( measurable range up to 7 ng / dl ) ; t4 , 512 g / dl ; and 
 ft3 , 3.14.9 pg / ml ( measurable range up to 30 pg / ml ) . trab ( normal range 010% ) was assayed with trab - ct 
 ( cosmic corporation , tokyo , japan ) . normal ranges for the thyroid scan and uptake are as follows : 0.43.0% 
 for tc , 13% for i ( we used the 6-h uptake after oral administration , and patients 
 had restricted intake of iodine - containing food for a week prior to the scan ) . calculations were performed 
 using statview , version 5.0 ( sas institute , inc . , mmi efficacy was assessed in 8 children in the hd group and 19 children in the ld group . mean age , sex , number 
 of complications , initial ft3 value , initial ft4 value , initial tsh value , trab , tc uptake and 
 i uptake before treatment showed no significant differences between the groups ( table 2).table 2   comparison of clinical data between the hd and ld groupshdldp valuenumber of patients819mean age  sd ( yr)9.5  3.412.0  3.10.08sex male03sex female816number with complications4 ( 50%)5 ( 26.3%)mmi dose  sd ( mg / kg / d)0.85  0.130.51  0.12<0.0001initial ft3 value sd ( pg / dl)21.8  6.9 ( n=7)18.0  7.9 ( n=18)0.28initial ft4 value  sd ( ng / dl)5.5  2.85.0  2.40.59initial tsh value  sd ( u / ml)<0.01<0.01trab  sd ( % ) 56.2  29.360.9  27.20.69tc uptake51.1 ( n=1)46.6  29.9 ( n=9)i uptake65.9  9.1 ( n=3)37.8  12.6 ( n=2)0.06period in hospital  sd ( day)31.4  3.426.0  23.90.63number of remission3/46/8**hd : introduced to another hospital ( n=2 ) within 2 yr after diagnosis of gd ( n=2 ) . ld : introduced to 
 another hospital ( n=5 ) within 2 yr after diagnosis of gd ( n=6 ) . * hd : introduced to another hospital ( n=2 ) within 2 yr after diagnosis of gd ( n=2 ) . ld : introduced to 
 another hospital ( n=5 ) within 2 yr after diagnosis of gd ( n=6 ) . the mean time required to achieve normal ft4 or t4 levels was 22.5  7.4 d in the hd group and 28.8  16.2 d in 
 the ld group ( p=0.30 ) . although differences between the groups were not statistically significant , children in 
 the ld group tended to require more time to achieve normal ft4 levels than those in the hd group ( fig . mg / kg / d ) and low - dose ( ld ; < 0.7 mg / kg / d ) mmi groups among children with graves disease . efficacy was 
 defined as achieving normal ft4 levels ( 1.6 ng / dl ) or t4 levels ( 12 g / dl ) . the numbers above the 
 columns represent the p values for the nonparametric t - test analysis of the mmi hd and ld 
 groups . the bars in the columns indicate the mean time needed to achieve normal ft4 
 levels . ) . initial ft3 level , age , trab , antithyroid peroxidase antibody ( tpoab ) and complications did not 
 influence the time needed for ft4 to normalize ( data not shown ) . mg / kg / d ) and low - dose ( ld ; < 0.7 mg / kg / d ) mmi groups among children with graves disease . efficacy was 
 defined as achieving normal ft4 levels ( 1.6 ng / dl ) or t4 levels ( 12 g / dl ) . the numbers above the 
 columns represent the p values for the nonparametric t - test analysis of the mmi hd and ld 
 groups . the bars in the columns indicate the mean time needed to achieve normal ft4 
 levels . at the time that ft4 normalized , the ft3 levels in the hd and ld groups were 5.3  0.9 and 6.4  1.4 pg / dl , 
 respectively ( p=0.14 ) . days in the hospital and remission 
 rates did not differ significantly between the hd and ld groups . side effects occurred in 1 ( 12.5% ) patient in 
 the hd group and 7 ( 36.8% ) patients in the ld group . all side effects were minor , with the most common effect 
 being a rash . the ft3 levels reached normal ranges in 43.2  20.8 d in the hd group and 64.3  48.3 d in the ld group 
 ( p=0.37 ) , and the tsh levels reached normal ranges in 90.2  42.3 d in the hd group and 111.6  59.1 d in the ld 
 group ( p=0.48 ) . thus these results 
 include patients whose mmi dose was lowered before the ft3 or tsh levels became normal . after the ft4 levels 
 normalized , the dosages were determined individually by the treating physicians , and there were differences 
 among the patients . we also divided the patients into 2 groups based on the severity of the initial ft4 level and analyzed which 
 patient group should receive hd mmi based on the time of efficacy of treatment ( i.e. , achieving normal ft4 
 levels ) . in the severe ft4 group ( initial ft47 ) , efficacy occurred in 25.0  6.0 d in the hd group and 28.0  
 9.8 d in the ld group ( p=0.66 ) . in the mild ft4 group ( initial ft4<7 ) , efficacy occurred in 21.0  8.5 d in 
 the hd group and 29.1  17.8 d in the ld group ( p=0.35 ; fig . 3fig . 3 
 comparison of treatment efficacy between the high - dose ( hd ; 0.7 mg / kg / d ) and low - dose ( ld ; < 0.7 
 mg / kg / d ) mmi groups among children with graves disease based on the initial ft4 levels . the bars in the 
 columns indicate the mean time needed to achieve normal ft4 levels . the severe ft4 group included patients 
 that had an initial ft47 ng / dl , and the mild ft4 group included patients that had an initial ft4<7 
 ng / dl . ) . comparison of treatment efficacy between the high - dose ( hd ; 0.7 mg / kg / d ) and low - dose ( ld ; < 0.7 
 mg / kg / d ) mmi groups among children with graves disease based on the initial ft4 levels . the bars in the 
 columns indicate the mean time needed to achieve normal ft4 levels . the severe ft4 group included patients 
 that had an initial ft47 ng / dl , and the mild ft4 group included patients that had an initial ft4<7 
 ng / dl . because of the risk of thyroid cancer associated with radioiodine therapy and the difficulty of performing 
 surgery , many endocrinologists use an atd ( antithyroid drug ) as the nitial treatment for gd in childhood , even 
 if the remission rates are low ( 2 , 5 , 13,14,15,16 ) . in a survey of members of the 
 european thyroid association ( eta ) and of the european society for pediatric endocrinology ( espe ) , 99% of 
 respondents reported that an atd was the initial treatment choice for children with uncomplicated gd ( 3 ) . in japan , both mmi and ptu have been used as atds . however , ptu has a much higher rate of adverse effect in 
 pediatric gd , including a high prevalence of increased antineutrophil cytoplasmic antibodies ( 14 ) . in april 2009 , the lawson wilkins pediatric endocrine society raised concerns about serious hepatic toxicities 
 ( even requiring liver transplantation ) and death among children with gd receiving ptu . these problems have not 
 been reported with mmi use in children ( 4 ) . thus , mmi has become the more 
 popular choice for treatment of gd in children . in addition , the long duration of action of mmi allows for 
 once - daily dosing , which helps increase compliance with treatment ( 12 ) . the recommended dosage for initial therapy with mmi is 0.51.0 mg / kg / d for children with gd ( 3 ) , but there is little evidence to support this dosage . more than half of the 
 pediatric endocrinologists and thyroidologists responding to a questionnaire survey indicated that they started 
 mmi for pediatric gd at 1 mg / kg / d ( 1 ) . therefore , if the dose is based on 
 body weight , many children will start near 30 mg / d and exceed the dose recommended for adults . several reports have compared 15 mg / d and 30 
 mg / d of mmi and concluded there is no difference between dosages in mean time to euthyroidism ( 6,7,8,9 ) . however , it is generally recommended that patients with 
 severe gd start at 30 mg / d of mmi to induce euthyroidism quickly ( 6,7,8,9 ) . it has been demonstrated that the frequency of adverse events is lower with 15 mg / d than with 30 
 mg / d ( 6 , 7 , 10 , 11 ) , and we thought the lower dosage might also be 
 appropriate for children with gd . in our study , there were no significant differences in the time needed to achieve normal ft4 levels between the 
 hd and ld groups . thus , 
 there does not appear to be any benefit to using a higher dose of mmi in children . in the ld group , thus , we believe that a starting dose of mmi of 0.5 mg / kg / d for children with gd 
 is sufficient . ( 17 ) reported no 
 differences in time to efficacy between hd ( mmi0.7 mg / kg / d ) and ld ( mmi<0.7 mg / kg / d ) groups , with efficacy 
 achieved in 1.8  1.3 months in the hd group ( n=24 ) and 2.0  1.3 months in the ld group ( n=23 ) . however , they 
 did not report the ft4 levels , and no information was provided regarding how they defined efficacy . in their 
 research , those receiving ld mmi took a slightly longer time to achieve efficacy , but as with our study , the 
 results did not differ significantly between groups . it is known that there are many factors related with 
 remission rate in treatment of gd . our data seem to indicate there was at least no strong relation between 
 remission rate and initial mmi dose . for pediatric patients , their school life and physical activity are also restricted 
 before euthyroidism occurs . until now , there was a tendency to use a high dose of mmi , which can induce 
 euthyroidism quickly , to shorten the inpatient stay . however , our data shows no significant difference in time 
 to euthyroidism between the high and low doses of mmi . because all types of therapy should be initiated at the 
 minimum effective dose , a lower dose of mmi may be more appropriate for children with mild or moderate gd . in terms of severe gd , adults have been generally prescribed a higher dosage ( i.e. , mmi 30 mg / d ) ( 7 ) . we had a few patients with severe gd ( initial ft47 ) , and there was no 
 clear differentiation between the hd and ld in this group . this finding suggests that even in children with 
 severe disease , a low dose of mmi can be used to normalize thyroid function safely . however , our study included 
 only a small number of patients , especially of severe patients , and was retrospective in design , which limits 
 the ability to generalize these findings to larger populations . further prospective studies may more precisely 
 clarify the optimal dose of mmi for children with gd . for children with mild or moderate gd , an initial dose of mmi<0.7 ( mean 0.51  0.12 ) mg / kg / d is as effective 
 as a higher dose (  0.7 ( 0.85  0.13 ) mg / kg / d ) in normalizing the serum ft4 level .
antithyroid drugs are widely used in the therapy of graves disease ( gd ) , and methimazole ( mmi ) is preferred 
 for treatment of pediatric gd . 
 the recommended initial dosage of mmi is 0.51.0 mg / kg / d for pediatric gd , 
 although there are few studies on the optimal mmi dosage for initial treatment in children . 
 we retrospectively 
 compared the efficacy of different doses of mmi in 35 children with gd . 
 eight children were excluded due to 
 lack of follow - up , etc . 
 the remaining 27 children were divided into a high - dose group ( hd ; mmi0.7 ( 0.85  
 0.13 ) mg / kg / d , n=8 ) and a low - dose group ( ld ; mmi<0.7 ( 0.51  0.12 ) mg / kg / d , n=19 ) , and we compared the 
 time needed for the serum ft4 levels to normalize ( 1.6 ng / dl ) between the groups . 
 there were no significant 
 differences between the ft4 levels ( hd : 5.5  2.8 ng / dl ; ld : 5.0  2.4 ng / dl p=0.59 ) or thyroid stimulating 
 hormone receptor antibody levels ( hd : 56.2  29.3% ; ld : 60.9  27.2% p=0.69 ) between the groups before 
 treatment . 
 the mean time required to normalize the ft4 levels was 22.5  7.4 d in the hd group and 28.8  16.2 
 d in the ld group ( p=0.30 ) . 
 in addition , no other factor influenced the time to efficacy of mmi . 
 a dose of 
 mmi<0.7 ( 0.51  0.12 ) mg / kg / d appears to as effective as a higher dose in normalizing the serum ft4 level 
 in children with mild or moderate gd .