Treatment and prognosis of Graves disease in children and adolescents

INTRODUCTION — Hyperthyroidism in children and adolescents has unique effects on growth and development, in addition to causing many of the same symptoms that it does in adults. Graves disease is the most common cause of hyperthyroidism in this age group, accounting for more than 95 percent of cases [1]. Nearly all children with Graves disease have a diffuse goiter. Thyroid eye disease (also called Graves ophthalmopathy) also may be present but is less severe than in adults.

The treatment and prognosis of Graves disease in childhood and adolescence will be discussed here. The clinical manifestations and diagnosis are presented separately. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

Rarely, conditions other than Graves disease may cause hyperthyroidism in children. These include autoimmune thyroiditis (also known as chronic lymphocytic or Hashimoto thyroiditis); subacute granulomatous thyroiditis (de Quervain disease); solitary hyperfunctioning thyroid nodules or toxic multinodular goiter; pituitary thyroid-stimulating hormone (TSH)-secreting adenoma; and hyperthyroidism induced by iodine, neck trauma, or radiation. Treatment of these conditions is similar to that for adults, except that children with hyperfunctioning nodules generally are treated with surgery rather than radioactive iodine (RAI). (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

SELECTION OF TREATMENT — Children and adolescents with Graves hyperthyroidism can be treated with an antithyroid drug (ATD), radioactive iodine (RAI), or thyroidectomy. The choice of therapy is determined by individual consideration of the risks and benefits of the three treatment modalities. Regardless of the choice of treatment, all patients will require lifelong monitoring. An overview of treatment is shown in the algorithm (algorithm 1).

Most pediatric endocrinologists recommend ATD therapy as initial treatment, with the hope that the patient will have a remission of Graves disease and remain euthyroid after treatment is discontinued. RAI therapy generally is used for children who do not achieve a permanent remission after a period of ATD treatment or for those who experience serious adverse effects necessitating discontinuation of ATD treatment. RAI also may be used as initial treatment for children older than 10 years [2]. Surgical near-total thyroidectomy is also an effective and safe treatment.

The primary considerations for each of these therapies are (table 1):

●ATDs – ATDs are the best-established treatment in the pediatric age group and provide a chance of achieving sustained remission with euthyroidism. However, improvement is gradual, the course of treatment is long, and patients must be monitored for potential adverse medication effects.

●RAI – Permanently cures hyperthyroidism in most cases and replaces it with hypothyroidism, which requires lifelong thyroid hormone replacement therapy. Although there are theoretical concerns about the risks of radiation exposure, small studies in children have not demonstrated increased long-term risks of thyroid cancer or other cancers.

●Surgery – Provides the most rapid resolution of hyperthyroidism and avoids the theoretical risk of radiation exposure. The patient is exposed to modest surgical risks and is rendered hypothyroid, which requires lifelong thyroid hormone replacement therapy.

Details about each of these treatments are discussed in the following sections.

ANTITHYROID DRUGS — Most children and adolescents with Graves hyperthyroidism respond well to an antithyroid drug (ATD), with 87 to 100 percent becoming euthyroid within a few weeks to a few months [2-6]. We recommend using methimazole (MMI; 0.25 to 1.0 mg/kg per day). Propylthiouracil (PTU; 5 to 10 mg/kg per day) also is effective but should not be used as initial therapy, because it has more frequent and severe side effects, including a small risk of severe hepatotoxicity [7,8]. Because of these safety concerns, the Endocrine Society (ES), American Thyroid Association (ATA) and European Thyroid Association (ETA) recommend against the use of PTU as first-line treatment for Graves disease in children [9-11] and the US Food and Drug Administration (FDA) has issued a boxed warning [12]. PTU may be reserved for children who experience a minor side effect with MMI that is not a contraindication to continued ATD use and for whom RAI or surgery are not treatment options [13]. (See 'Adverse effects' below and "Thionamides: Side effects and toxicities" and "Thionamides in the treatment of Graves' disease".)

Initiating and adjusting therapy

●Pretreatment tests and counseling – Before initiating therapy, we perform laboratory screening with a white blood cell (WBC) count and differential, and with serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin [10,11]. Modest decreases in WBC and elevations in liver enzymes can be caused by hyperthyroidism itself, as well as by ATD treatment.

Adolescent females of reproductive age should be warned about the risks of birth defects reported with ATD use during pregnancy and provided with counseling about contraceptives as needed [14]. Birth defects in babies born to mothers who take MMI and PTU in the first trimester occur at approximately twice the rate of a control population [15]. MMI is associated with an embryopathy characterized by cutis aplasia, congenital heart defects (septal defects) [16], urinary tract malformations, and omphalocele. PTU is associated with malformations of the face and neck and urinary tract malformations [17].

●Initial dosing – We choose an initial methimazole (MMI) dose between 0.25 and 1.0 mg/kg/day based on clinical severity, size of goiter, and biochemical severity. Patients with mild features of hyperthyroidism, a small goiter, and milder elevations of serum free T4 (thyroxine) and T3 (triiodothyronine) are started at the lower end of the dose range (around 0.25 mg/kg/day). Patients with more severe clinical features of hyperthyroidism, a large goiter, and more severe elevations of serum free T4 and T3 are started at the higher end of the dose range (0.5 to 1.0 mg/kg/day). Children younger than seven years of age typically also require this higher dose [18]. MMI usually is dosed once daily, but, in our experience, two divided doses may be more efficacious in children with severe hyperthyroidism. Since MMI is available as 5 mg or 10 mg tablets, for practical purposes, we round doses so that whole or one-half tablets can be used.

●Dose adjustments – After initiating treatment, we adjust the MMI dose based on serial measurements of serum thyroid-stimulating hormone (TSH), free T4, and total T3. We measure these every four to six weeks initially. We measure total T3 rather than free T3 because assays for free T3 are less accurate, and age-reference ranges for children are still being established. If free T4 and total T3 concentrations remain elevated, then we increase the dose of MMI by approximately 0.25 mg/kg increments (again rounding the dose to whole or one-half tablets) until thyroid function is normal. If the free T4 and total T3 levels show a downward trend and fall below the normal range, we titrate the dose down.

Early in the course of treatment, MMI dose adjustments should be based only on free T4 and total T3 concentrations, until TSH levels have recovered from suppression. This is because prolonged hyperthyroidism typically suppresses serum TSH until free T4 and T3 levels normalize and for up to several months thereafter. For this reason, some clinicians choose not to measure TSH concentrations until thyroid hormone levels have normalized on treatment.

After thyroid function has normalized, follow-up visits can be scheduled at three- to four-month intervals and include measurement of serum free T4, T3, and TSH. Once the TSH has recovered fully from suppression, the goal of treatment should be to maintain the TSH concentration in the age-appropriate reference range.

Adverse effects — MMI and PTU are associated with similar types of side effects, but side effects tend to be more frequent and more severe with PTU [19].

●Major adverse effects – Major adverse effects include agranulocytosis (granulocyte count <500/mm³), vasculitis (lupus-like syndrome), hepatitis, and liver failure:

•Agranulocytosis occurs in 0.1 to 0.5 percent of patients treated with either PTU or MMI. The risk appears to be dose-related for MMI but not for PTU [19,20]. If agranulocytosis occurs, it usually develops within the first 90 days after starting an ATD (85 percent of patients) [21].

•Antineutrophil cytoplasmic antibodies (ANCA), markers of vasculitis, are more common with PTU treatment [22,23]. A review reported that ANCA are present in 4 to 64 percent of patients on PTU and 0 to 16 percent of patients on MMI; however, only approximately 15 percent (1 in 6) of ANCA-positive patients develop clinical evidence of vasculitis [24].

•Severe hepatitis develops in up to 0.1 percent of children treated with PTU, with liver failure occurring in 1:2000 to 1:4000 [7,19]. Almost all cases of ATD-associated severe hepatitis have occurred with PTU treatment. Routine biochemical surveillance of liver function probably is not effective in avoiding the risk of liver failure.

●Minor adverse effects – Minor adverse effects include papular or urticarial skin rashes, arthralgias, nausea, and abnormal taste sensation and are more common with PTU than with MMI (30 versus 13 percent in one series) [19]. In a series of 100 patients treated with MMI, the following minor side effects were reported: pruritus and hives (8 percent), diffuse arthralgia (3 percent), neutropenia (2 percent), and Stevens-Johnson syndrome and cholestatic jaundice (1 percent each) [25]. In patients who have one of these minor side effects, we discontinue the drug for a few days until the symptom subsides and then resume it, with monitoring for recurrence. Mild pruritus or hives sometimes can be managed temporarily with an antihistamine, without discontinuing the ATD, until the symptoms resolve.

●Monitoring – If a patient develops a febrile illness or pharyngitis, ATD treatment should be stopped immediately and WBC and differential measured; if the granulocyte count is normal, ATD treatment may be restarted. We recommend giving patients, parents or caregivers, and primary care clinicians written instructions that describe these guidelines. This is important because a potential complication of ATD treatment is a drop in WBC; rarely, agranulocytosis or even pancytopenia develop, which can be life-threatening if not detected promptly [20]. If the granulocyte count is low (<1500/mm³) but not meeting criteria for agranulocytosis (ie, <500/mm³), we hold the MMI, monitoring the WBC twice weekly; these counts usually recover spontaneously within one to two weeks [26]. Once the granulocyte count is >1500/mm3, we restart MMI. Agranulocytosis (<500/mm³) is a contraindication to future ATD treatment [13]. Routine (rather than symptom-driven) monitoring of WBC is not recommended, because of the rarity of agranulocytosis and its sudden onset, which is generally associated with symptoms [13].

Similarly, we remeasure liver enzymes and serum bilirubin only if we note any clinical evidence of liver disease, such as jaundice, and not on a routine basis. (See "Thionamides: Side effects and toxicities" and "Drug-induced neutropenia and agranulocytosis".)

In any patient who has a major adverse effect, the ATD should be discontinued immediately; the patient should be treated with RAI or surgery instead of an ATD. If a patient becomes pregnant, guidelines recommend use of PTU in the first trimester as it appears to be associated with a lower rate of birth defects compared with MMI, though consideration may be given to stopping the ATD and then restarting MMI in the second trimester. (See "Thionamides: Side effects and toxicities".)

Adjunctive therapies — Adjunctive therapies may be used in some children with Graves disease.

●Beta adrenergic blockers – Patients with prominent symptoms of adrenergic overactivity, such as palpitations or tremor, can be treated with beta blockers until thyroid hormone levels normalize in response to ATD therapy [26]. We suggest atenolol (1 to 2 mg/kg daily) over other beta blockers because it is administered once daily and is cardioselective. Propranolol, which has the potential benefit of decreasing T4 to T3 conversion, is preferred by some clinicians. Propranolol (0.5 to 2.0 mg/kg daily) is divided into three or four doses daily.

●Adjunctive levothyroxine (not recommended) – We do not recommend adjunctive treatment with levothyroxine during ATD therapy (the so-called "block and replace" method), consistent with current guidelines [11]. Adding levothyroxine does not affect the likelihood of sustained remission [27-29] but does make it more difficult to judge when a remission may have occurred and, therefore, when the ATD can be discontinued. In addition, patients managed with combination therapy are more likely to be treated with a higher dose of ATD, exposing them to the dose-related side effects of ATD.

●Iodine – Iodine occasionally is used as an adjunctive treatment for severe hyperthyroidism (eg, thyroid storm) or as a bridge to thyroid surgery when ATDs are contraindicated (usually due to a major adverse effect). Administration of a large amount of iodine suppresses thyroid hormone synthesis (Wolff-Chaikoff effect) and release. Normal individuals will "escape" from this effect after several days, but individuals with Graves disease may not escape normally, allowing iodine to be effective in some patients for controlling hyperthyroidism for weeks or longer [30] (see "Iodine in the treatment of hyperthyroidism"). However, because the timing of escape is not predictable, iodine is most useful in children as a bridge to definitive therapy when ATDs cannot be used, and careful monitoring for recurrent hyperthyroidism is necessary as long as iodine is the sole treatment in use. Treatment with (nonradioactive) iodine precludes definitive therapy with RAI in the short term, so surgery generally is required for patients treated temporarily with iodine after discontinuing ATDs. Iodine also may be used in the preparation for surgical treatment of Graves hyperthyroidism. (See 'Surgery' below.)

●Treatment of thyroid eye disease – The treatment of thyroid eye disease in children and adolescents is similar to that in adults. In general, thyroid eye disease tends to have a mild course in children and treatment with glucocorticoids, rituximab, radiation, or surgery is rarely required. In adults with moderate to severe thyroid eye disease, teprotumumab (an insulin-like growth factor 1 [IGF-1] receptor antagonist) may be effective, but teprotumumab is contraindicated in children due to its inhibitory effects on IGF-1 signaling. (See "Treatment of thyroid eye disease".)

Subsequent management

Duration of antithyroid drug therapy — In children, prolonged courses of ATDs are often necessary and efficacious for achieving remission (see 'Remission rate' below). For this reason, we do not recommend a trial off of ATD after a prescribed period of treatment (as is common in adults) and we prescribe MMI indefinitely, provided that this continues to be the preferred treatment choice of the patient and parents and no major adverse effects occur. Long-term ATD treatment is safe, and the likelihood of remission increases with the duration of treatment, reaching a maximum probability of remission of 40 to 50 percent after 6 to 10 years of therapy [31,32].

As noted, approximately one-half of children eventually enter remission and are able to stop ATD treatment. There are two general approaches to identify candidates for stopping ATD treatment:

●Dose titration method – Our practice is to use dose titration to determine when to stop ATD therapy. As the hyperthyroidism improves with therapy, the dose is gradually reduced to maintain normal levels of TSH, free T4, and total T3 (algorithm 1). When only a low dose (eg, 2.5 to 5 mg of MMI) is needed to maintain a euthyroid state, the drug can be stopped and the patient followed closely, as described below (see 'Lifelong monitoring' below). Using this approach, a typical course of ATD treatment is approximately two to five years [6]. The course is shorter in some patients, while others continue treatment for as long as eight to ten years. This practice is supported by several reports demonstrating that remission rates improve with long-term treatment. (See 'Remission rate' below.)

●Antibodies to the TSH receptor (TSHR-Ab) titers – Alternatively or in addition, TSHR-Ab can be used to help determine whether to stop ATD. If a patient has a positive TSHR-Ab titer, remission is very unlikely; in one study, 100 percent of children who relapsed after stopping ATD treatment had detectable TSHR-Ab [33]. Thus, we recommend continuing treatment in children with persistently positive TSHR-Ab. Children with negative TSHR-Ab have a good chance to enter remission, but this test is not a perfect predictor. In the same study, 75 percent of patients with undetectable TSHR-Ab achieved remission, but 25 percent relapsed. Thus, if a decision is made to stop ATD treatment, thyroid function tests should be rechecked four to six weeks later, then every three to four months for the next year.

Patients who enter remission need lifelong monitoring after ATDs are stopped. (See 'Lifelong monitoring' below.)

Remission rate — The rate of remission of Graves hyperthyroidism in children and adolescents (defined as the proportion of patients who remain euthyroid for at least 12 months after discontinuation of ATD therapy) varies in different series, but most showed that one-half or more of patients achieved remission with long-term ATD treatment [2-6,34,35].

In a report of treatment of a large group of children from France (n = 154), estimated remission rates were 20, 37, 45, and 49 percent after 4, 6, 8, and 10 years of follow-up, respectively [31]. In a long-term study from Japan (n = 1138), 46.2 percent achieved a remission after a median treatment period of 3.8 years (range 0.3 to 24.8 years) [32]. More striking results were observed in a randomized trial that compared long-term therapy with MMI (mean 9.1 years) to short-term therapy (18 to 24 months) [36]. Among children treated with long-term therapy, Graves disease remained in remission in 92 percent of subjects one year after stopping therapy and 88 percent of subjects four years after stopping therapy, compared with 46 and 33 percent, respectively, for those treated with short-term therapy. By contrast, studies in adults indicate that the probability of remission is not improved if therapy is continued beyond 18 months [37].

Studies of factors that may predict Graves disease remission have yielded inconsistent results. In general, lower thyroid hormone concentrations at diagnosis and a more rapid initial response to ATD therapy may be associated with an increased likelihood of remission [31,38,39]. Smaller goiter size [40,41], older age [39,42], lower concentrations of TSHR-Ab at diagnosis [39], and presence of other autoimmune conditions [31] were associated with an increased likelihood of remission in some but not all studies. In contrast, the largest study of this issue (n = 1138) found no clinical factors statistically associated with Graves disease remission on multivariable analysis [32].

Patients who relapse or do not achieve sustained remission — In patients who do not achieve sustained remission, hyperthyroidism usually recurs within the first year after stopping ATD therapy, but later relapses do occur. In two studies of children who discontinued ATD therapy, approximately 55 percent of relapses occurred within the first year and approximately 70 percent occurred within the first two years off of therapy [37,42]. In one study that followed patients for up to 27 years, nearly all relapses (98 percent) occurred within 10 years of stopping ATD therapy [32]. (See 'Duration of antithyroid drug therapy' above.)

These children can be offered any of the same three treatment options offered to newly diagnosed patients, ie, continuing ATD (indefinite duration) or proceeding to RAI or surgery (table 1). The choice of treatment is usually based on patient and parent preference. Younger patients who relapse after ATD withdrawal and those previously treated with ATDs for shorter periods are usually restarted on ATD. In addition, some patients who do not achieve a remission while on ATD therapy may choose to proceed to a definitive treatment due to changes in preferences or life circumstances (eg, before leaving home for college).

RADIOACTIVE IODINE

Patient selection and dose — RAI (iodine-131) therapy is an effective treatment for children and adolescents with Graves hyperthyroidism (algorithm 1). We recommend RAI as a second-line therapy for patients who have recurrent hyperthyroidism after long-term treatment with an antithyroid drug (ATD) who request definitive treatment and for those who have a major adverse effect while receiving an ATD. However, some pediatric endocrinologists consider it the initial treatment of choice in older children and adolescents [2,43,44]. (See "Radioiodine in the treatment of hyperthyroidism".)

●Patient selection – Patient selection for RAI therapy depends on the child's age, consistent with guidelines from the American Thyroid Association (ATA) and European Thyroid Association (ETA) [10,11]:

•Age ≥10 years – RAI is an appropriate second-line option.

•Age 5 to 10 years – RAI may be used, but the total dose should be limited, as discussed below.

•Age <5 years – RAI should not be used.

These recommendations are based on observations suggesting that young children may be particularly sensitive to radiation, raising the theoretical concern that young children might therefore have an increased risk for malignancies after radiation exposure (see 'Other side effects or concerns' below). For children with a very large goiter, surgery may be more effective than RAI, as discussed below (see 'Surgery' below). RAI treatment should be avoided in children with moderate to severe active thyroid eye disease. (See 'Other side effects or concerns' below.)

●Dose – The dose of RAI should be sufficient to completely ablate the thyroid gland and render the patient hypothyroid. The recommended dose for children ≥10 years is 0.15 to 0.3 milliCi/gram of thyroid tissue [10,11,45]. For children between 5 and 10 years, the total dose should be limited to <10 milliCi. This dose leads to permanent hypothyroidism in a high percentage of patients, necessitating lifelong thyroid hormone replacement, and minimizes the risk of developing future thyroid cancer. To assess quantitatively the thyroid gland mass for iodine-131 dose calculation, guidelines recommend obtaining an ultrasound examination prior to RAI administration rather than estimating based on neck palpation (assume 1 mL = 1 gram) [10,11].

In addition, we measure iodine-123 uptake and use the fractional uptake at 24 hours to calculate the treatment dose as follows:

Some clinicians prefer to use a fixed dose of iodine-131 rather than using the above formula. In one study, a fixed dose of 14.7 milliCi (range 13.8 to 15.6 milliCi) produced permanent hypothyroidism in all patients at an average of 77 days (range 28 to 194 days) after receiving RAI [46].

●Preparation – ATDs should be stopped three to five days before RAI administration to permit adequate uptake of RAI by the thyroid [10,11,47]. A low-iodine diet is not necessary prior to RAI therapy for Graves disease [48].

Hypothyroidism after radioactive iodine — The major (and intended) consequence of RAI treatment is hypothyroidism. With the RAI doses recommended above, most patients will become hypothyroid; however, some children (10 to 15 percent in one multicenter study) may remain euthyroid and a few may develop recurrent hyperthyroidism [49]. (See "Radioiodine in the treatment of hyperthyroidism".)

We measure serum TSH and free T4 six weeks after RAI treatment and then at three-month intervals. When hypothyroidism develops, it is treated with thyroid hormone replacement, similar to other causes of hypothyroidism. Laboratory monitoring can be performed less frequently thereafter, usually every six months. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

Other side effects or concerns — Other side effects or possible concerns with RAI are:

●Immediate side effects – Immediate side effects of RAI include local pain associated with radiation thyroiditis and the rare risk of "thyroid storm" [50,51]. Because the antithyroid action of RAI is slow, patients with significant symptoms may benefit from treatment with a beta blocker (atenolol preferred) or an ATD (started three days after RAI administration) for four to eight weeks after receiving a therapeutic dose of RAI.

●Thyroid eye disease – There is no direct evidence that RAI causes or worsens thyroid eye disease in children or adolescents, as has been described in adults [52-54]. Nevertheless, based on adult data it is prudent to avoid RAI therapy in children with moderate to severe active thyroid eye disease to avoid the possibility of exacerbation. For some children with mild active thyroid eye disease, some practitioners recommend a course of oral glucocorticoids to prevent potential exacerbation of eye disease. (See "Treatment of thyroid eye disease".)

●Cancer concerns – Concerns about the long-term risks of RAI in children and adolescents have centered on the possibility that the treatment could result in thyroid cancer or other neoplasms. The concern about thyroid cancer arose from observations of the increased incidence of thyroid cancer in infants and children who were exposed to external radiation during the 1940s and 1950s for a variety of "indications" including enlarged tonsils, croup (large thymus), or acne [55]. In addition, there was a dramatic rise in thyroid cancer in children exposed to radiation from the Chernobyl nuclear accident [56] (see "Radiation-induced thyroid disease"). However, it should be noted that there is increasing evidence to suggest that exposure to therapeutic or diagnostic doses of RAI does not increase the risk of thyroid cancer [57]. The exposures at Hiroshima and Chernobyl and to external beam radiation all included ionizing radiation. By contrast, among children whose environmental exposure was limited to RAI, there is no increase in thyroid cancer or autoimmune thyroid disease with up to 50 years' follow-up [58]. Similarly, in one older study in children treated with lower doses of RAI, there was a small increase in the incidence of benign thyroid adenomas but no increase in thyroid carcinoma [59]. Subsequent studies have not revealed an increased risk of thyroid cancer, leukemia, or other cancers [60].

A cohort study of 18,805 adults with hyperthyroidism treated with RAI reported a statistically significant, though modest, positive dose-response relationship for risk of death for all solid cancers (6 percent increase in risk per 100-mGy dose to the stomach) and breast cancer (12 percent increase in risk per 100-mGy dose to the breast) [61]. This study did not include children. While findings from studies that did include children are reassuring, a small risk of other cancers cannot be excluded, due to the relatively small number of children treated with RAI.

●Reproductive concerns – Evidence does not support concerns that RAI therapy affects future fertility or damage sperm or ova, thereby affecting the patient's offspring. For women who were treated with RAI during childhood or adolescence, 3 percent of their offspring have congenital anomalies, a rate similar to that of the general population [62], and the incidence of infertility, miscarriage, and prematurity is not increased [63].

SURGERY — Surgery, usually near-total thyroidectomy, is an effective therapy for Graves hyperthyroidism. Near-total thyroidectomy is preferred to less complete resection to minimize the risk of persistent or recurrent hyperthyroidism.

●Candidates – Surgery is used for treatment of Graves disease in the following groups (algorithm 1):

•As a secondary therapy for children initially treated with antithyroid drug (ATD) therapy who experienced adverse effects or who desire definitive treatment. For children older than five years, RAI therapy is a reasonable alternative. For children younger than five years, surgery is the preferred definitive therapy because RAI is not recommended for this age group [11].

•As an initial therapy for patients who desire definitive therapy rather than ATD. This may be particularly helpful for young children or those with very large goiters. Studies in adults suggest that individuals with large thyroid glands (greater than 80 grams) are less likely to have their hyperthyroidism cured by RAI treatment [64].

Selection of surgery for definitive treatment also depends on availability of an experienced thyroid surgeon [11].

●Preoperative preparation – If surgery is planned, preoperatively, the patient should be rendered euthyroid (or nearly so) if possible, by treatment with an ATD and/or inorganic iodine, as well as treated with a beta blocker if necessary for symptoms. Preoperative treatment with iodine is recommended and reduces thyroid blood flow and blood loss during surgery [11,65].

We use either of the following for 7 to 10 days prior to surgery:

•Potassium iodide (SSKI; 35 to 50 mg/drop), 1 to 3 drops by mouth three times daily, or

•Potassium iodide and iodine (Lugol's solution: 8 mg/drop, 20 drops per mL), 5 to 7 drops by mouth three times daily

Adjunctive treatment with a beta blocker such as atenolol (1 to 2 mg/kg once daily) over this same 7- to 10-day period will help to reduce adrenergic symptoms, if present.

●Complications – Complications of surgery in children are similar to those in adults. Transient hypocalcemia occurs in 10 to 30 percent of children and permanent hypoparathyroidism in 1 to 2 percent. Injury to the recurrent laryngeal nerve occurs in approximately 1 percent and postoperative hemorrhage in up to 4 percent [66]. Hypothyroidism is the intended consequence of surgery and occurs in virtually all patients after near-total thyroidectomy, with a very low rate of recurrent hyperthyroidism. (See "Surgical management of hyperthyroidism".)

LIFELONG MONITORING — Regardless of which treatment is used for children and adolescents with Graves hyperthyroidism, lifelong monitoring of thyroid function is necessary. For those who become hypothyroid after definitive therapy, lifelong monitoring will be needed to manage thyroid hormone replacement. For those who remain on antithyroid drug (ATD) therapy or enter a sustained remission after ATD therapy is discontinued (and for the small percentage of patients who are euthyroid rather than hypothyroid after radioactive iodine [RAI] or surgery), lifelong monitoring is needed to detect hyperthyroidism or hypothyroidism, which may develop at any time.

Long-term monitoring consists of checking thyroid-stimulating hormone (TSH) every six months until growth and puberty are complete. After completion of growth, we monitor TSH yearly.

Females should be counseled that when they reach reproductive age, there is a risk of neonatal Graves disease in their offspring because persistent stimulatory antibodies to the TSH receptor (TSHR-Ab) may cross the placenta. (See "Evaluation and management of neonatal Graves disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism" and "Society guideline links: Pediatric thyroid disorders".)

SUMMARY AND RECOMMENDATIONS

●Initial choice of treatment – Children and adolescents with Graves hyperthyroidism can be effectively treated with antithyroid drug (ATD) therapy, radioactive iodine (RAI), or surgery (thyroidectomy). The choice of therapy is determined by individual consideration of the risks and benefits of the three treatment modalities and patient/family preference (table 1). An overview of treatment is shown in the algorithm (algorithm 1). (See 'Selection of treatment' above.)

•For most children, we suggest initial treatment with an ATD (thionamides) (Grade 2C). This is generally the treatment choice with the lowest risk, and a significant percentage of children will achieve a remission (albeit after several years of treatment) and remain euthyroid off of treatment. (See 'Selection of treatment' above and 'Remission rate' above.)

•RAI or surgery are acceptable options for initial treatment (eg, RAI for adolescents, surgery for children <5 years) and are preferred by some patients and their parents. These also may be more appropriate treatments than ATDs in settings where close follow-up is unlikely. These modalities cause the patient to become hypothyroid, which requires lifelong thyroid hormone replacement therapy.

●ATDs

•When ATD treatment is chosen, we recommend treating with methimazole (MMI) rather than propylthiouracil (PTU) because MMI has fewer adverse effects (Grade 1A). (See 'Antithyroid drugs' above.)

•We do not do a trial off of ATD after an arbitrary period of treatment, as is commonly done in adults. Instead, we prescribe ATD treatment indefinitely, provided that it remains the preference of the patient and parents and that no major adverse medication effects occur. For most patients, ATD therapy can be weaned after 2 to 10 years, guided by thyroid function tests and sometimes by measurement of antibodies to the thyroid-stimulating hormone receptor (TSHR-Ab). (See 'Duration of antithyroid drug therapy' above and 'Patients who relapse or do not achieve sustained remission' above.)

●Second-line therapies – RAI or surgery are options for secondary therapy for patients with persistent or recurrent hyperthyroidism after long-term ATD treatment who request definitive treatment and for those who have a major adverse effect while receiving an ATD. In addition to patient and family preference, we select the preferred treatment modality based on patient age and thyroid size (algorithm 1):

•For patients under five years of age or with a very large thyroid, we suggest surgery rather than RAI (Grade 2C). Thyroid surgery should be performed by an experienced thyroid surgeon. (See 'Surgery' above and "Surgical management of hyperthyroidism".)

•For children older than 10 years who do not have a very large thyroid, we suggest RAI rather than surgery (Grade 2C). (See 'Radioactive iodine' above.)

•Guidelines recommend that RAI not be used in children younger than five years of age. For patients between 5 and 10 years of age, either surgery or RAI (at limited doses) are appropriate choices. (See 'Radioactive iodine' above.)

●RAI dosing – When RAI is selected for therapy, a dose of 0.15 to 0.3 milliCi/gram of thyroid tissue should be used. This dose leads to permanent resolution of the hyperthyroidism in a high percentage of patients, and most will become hypothyroid and require lifelong thyroid hormone replacement. (See 'Patient selection and dose' above and 'Hypothyroidism after radioactive iodine' above.)

•For children between 5 and 10 years, guidelines suggest restricting the total RAI dose to <10 milliCi

•Children on ATDs who are to be treated with RAI should have their ATD discontinued three to five days before RAI administration

●Monitoring – All children with a history of hyperthyroidism should have lifelong monitoring of thyroid function, regardless of treatment choice and outcome. All children have a risk of recurrent hyperthyroidism or developing hypothyroidism, either of which may occur at any time. Offspring of women with a history of Graves disease have an increased risk for developing Graves disease in the fetal or neonatal period. (See 'Lifelong monitoring' above.)