Pediatrics

Thyrotoxicosis/thyroid storm

OVERVIEW: What every practitioner needs to know

Thyroid storm is a rare disorder in children characterized by severe manifestations of thyrotoxicosis, but in addition, usual features include hyperthermia and altered mental status, ranging from agitation or delirium to extreme lethargy or coma, and, rarely, seizures.

Presentation is usually triggered by a precipitating event, such as an acute infection, trauma, or a surgical procedure.

Thyroid storm occurs most commonly in children with long-standing, undiagnosed Graves' disease, but it can occur in previously diagnosed patients poorly compliant with anti-thyroid drug treatment. It also has been reported in patients taken off their anti-thyroid drug, in preparation for radioactive iodine (RAI) treatment or after administration of RAI. It rarely is described with other causes of thyrotoxicosis.

Thyroid storm is a clinical diagnosis (see Table I with diagnostic score, below). It is accompanied by elevated serum thyroid hormone levels and suppressed TSH levels, but values are not different from thyrotoxic children not manifesting thyroid storm.

Table I.

Diagnostic Criteria for Thyroid Storm: Scoring System*

Patients with thyroid storm should be admitted to a pediatric intensive care unit (PICU) for management. The cornerstones of treatment include beta-adrenergic antagonists and anti-thyroid drugs, followed by iodine (short duration) and glucocorticoids. Supportive treatment, for example, antibiotics for an acute infection, and attention to cardiorespiratory status are important.

Patients who appear to have "impending storm" may be hospitalized for initial treatment and observation of clinical course, but they may not need ICU care. Patients with clinical manifestations of thyrotoxicosis only are typically managed as outpatients.

Thyroid storm is a life-threatening disorder, with up to a 30% mortality rate reported in adults; prognosis may be better in children, as there are no published reports of death.

Are you sure your patient has thyrotoxicosis? What are the typical findings for this disease?

1. Symptoms and signs of thyrotoxicosis: history of weight loss despite increased appetite, hyperactivity, emotional lability, sleep disturbance, decreasing school performance, and heat intolerance; on exam, tachycardia, goiter, possible eye findings (lid lag, proptosis), tremor, and brisk reflexes.

2. Features of thyroid storm: hyperthermia; tachycardia; possible atrial fibrillation; heart failure; GI-hepatic dysfunction: nausea/vomiting, diarrhea, jaundice; altered mental status: agitation, delirium, extreme lethargy, seizure, coma; precipitating event, such as an acute infection, trauma, or surgical procedure.

Thyrotoxicosis/Thyroid Storm

Thyroid storm occurs in patients with long-standing thyrotoxicosis, accompanied by a precipitating event.

Graves' disease is the cause of thyrotoxicosis in over 90% of cases in children. Graves' hyperthyroidism can be insidious in onset, and many children are not known to have thyrotoxicosis at the time of diagnosis of thyroid storm. Other children have been diagnosed with Graves' disease, but they may have been poorly compliant with medical therapy, or they may have been taken off their anti-thyroid drug treatment in preparation for radioactive iodine administration.

Rarely, thyroid storm has been reported in children with other causes of thyrotoxicosis, including autonomous thyroid nodules associated with McCune-Albright syndrome and even with levothyroxine ingestion.

Thyrotoxicosis/Thyroid Storm

Thyroid storm is a rare disorder in children characterized by severe clinical manifestations of thyrotoxicosis and (usually) a precipitating event. Typical clinical features of thyrotoxicosis, such as weight loss, tachycardia, goiter, and eye findings, are accompanied by features atypical for thyrotoxicosis, including marked elevation of body temperature (as high as 102 to 104°F), nausea, vomiting, or jaundice, and altered mental status, ranging from agitation or delirium to extreme lethargy or coma, and, rarely, seizures.

Thyroid storm usually occurs in the context of long-standing thyrotoxicosis, which may be first recognized at the time of diagnosis of thyroid storm. Other patients are known to have hyperthyroidism, but they may have been poorly compliant with medical treatment, or their anti-thyroid drug treatment may have been discontinued, for example, in preparation for radioactive iodine administration. Common precipitating events include an acute infection, trauma, or a surgical procedure.

Thyroid storm is a clinical diagnosis; a scoring system allocating points for manifestations has been developed for adults and can be applied to children (see Table I). Thyroid function tests will show elevation of serum total and free T4 and T3 levels with suppressed TSH levels, although the values are not different from levels seen in thyrotoxic children who are not in thyroid storm. Other nonspecific laboratory changes include an elevated WBC count, hyperglycemia, hypercalcemia, and abnormal liver function tests.

What other disease/condition shares some of these symptoms?

Acute infection (fever, tachycardia)

  • Central nervous system disorder, with increased intracranial pressure (nausea, vomiting, mental status changes)

  • Primary hepatic disorder with failure (nausea, vomiting, jaundice, mental status changes)

  • Primary cardiac disorder with congestive heart failure (tachycardia, arrhythmia, edema)

  • Drug ingestion (nausea, vomiting, mental status changes, elevated temperature)

  • Thyroid disorders other than those associated with thyrotoxicosis:

    • Autoimmune thyroiditis with goiter

    • High binding protein states, e.g., TBG excess, with elevated total T4 and T3, but normal free T4 and T3, normal TSH

    • Resistance to thyroid hormone, with goiter and elevated total and free T4 & T3, but normal TSH

What caused this disease to develop at this time?

Thyroid storm is associated with long-standing, usually untreated, thyrotoxicosis; typically, its onset is associated with a precipitating event, such as an acute infection, trauma, or a surgical procedure. Some children with hyperthyroidism have been reported to develop thyroid storm when their anti-thyroid drug treatment was discontinued, either because of a drug side effect or in preparation for radioactive iodine treatment.

There are also case reports of thyroid storm following RAI administration, perhaps caused by a destructive thyroiditis and release of preformed, stored thyroid hormone. Thyroid storm has been reported in a toddler after a large levothyroxine ingestion.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Thyroid function should be evaluated by measuring serum free T4, total T3, and TSH levels; thyrotoxicosis is confirmed by finding elevated free T4 and total T3 and suppressed TSH values. Serum free T3 could be measured in place of total T3, although there is less information about normal reference ranges in children.

  • Once thyrotoxicosis is confirmed, studies to determine the specific etiology should be carried out. Graves' disease, the cause of over 90% of hyperthyroidism in children, is caused by a TSH receptor stimulating antibody (TRS-Ab). TRS-Ab can be evaluated by measuring either a thyroid stimulating immunoglobulin (TSI) level, a TSH receptor antibody (TRAb), or a thyrotropin binding inhibitor immunoglobulin (TBII) level. TSI, a bioassay, is more specific for Graves' disease; TRAb and TBII, competitive inhibition assays, need to be correlated with thyroid function.

  • Other causes of thyrotoxicosis in children are much less common than Graves' disease, and they rarely have been reported to cause thyroid storm.A hyperfunctioning adenoma ("hot nodule") or toxic, multinodular goiter are the next most common causes of hyperthyroidism. (See below, under "Would imaging studies be helpful?" for details on diagnosis of these two conditions.)

  • Hyperthyroidism can occur as the initial phase of Hashimoto's thyroiditis ("Hashitoxicosis"). Anti-thyroglobulin and anti-thyroid peroxidase (TPO) antibodies are positive in both patients with Hashimoto's thyroiditis and Graves' disease, although levels are usually higher in Hashimoto's thyroiditis. (TSI is negative in patients with Hashitoxicosis.) Hyperthyroidism also occurs in the initial phase of subacute thyroiditis (de Quervain's disease). Subacute thyroiditis results from a viral infection, and thyroid autoantibodies are negative.

  • Patients with resistance to thyroid hormone, predominantly in the pituitary gland, present with clinical thyrotoxicosis and elevated serum free T4 and T3 levels, whereas serum TSH is normal or slightly elevated. TSH secreting pituitary adenomas are a rare cause of hyperthyroidism.

  • There are no published reports of Hashitoxicosis, subacute thyroiditis, pituitary thyroid hormone resistance, or TSH adenomas causing thyroid storm in children.

  • Other laboratory tests should be carried out in patients with thyroid storm to aid assessment of clinical status. These include a CBC and differential, and a comprehensive metabolic panel that includes liver function tests, glucose, and calcium measurements. Other tests, such as blood or urine culture, chest X-ray, or lumbar puncture with evaluation of CSF, may be carried out, as indicated, to evaluate patients for a precipitating event.

Would imaging studies be helpful? If so, which ones?

  • In patients with thyrotoxicosis and thyroid storm confirmed to be caused by Graves' disease, imaging tests such as radioactive iodine uptake and scan are not necessary for the diagnosis.

  • In patients with laboratory confirmation of thyrotoxicosis, but negative tests for TRS-Abs, a radioactive iodine uptake and scan is the best study to evaluate for a hyperfunctioning adenoma or toxic multinodular goiter. The radionuclide of choice is 123-I, but 131-I is an acceptable alternative. Patients with a hyperfunctioning adenoma will show uptake only in the "hot nodule," with suppressed uptake in the remainder of the gland. Patients with toxic multinodular goiter manifest increased uptake, present in the multiple "hot nodules."

Confirming the diagnosis

Please see the attached flowchart on Thyrotoxicosis and Thyroid Storm: Diagnostic Algorithm ( Figure 1).

Figure 1.

Thyrotoxicosis and Thyroid Storm: Diagnostic Test Algorithm

If you are able to confirm that the patient has thyroid storm, what treatment should be initiated?

  • Patients who meet the diagnostic criteria and score consistent with thyroid storm (see Table I) are best managed in a PICU setting. The cornerstone of initial management is the administration of beta adrenergic antagonists and anti-thyroid drugs. Beta blockers are given to control the excess adrenergic nervous system symptoms and signs associated with thyrotoxicosis. They should be used with caution if signs of heart failure are present (more of a problem in adults) or if the patient has a medical contraindication, such as a history of asthma.

  • Once hyperthyroidism has been confirmed, anti-thyroid drug treatment will block further production of thyroid hormone. However, patients will continue to secrete pre-formed, stored thyroid hormone, e.g., patients with Graves' disease caused by a TRS-Ab continue to stimulate thyroid hormone secretion. Thus, once an anti-thyroid drug is started, the next step is to add iodine to the treatment regimen; iodine will inhibit secretion of the pre-formed, stored thyroid hormone.

  • Most patients with thyroid storm are also treated with stress doses of a glucocorticoid. Glucocorticoids reduce the peripheral conversion of T4 to T3, and they may affect the underlying autoimmune process (if thyroid storm is associated with Graves' disease); in addition, they help to optimize cardiovascular function and treat any underlying adrenal insufficiency.

  • Patients with uncomplicated thyrotoxicosis generally can be treated with an anti-thyroid drug and a beta blocker as an outpatient. Once they become euthyroid, the beta blocker can be discontinued. If there is any uncertainty, e.g., patients with an intermediate diagnostic score and potential "impending thyroid storm," such patients are best admitted to an inpatient setting and treated until their clinical course is such that they can be treated as outpatients.

It is important to evaluate patients for a precipitating cause of thyroid storm. If a cause is identified, e.g., an acute infection, an appropriate antibiotic and other supportive treatment should be initiated. Seizures should be treated with an anti-convulsant.

Details of drug treatment:

1. Beta adrenergic antagonists - choose one of:

  • Propranolol 1-2 mg/kg/24 hr by mouth divided every 6 to 8 hrs.

    • If unable to take by mouth: 0.01-.10 mg/kg IV every 6 to 8 hrs

    • Atenolol 1-2 mg/kg by mouth once daily - this cardioselective beta blocker may be preferred in patients with a history of reactive airway disease

    • Esmolol loading dose 250-500 mcg/kg IV over 1-3 min, then 50-100 mcg/kg per minute; esmolol is a short-acting beta blocker used to achieve rapid control of adrenergic nervous system signs, e.g., tachycardia, with quick titration to clinical response.

2. Anti-thyroid drugs - choose one of:

  • Methimazole (MMI) 0.25-1.0 mg/kg/24 hrs by mouth, divided every 8 to 12 hrs

  • Propylthiouracil (PTU) 5-10 mg/kg/24 hrs by mouth divided every 6 to 8 hrs

    • PTU has the advantage of blocking the conversion of T4 to T3, so it is usually recommended over MMI in the initial management of thyroid storm. It should be noted that PTU is not recommended as a first-line anti-thyroid drug in children with hyperthyroidism, as there are rare reports of severe hepatic toxicity, resulting in either liver transplantation or death. Thus, patients started on PTU should be switched to MMI when thyroid storm has resolved. In patients who are unable to take medications orally, both PTU and MMI can be made into a suspension and temporarily administered via nasogastric tube or into a suppository and administered per rectum.

3. Iodine - choose one of:

  • Lugol's solution (8 mg/drop, 20 drops per mL) 1 drop by mouth 3 times daily

  • SSKI (saturated solution of potassium iodide) (35-50 mg/drop) 1 drop by mouth daily

    • Iodine should not be started until an hour after the first dose of PTU or MMI. Iodine can be toxic to esophageal and intestinal mucosa; it should be diluted in another liquid. Overdosing of SSKI has been reported to cause hyperkalemia and arrhythmias.

4. Glucocorticoids

  • Hydrocortisone (Solu-Cortef®) 1-2 mg/kg IV every 8 hrs

  • Once thyroid storm has resolved (afebrile, improvement in central nervous system, GI-hepatic and cardiovascular function), iodine and glucocorticoids can be discontinued. Generally, they are only needed for 3-5 days; in any event, iodine should not be used longer than 10-14 days, as patients "escape" from its inhibitory effect after that time. If high-dose steroids are needed for longer than 7 days, doses should be tapered and discontinued over a week or two. At discharge, patients with ongoing hyperthyroidism (e.g. Graves' disease) are continued on MMI and a beta blocker. Once patients are euthyroid, the beta blocker can be discontinued.

What are the adverse effects associated with each treatment option?

1. Beta adrenergic antagonists - adverse effects include bradycardia, hypotension, and bronchospasm, and, as with most drugs, hypersensitivity reaction.

2. Anti-thyroid drugs - adverse effects with PTU and MMI are generally divided into minor and major adverse effects:

  • Minor side effects (5%-25%) include skin rashes (papular or urticarial), arthralgias, abnormal taste sensation, and transient granulocytopenia (<2,000 mm3).

  • Major side effects (2%-5%) include a lupus-like syndrome with a vasculitis and glomerulonephritis, hepatitis, and agranulocytosis. Development of any of these major side effects necessitates immediate discontinuation of the anti-thyroid drug and precludes any future use.

3. Iodine - Either Lugol's solution or SSKI may cause esophageal or small intestine mucosal injury and hemorrhage. Overdosage with SSKI may lead to hyperkalemia and arrhythmia.

4. Glucocorticoids - High-dose administration of glucocorticoids may cause hyperglycemia, fluid retention with edema and elevated BP, GI ulceration, suppression of immune function leading to impaired wound healing, and Cushing's syndrome. As noted above, steroids should be discontinued with resolution of thyroid storm.

What are the possible outcomes of thyroid storm and thyrotoxicosis?

Thyroid storm is a rare, but potentially life-threatening disorder. Mortality has been reported to be as high as 30% in adults. There are only case reports of thyroid storm in children, but a literature search did not disclose any deaths, so it may be that children have a better prognosis than adults. The outcome likely is influenced by the severity of the precipitating event, its treatment, and prognosis. Children with thyroid storm complicated by seizures require consultation by a pediatric neurologist and likely anti-convulsant therapy.

Thyroid storm is associated with severe thyrotoxicosis. Once thyroid storm has resolved, thyrotoxicosis persists and requires continuing treatment. Graves' disease, the most common cause of hyperthyroidism in children, initially is treated with anti-thyroid drugs, and often for many years. Some children will achieve a remission with anti-thyroid drugs, but those who do not will eventually require another, more definitive treatment. Definitive treatment options include radioactive iodine ablation or surgical thyroidectomy. Most children undergoing either of these procedures will become hypothyroid.

Like other rare disorders, most of the evidence for benefit of various treatment protocols of thyroid storm comes from case reports, and so would fall in the category of expert opinion. As thyroid storm is potentially a life-threatening disorder, the consensus of experts is that patients meeting diagnostic criteria should be treated with the drug regimen described above, along with supportive care, as appropriate. It is important to evaluate patients for contraindications to drug treatment and manage accordingly. It is equally important that patients be monitored for adverse effects, as described above. Most of the adverse effects are reversible if recognized and the offending drug discontinued.

Once thyroid storm has resolved, there are risks/benefits of the three main treatment options for thyrotoxicosis: anti-thyroid drugs, radioactive iodine, or surgery. Most patients/parents initially choose anti-thyroid drug treatment. With good compliance, nearly all patients will become euthyroid on anti-thyroid drugs.

All studies agree that approximately 30% of patients achieve a remission by 2 years (defined as remaining euthyroid for a year off treatment). There is controversy, however, about the likelihood of a further rate of remission with more prolonged treatment. Some studies do not report a further increase, but others do report further remission, with one study reporting a 25% remission rate for every 2 years of anti-thyroid drugs, with a 50% remission rate after 4.5 years of treatment. Patients must be monitored for side effects of anti-thyroid drug treatment (see above); any major adverse effects require discontinuation of anti-thyroid drug treatment and selection of another treatment option.

In most centers, radioactive iodine ablation is the second most popular treatment modality, and, in some centers, it is the first treatment option for adolescents. American Thyroid Association guidelines for treatment of hyperthyroidism recommend not using radioactive iodine for children less than 10 years of age. The dose of radioactive iodine is chosen at the high end of the recommended range, so as to reduce the likelihood of needing a second treatment dose; as such, most children will become hypothyroid and require thyroid hormone treatment. Radioactive iodine treatment is relatively well tolerated. Studies do show a small, but increased risk of neoplasms developing later.

Patients undergoing surgical thyroidectomy do best if treated to achieve a euthyroid (or near-euthyroid) state prior to surgery. The procedure of choice is a near-total thyroidectomy, so as to reduce the risk of recurrence of hyperthyroidism. The risks of surgical thyroidectomy include hemorrhage, infection, damage to the recurrent laryngeal nerve, transient or permanent hypocalcemia from hypoparathyroidism, and keloid formation at the incision site. Post-op, the majority of patients will be hypothyroid and require thyroid hormone replacement.

What causes this disease and how frequent is it?

  • Epidemiology

    • Graves' disease occurs in approximately 1:5,000 children. There is no seasonal variation. The peak age of Graves' disease is in adolescence; it is more common in females (~5:1 female:male ratio). Other causes make up less than 10% of cases of thyrotoxicosis in children. Hyperfunctioning adenomas or toxic multinodular goiter occur at any age (often younger than Graves' adolescents), with an equal sex ratio. The incidence of thyroid storm is unknown, but it appears to be a rare complication of thyroxicosis in children.

    • Graves' disease is an autoimmune disorder. It is not infectious or transmissible. As described above, an acute infection may precipitate thyroid storm in a patient with thyrotoxicosis.

      • Genetics: Graves' disease is an autoimmune disorder characterized by a genetic predisposition with an environmental trigger. Graves' disease is associated with certain HLA haplotypes which appear to be linked with changes in immune function. Some hyperfunctioning adenomas and toxic multinodular goiters have been shown to be the result of activating mutations in the TSH receptor; these may be inherited in an autosomal dominant fashion. There is no described genetic predisposition to thyroid storm.

How do these pathogens/genes/exposures cause the disease?

  • N/A (except as a precipitating event for thyroid storm).

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

For complications from thyroid storm or thyrotoxicosis or treatment, see above, under "What are the adverse effects associated with each treatment option?" and "What are the possible outcomes of thyroid storm and thyrotoxicosis?"

Are additional laboratory studies available; even some that are not widely available?

Thyroid storm is a clinical diagnosis; thyrotoxicosis is easily diagnosed by the routine laboratory tests described above (see "What laboratory studies should you request to help confirm the diagnosis?" and "Would imaging studies be helpful?")

How can thyroid storm be prevented?

Genetic counseling: If a patient has been confirmed to have Graves' disease, there is an increased risk of other family members developing autoimmune thyroid disease (approximately 30% of family members have an associated autoimmune thyroid disorder). In addition, patients with one autoimmune disease are at some risk for developing other autoimmune disorders.

In general, in a patient with Graves' disease, the risk of other autoimmune disorders, e.g., type 1 diabetes mellitus, is small and testing can be based on development of suspicious clinical features. It might be reasonable to screen patients for celiac disease (by measurement of tissue transglutaminase IgA antibodies along with a serum IgA level).

Ongoing controversies regarding etiology, diagnosis, treatment

Thyroid storm is a rare complication of thyrotoxicosis. The reasonsome children develop this clinical disorder, yet most children withessentially the same degree of thyrotoxicosis do not, illustrates thatthe underlying etiology is incompletely understood. It is not simply thedegree of elevation of thyroid hormone levels. Most likely, theprecipitating event plays an important causative role, but even so, mostchildren with thyrotoxicosis and an acute infection, trauma, etc., donot develop thyroid storm. Thus, there are likely other predisposingfactors that remain to be elucidated, in particular, to explain thecentral nervous system manifestations, including seizures and coma.

Thyroid storm is a clinical diagnosis. The diagnostic scoring system of Burch and Wartofsky (see Table I) addsan objective parameter to the clinical diagnosis. However, it is clearthat some patients may meet a score "suggestive" of thyroid storm and inretrospect turn out not to have storm, while other patients with anintermediate, "supportive" score, when managed as outlined, appear tobenefit from treatment for thyroid storm. An argument can be made thatsuch patients may have had "impending" storm. This is a disorder whereclinical judgment plays a significant role.

Thetreatment regimen outlined above by and large is based on individualcase management, and so it falls in the category of "expert opinion."Given that thyroid storm is a rare disorder, it is unlikely that onecenter will ever be able to carry out randomized, controlled trials.That said, since thyroid storm almost always occurs in the setting oflong-standing thyrotoxicosis, the time-honored strategy of beta blockersand anti-thyroid drugs makes physiologic sense. Adding iodine for alimited period also has a physiologic basis, as does high-dose steroidtreatment, with the caveat that the treatment regimen must beindividualized for every patient and adjusted as clinically indicated.

Finally,as noted above, once thyroid storm resolves, there remains thecontroversy about the three treatment options for hyperthyroidism. Allthree have pros and cons (as outlined in the sections above: "What arethe adverse effects associated with each treatment option?" and "Whatare the possible outcomes of thyroid storm and thyrotoxicosis?").Fortunately, the majority of children with Graves' hyperthyroidism dowell on anti-thyroid drugs, or following radioactive iodine ablation, orwith surgical thyroidectomy.

What is the evidence?

Burch, HB, Wartofsky, L. "Life-threatening thyrotoxicosis. Thyroid storm". Endocrinol Metab Clin North Am. . vol. 22. 1993. pp. 263-277.

(Excellent analysis to date [1993] of thyroid storm, with development of the diagnostic criteria scoring system.)

Isozaki, O, Satoh, T, Wakino, S. "Treatment and management of thyroid storm: analysis of the nationwide surveys: The taskforce committee of the Japan Thyroid Association and Japan Endocrine Society for the establishment of diagnostic criteria and nationwide surveys for thyroid storm". Clin Endocrinol. 2015 Sept 21.

(Analysis of treatment modalities and outcome in 356 adults with thyroid storm)

Aslan, IR, Baca, EA, Charlton, W, Rosenthal, SM. "Respiratory syncytial virus infection as a precipitant of thyroid storm in a previously undiagnosed case of Graves' disease in a prepubertal girl". Int J Pediatr Endocrinol. 2011. pp. 138903.

(Illustrative case, with recent literature review)

Lee, HS, Hwang, JS. "Seizure and encephalopathy associated with thyroid storm in children". J Child Neurol. vol. 26. 2011. pp. 526-528.

(Description of thyroid storm presenting with seizures in 3 patients previously diagnosed with thyrotoxicosis)

Cao, LY, Wei, H, Wang, ZL. "Neonatal thyroid storm accompanied with severe anemia". J Pediatr Endocrinol Metab. vol. 28. 2015. pp. 773-776.

(Baby born to mother with Graves’ disease, discharged after anti-thyroid treatment started, then readmitted in thyroid storm)

Mailesi, MN, Greller, HA, McGuigan, MA. "Thyroid storm after pediatric levothyroxine ingestion". Pediatrics . vol. 126. 2010. pp. e470-3.

(Case report in a 2-year old estimated to have ingested forty 150 mcg levothyroxine tablets.)

Landgraf, L, Grubina, R, Chinsky, J. "Altered mental status in a 16-year-old girl: the calm before the storm". Clin Pediatr. . vol. 47. 2008. pp. 720-724.

(Illustrative case report)

Morrison, MP, Schroeder, A. "Intraoperative identification and management of thyroid storm in children". Otolaryngol Head Neck Surg. vol. 136. 2007. pp. 132-133.

(3-year-old patient with undiagnosed Graves' hyperthyroidism, uncovered during elective myringotomy.)

Kadmon, PM, Noto, RB, Boney, CM. "Thyroid storm in a child following radioactive iodine (RAI) therapy: a consequence of RAI versus withdrawal of antithyroid medication". J Clin Endocrinol Metab. vol. 86. 2001. pp. 1865-1867.

(Case report drawing attention to the risk of thyroid storm with discontinuation of anti-thyroid drug treatment.)

Rohrs, HJ, Silverstein, JH, Weinstein, DA, Amdur, RJ, Haller, MJA. "Thyroid storm following radioactive iodine (RAI) therapy for pediatric Graves disease". Am J Case Rep. 2014 May 14.

(A case report of an 11 year old girl who developed thyroid storm following radioactive iodine treatment, given shortly after diagnosis and a short course of anti-thyroid drug treatment.)

Lawless, ST, Reeves, G, Bowen, JR. "The development of thyroid storm in a child with McCune-Albright syndrome after orthopedic surgery". Am J Dis Child. vol. 146. 1992. pp. 1099-1102.

(Case report of autonomous thyroid adenomas associated with McCune-Albright syndrome causing hyperthyroidism, complicated by thyroid storm precipitated by surgery.)

Aiello, DP, DuPlessis, AJ, Pattishall, EG, Kulin, HE. "Thyroid storm. Presenting with coma and seizures. In a 3-year old girl". Clin Pediatr. vol. 28. 1989. pp. 571-574.

Hayek, A. "Thyroid storm following radioiodine for thyrotoxicosis". J Pediatr. vol. 93. 1978. pp. 978-980.

(Another case report: anti-thyroid drug treatment stopped after rash, thyroid storm developing 2 days after RAI administration)

Galaburda, M, Rosman, NP, Haddow, JE. "Thyroid storm in an 11-year-old boy managed by propranolol". Pediatrics. vol. 53. 1974. pp. 920-922.

(Case report illustrating the usefulness of beta blockers in the treatment of thyroid storm.)

Darby, CP. "Three episodes of spontaneous thyroid storm occurring in a nine-year-old child". Pediatrics . vol. 30. 1962. pp. 927-931.

(The recurrences may not meet current diagnostic criteria for thyroid storm - more like exacerbations of thyrotoxicosis.)

Grossman, A, Waldstein, SS. "Apathetic thyroid storm in a 10-year-old child". Pediatrics . vol. 28. 1961. pp. 447-451.

("Apathy" as the mental status change to diagnose thyroid storm.)

LaFranchi, SH, Hanna, CE, Braverman, LE, Utiger, RD. "Werner and Ingbar’s The Thyroid: a Fundamental and Clinical Text". Lippincott. 2005. pp. 1049-1059.

(Textbook chapter presenting clinical manifestations, treatment options, and prognosis of hyperthyroidism in children.)

Bahn Chair, RS, Burch, HB, Cooper, DS. "Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists". Thyroid. vol. 21. 2011. pp. 593-646.

Kjaer, RH, Andersen, MS, Hansen, D. "Increasing incidence of juvenile thyrotoxicosis in Denmark: a nationwide study". Horm Res Paediatr. . vol. 84. 2015. pp. 102-107.

(This nationwide study from Denmark reports that the incidence of Graves’ disease in children <15 years has doubled from 0.79/100,000 person-years in 1982-1988 to 1.58/100,000 person-years in the 1998-2012 period.)

Stafford, D, Vaidyanathan, P, Kaplowitz, P. "Children with hyperthyroidism younger than age 7 require higher mg/kg doses of methimazole to normalize free T4 compared to older children". J Pediatr Endocrinol Metab. vol. 28. 2015. pp. 1339-1342.

(Older children treated with 0.50 mg/kg/d normalized their serum free T4 after 3 months of treatment, whereas children younger than age 7 years required a higher dose of methimazole, 0.71 mg/kg/d, and took up to 6 months to normalize serum free T4.)

Léger, J, Gelwane, G, Kaguelidou, F. "Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves' disease: national long-term cohort study". J Clin Endocrinol Metab. vol. 97. 2012. pp. 110-119.

(Large French multi-center study of 154 children with Graves' disease, reporting approximately a 50% remission rate with antithyroid drug treatment alone in patients followed up to 12 years.)

Ohye, H, Minagawa, A, Noh, JY. "Antithyroid drug treatment for Graves' disease in children: A long-term retrospective study at a single institution". Thyroid . vol. 24. 2014. pp. 200-2007.

(This long-term, retrospective study of 1138 children from Japan with Graves’ disease treated with anti-thyroid drugs reports that almost half [46.2%] achieved a remission after a median treatment period of 3.8 years.)

Diana, T, Brown, RS, Bossowski, A. "Clinical relevance of thyroid-stimulating autoantibodies in pediatric Graves’ disease – a multicenter study". J Clin Endocrinol Metab. vol. 99. 2014. pp. 1648-1655.

(Using a novel TSH receptor Ab bioassay employing a cAMP responsive element-dependent luciferase, these investigators reported that a TSH receptor Ab was present in 94% of children with Graves’ disease, including 100% of untreated children at diagnosis.)
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