Thyroid Storm in a Toddler Presenting as a Febrile Seizure Jennifer M. Ladd, MD,a Bayane Sabsabi, MD,b Julia E. von Oettingen, MD, PhD, MMSca,c

Although simple febrile seizures are relatively common and benign in abstract toddlers, it is important to rule out any underlying critical disease that necessitates further intervention and treatment. Thyroid storm, the extreme manifestation of hyperthyroidism, is relatively rare and not often considered in the differential diagnosis of a febrile seizure despite its high mortality rate. Here, we report 1 of the youngest patients with thyroid storm, who initially presented with a febrile seizure. After reevaluation, the 2-year-9-month-old patient was discovered to have thyromegaly, which led to recognition that her persistent tachycardia and widened pulse pressure were likely signs of thyrotoxicosis. Laboratory results were consistent with primary hyperthyroidism due to Graves’ disease. Thyroid storm was then diagnosed aDivision of Pediatric Endocrinology, Department of on the basis of clinical features including gastrointestinal and central Pediatrics and bDivision of General Pediatrics, Department of Pediatrics, McGill University, Montreal, Canada; and cThe nervous system disturbances. Treatment with methimazole, propranolol, Research Institute of the McGill University Health Centre, hydrocortisone, and Lugol’s iodine solution was used. This medication Montreal, Canada regimen was safe and effective with restoration of a euthyroid state after Dr Ladd conceptualized the case report and drafted 2 months and no recurrence of seizures. Improved awareness of the initial manuscript; Dr Sabsabi assisted in hyperthyroidism and thyroid storm can lead to prompt diagnosis and drafting the initial manuscript; and all authors reviewed and revised the manuscript, approved the treatment of this endocrine emergency, thus reducing mortality and final manuscript as submitted, and agree to be morbidity. Pediatricians should consider this diagnosis in children with accountable for all aspects of the work. febrile seizures and suggestive vital signs and physical examination findings. DOI: https://doi.org/10.1542/peds.2019-1920 Accepted for publication Oct 2, 2019 Address correspondence to Jennifer M. Ladd, MD, Division of Pediatric Endocrinology, Department of Febrile seizures represent the most presented with a febrile seizure. Increased Pediatrics, Montreal Children’s Hospital, 1001 frequent convulsive condition in children, awareness of thyroid storm is likely to Decarie Blvd, Montreal, QC, Canada H4A 3J1. E-mail: affecting up to 5% of patients aged lead to earlier recognition and treatment [email protected] 6monthsto5years.1 A simple febrile of affected patients, thereby reducing PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, seizure is benign and does not merit long- morbidity and mortality. 1098-4275). term treatment.1 However, it is imperative Copyright © 2020 by the American Academy of to first rule out any underlying critical Pediatrics illness that may require intervention.2 CASE PRESENTATION FINANCIAL DISCLOSURE: The authors have indicated fi Although pediatricians may consider they have no nancial relationships relevant to this A 2-year-9-month-old girl presented to article to disclose. meningitis or hypoglycemia as possible the emergency department after FUNDING: Dr von Oettingen is supported by a Fonds underlying diseases, hyperthyroidism, and seizurelike activity in the context of de Recherche Québec–Santé Junior Clinician- its extreme manifestation of thyroid 2 days of fever, emesis, and diarrhea. Scientist award. storm, is not typically considered in the Her mother observed full-body POTENTIAL CONFLICT OF INTEREST: The authors have differential diagnosis. Although thyroid stiffening and clonic movements lasting indicated they have no potential conflicts of interest storm is rare, especially in young children ,1 minute, followed by a postictal to disclose. who are most prone to febrile seizures, it phase. Her past medical history was carries a high mortality rate3,4 and thus is only significant for language delay. On To cite: Ladd JM, Sabsabi B, von Oettingen a diagnosis not to be missed. Here, we arrival, vital signs were notable for JE. Thyroid Storm in a Toddler Presenting as describe 1 of the youngest reported fever to 39.1°C, tachycardia to 202 a Febrile Seizure. Pediatrics. 2020;145(2): e20191920 patients with thyroid storm, who initially bpm, and elevated systolic blood

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 145, number 2, February 2020:e20191920 CASE REPORT pressure with widened pulse IU/mL (reference range 0–9), dose of methimazole for .6 months. pressure (129/61 mm Hg). Her respectively. Additional studies Both her weight and height continue weight was 15 kg (85th percentile) revealed elevated alanine to track along the 85th percentile. with a height of 97.5 cm (85th aminotransferase of 95 U/L percentile). A neurologic examination (reference range 0–19) and total demonstrated irritability, but no bilirubin of 14.5 mmol/L (reference DISCUSSION – focality. An electrocardiogram range 0 6.7). A viral nasopharyngeal Hyperthyroidism can be a great revealed sinus tachycardia. The swab and blood, urine, and stool mimicker of many other conditions in laboratory investigation revealed an cultures had negative results. children; thus, a high index of elevated anion gap metabolic acidosis suspicion is necessary for diagnosis. The pediatric endocrinology service (capillary blood gas pH 7.29, pCO2 Classic symptoms include weight loss, was consulted. On the basis of clinical 29.1 mm Hg, bicarbonate 13.1 mmol/ hair loss, palpitations, and presentation and laboratory findings, L, anion gap 16 mmol/L) with hyperactivity, but many children often a diagnosis of Graves’ disease with positive urinary ketones. The present in subtler ways. For example, ’ thyroid storm was made. Criteria for patient s blood glucose was normal a child may present only with thyroid storm were met given (95 mg/dL), as was the total white difficulty concentrating and 9 hyperpyrexia, tachycardia, blood cell count (10.4 10 /L) but decreased school performance, which gastrointestinal dysfunction, and with a neutrophil predominance could be mistaken for attention- fl seizure,5,6 prompting a transfer to the (82%). She received uid deficit/hyperactivity disorder. The PICU for closer monitoring. She was resuscitation yet remained ill diagnosis may be especially difficult started on methimazole, propranolol, appearing. Although the working in younger children given nonspecific and hydrocortisone; Lugol’s iodine diagnosis for her presentation was symptoms and the rarity of the solution was soon added (dosing as a simple febrile seizure, she was condition, with an estimated annual per Table 1). The patient’s vital signs admitted to the wards for further incidence of only 0.1 in 100 000 and TFTs slowly improved (Fig 1), management of continued children ,4 years of age.7 However, and the echocardiogram revealed tachycardia and metabolic acidosis. careful review of vital signs may normal ventricular systolic function. reveal tachycardia and widened pulse She was transferred back to the Twelve hours later, the metabolic pressure, whereas examination may wards after 48 hours in the PICU. acidosis had resolved with volume reveal thyromegaly, exophthalmos, Lugol’s iodine solution was resuscitation, but the patient tremor, and brisk reflexes. Once discontinued on the sixth day of remained persistently febrile and considered, the diagnosis of hospitalization, and hydrocortisone tachycardiac. On reevaluation, the hyperthyroidism is easily made ’ was weaned over the course of 1 patient s mother reported an through blood tests revealing week. Thirteen days after enlarging neck mass, sweating, and suppressed TSH with elevated FT4 presentation, she was discharged poor weight gain for several months. and total T3. The family history was significant for from the hospital on 10 mg of hyperthyroidism in the mother and methimazole and 15 mg of The vast majority of cases of other maternal relatives. On repeat propranolol, both taken orally every hyperthyroidism are caused by examination, thyromegaly was noted 8 hours. Two and a half months after Graves’ disease, an autoimmune as well as a systolic cardiac murmur presentation, propranolol was process in which antibodies stimulate without hepatomegaly or discontinued and methimazole was the thyroid to produce thyroid adventitious lung sounds. Serum weaned to 10 mg every 12 hours hormone independent of TSH thyroid function tests (TFTs) were given low FT4. One month later, TSH signaling from the pituitary. In this then sent. Thyroid-stimulating was detectable and methimazole was disease, TSH-receptor antibodies are hormone (TSH) was suppressed to weaned again to 10 mg daily (Fig 1). specific when positive; anti–thyroid ,0.02 mIU/L (reference range The patient has now remained peroxidase and antithyroglobulin 0.34–5.6), with elevated free clinically stable and euthyroid on this antibodies may be additional thyroxine (FT4) of 60.30 pmol/L (reference range 8–18) and total TABLE 1 Treatment Regimen for Pediatric Thyroid Storm triiodothyronine (T3) of 4.7 nmol/L Medication Dosage – (reference range 1.34 2.73). Methimazole 5 mg PO every 6 h Anti–TSH-receptor antibodies and Propranolol 1 mg/kg PO every 8 h anti–thyroid peroxidase antibodies Hydrocortisone 50 mg/m2 IV every 8 h were markedly positive at 35.3 IU/L Lugol’s iodine solution 4 drops PO every 8 h (reference range 0–1.75) and .900 IV, intravenous; PO, per os.

Downloaded from www.aappublications.org/news by guest on September 23, 2021 2 LADD et al After obtaining TFTs to document the presence of hyperthyroidism, the diagnosis of thyroid storm is largely clinical. Although not specificto pediatrics, the Burch-Wartofsky Point Scale or the Japan Thyroid Association criteria for thyroid storm can be used.3,5,6,11 Our patient met the criteria for definite thyroid storm under both diagnostic schemes given laboratory findings, fever, tachycardia, gastrointestinal upset, and, most importantly, the central nervous system manifestation of seizure (.45 points by the Burch- Wartofsky scale and grade of TS1, or "definite" thyroid storm, by the Japan Thyroid Association criteria).

FIGURE 1 Urgent treatment of thyroid storm is The patient’s thyroid hormone levels (FT4 in blue and total T3 in red) trended over time. IV, imperative to block new thyroid intravenous; PO, per os. hormone synthesis and provide symptomatic relief. American Thyroid Association guidelines prefer the suggestive markers. Family history is seizures. Mortality remains as high as antithyroid medication often significant for autoimmune 10% to 30%, often related to cardiac propylthiouracil over methimazole processes. The differential diagnosis causes and tightly correlated to acute given that propylthiouracil both of hyperthyroidism also includes physiology and chronic health blocks new thyroid hormone hashitoxicosis, toxic adenoma, toxic evaluation (APACHE) II scores.3,4,6 synthesis and prevents conversion of multinodular goiter, McCune-Albright With the caveat that this score is thyroxine (T4) to the more syndrome, TSH-receptor mutations, calculated on the basis of adult data, biologically active T3 (methimazole and exogenous levothyroxine our patient’s acute physiology and does not do the latter),5 whereas ingestion, among others.8,9 chronic health evaluation II score on Japan Endocrine Society guidelines ICU admission was 12, giving an propose that methimazole is not Thyroid storm is the most extreme estimated 15% risk of death.6 inferior to propylthiouracil (given presentation of hyperthyroidism with the possibility that T4-to-T3 prominent hyperthermia, tachycardia, In studies including both children and conversion is inherently suppressed and organ system dysfunction. The adults, only 0.2% to 4% of patients in thyroid storm).6 b-blockers are incidence of thyroid storm in cases of with thyroid storm or thyrotoxicosis recommended for the management of pediatric hyperthyroidism is not presented with seizures.3,30 tachycardia in thyroid storm, with known but is likely rare with only Reassuringly, in 1 of those studies, American Thyroid Association single cases or small case series none of 7 such patients had seizure guidelines suggesting propranolol reported in the literature, mostly in recurrence once euthyroid.30 In our given its ability to block T4-to-T3 school-aged to teen-aged review of the limited pediatric conversion at high doses and Japan – children.10 29 Infection, surgery, literature, we found 8 reported cases Endocrine Society guidelines diabetic ketoacidosis, or of seizures in endogenously caused proposing use of the more cardio- nonadherence to antithyroid thyroid storm,10,14,18,21,26 perhaps selective esmolol. Guidelines agree on medications can trigger thyroid suggesting that seizures may occur the addition of saturated solution of storm, but an obvious precipitant is more often in thyroid storm in potassium iodide or Lugol’s iodine not always evident,11,17,25 as in our children than in adults. One of those solution to prevent new thyroid case. Initial presentation can include cases was similar to ours with an hormone synthesis and release as life-threatening congestive heart initial diagnosis of “presumed feverish well as the addition of hydrocortisone failure and arrhythmias as well as gastroenteritis with febrile seizures” in to prevent T4-to-T3 conversion and central nervous system disturbances a 2-year-old patient before the protect against relative adrenal including agitation, lethargy, and discovery of thyromegaly.10 insufficiency. If this medical

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 145, number 2, February 2020 3 management is not successful, 2. Hirtz DG. Febrile seizures. Pediatr Rev. 13. Darby CP. Three episodes of radioactive iodine or thyroidectomy 1997;18(1):5–8; quiz 9 spontaneous thyroid storm occurring in a nine-year-old child. Pediatrics. are next-line therapies. 3. Akamizu T, Satoh T, Isozaki O, et al; 1962;30:927–931 This 4-pronged medication approach Japan Thyroid Association. Diagnostic has been successful in many criteria, clinical features, and incidence 14. Galaburda M, Rosman NP, Haddow JE. of thyroid storm based on nationwide Thyroid storm in an 11-year-old boy previously reported cases of pediatric 11,13,17,18,22 surveys [published correction appears managed by propranolol. Pediatrics. thyroid storm. Similar to – 16,20,25 in Thyroid. 2012;22(9):979]. 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Downloaded from www.aappublications.org/news by guest on September 23, 2021 Thyroid Storm in a Toddler Presenting as a Febrile Seizure Jennifer M. Ladd, Bayane Sabsabi and Julia E. von Oettingen Pediatrics originally published online January 24, 2020;

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