J Pediatr Endocrinol Metab 2015; aop Patient report Byoungho H. Noh, Sang-Won Cho and Sung Yeon Ahn* Simultaneous occurrence of diabetic ketoacidosis, thyroid storm, and multiple cerebral infarctions due to Moyamoya disease DOI 10.1515/jpem-2015-0204 Received May 18, 2015; accepted June 26, 2015 Abstract: Diabetic ketoacidosis (DKA) is one of the precipitating factors that can evoke a thyroid storm. Thyroid storm may cause cerebral ischemia in Moyamoya disease, which can coexist in patients with Graves’ disease. A 16-year-old girl complaining of dizziness and palpitations visited the emergency department and was diagnosed with DKA combined with hyperthyroidism. A thyroid storm occurred 6 h after the start of DKA management. Her Burch and Wartofsky score was 65 points. Right hemiplegia developed during the thyroid storm, and brain magnetic resonance (MR) diffusion-weighted images revealed multiple acute infarcts in both hemispheres. MR angiography showed stenosis of both distal internal carotid arteries and both M1 portions of the middle cerebral arteries, consistent with Moyamoya disease. After acute management for the thyroid storm with methimazole, Lugol solution and hydrocortisone, the patient’s neurological symptoms completely resolved within 1 month, and free T4 level normalized within 2 months. Thyroid storm may trigger cerebral ischemia in Moyamoya disease and lead to rapid progression of cerebrovascular occlusive disease. As a simultaneous occurrence of DKA, thyroid storm and cerebrovascular accident in Moyamoya disease highly elevates morbidity and mortality, prompt recognition and management are critical to save the patient’s life. Keywords: diabetic ketoacidosis; Moyamoya disease; thyroid storm. *Corresponding author: Sung Yeon Ahn, MD, Department of Pediatrics, Ulsan University Hospital, 877 Bangeojinsunhwan-doro, Dong-gu, Ulsan 682-714, Korea, Phone: +82-52-250-7069, Fax: +82-52-250-7068, HP: +82-10-5551-4472, E-mail: zzidol74@empal.com Byoungho H. Noh and Sang-Won Cho: Department of Pediatrics, Kangwon National University Hospital, Chuncheon, Korea Introduction Thyroid storm is a life-threatening endocrine emergency. Its overall mortality rate is between 10% and 30% (1). Thyroid storm is typically triggered by stressful medical events, such as uncontrolled hyperthyroidism, discontinuation of antithyroid drug, surgery, infection, trauma and diabetic ketoacidosis (DKA) (2). Its pathophysiological mechanisms are thought to include a drastic increase in the release of thyroid hormones, hyperactivity of the sympathetic nervous system, relative adrenal insufficiency and increased peripheral cellular response to thyroid hormones (3). Thyroid storm is characterized by dysfunction of multiple organs including the cardiovascular system, thermoregulatory system, gastrointestinal system, hepatic system and central nervous system. Mortality is related to shock, multiple organ failure or disseminated intravascular coagulation (DIC). DKA is a severe metabolic disorder caused by insulin deficiency that can trigger thyroid storm in patients with hyperthyroidism. The coexistence of these two endocrine emergencies may have an atypical clinical presentation and rapidly progress to a life-threatening condition. Neurologic complications of DKA and/or thyroid storm significantly increase mortality. DKA may be complicated by cerebral edema, cerebral infarction, hemorrhage, thrombosis and central pontine and extra pontine myelinolysis (4–6), which are associated with excessive rehydration therapy or fluctuation of serum osmolality. Moyamoya disease is an occlusive disease of the cerebral arteries comprising the circle of Willis. The presence of Moyamoya disease in patients with Graves’ disease has been reported, but little is known about the pathogenic relationship between the two conditions. Cerebral infarction or hemorrhage may be developed in Moyamoya disease, if an underlying condition causes circulatory insufficiency. Here we report a 16-year-old girl who simultaneously developed thyroid storm, DKA and multiple cerebral infarctions due to Moyamoya disease. Brought to you by | HEC Bibliotheque Maryriam ET J. Authenticated Download Date | 9/15/15 12:03 PM 2 Noh et al.: Thyroid storm with diabetic ketoacidosis and multiple cerebral infarctions Case report A 16-year-old girl visited the emergency department complaining of dizziness and palpitations. Her vital signs were heart rate 212 beats/min, blood pressure 130/70 mm Hg and body temperature 36.3°C. She had no history of underlying disease or medication. Clinicians suspected paroxysmal supraventricular tachycardia, but the initial biochemical analysis revealed DKA on the basis of the following values: glucose 482 mg/dL, pH 7.193, HCO3− 7.6 mmol/L, pCO2 19.5 mm Hg. HbA1c was 11.8%. After initiating treatment for DKA, it was found that the DKA was combined with hyperthyroidism. Thyroid function test results were TSH < 0.001 U/mL, free T4 9.1 ng/dL and T3 7.24 ng/mL. The patient’s mental status was alert, and physical examination revealed dehydrated tongue and a grade II goiter. Her height was 159.6 cm, and weight was 44 kg. The pubertal stage was breast III and pubic hair II. Detailed history taking revealed that she had experienced increased appetite and polyphagia during the past 1 year. She started experiencing polydipsia and polyuria 2–3 weeks prior and had epigastric pain and vomiting 2 days before the hospital visit. Menarche occurred at 12 years old, but she had not menstruated since then. Her family had no history of endocrinological, renal or cardiovascular disease. At 6 h after the start of DKA management, she complained of feeling hot and stuffy, broke into a sweat and suddenly became agitated and confused. Under the suspicion of thyroid storm, 20 mg of methimazole was administrated via L-tube. Soon after, bradycardia below 30 beats/min developed, and the patient recovered after cardiopulmonary resuscitation. She was drowsy and her body temperature was 38.5°C. Burch and Wartofsky score was 65 points. Management of the thyroid storm was continued with methimazole (20 mg every 6 h), followed by hydrocortisone (100 mg every 8 h) and 5% Lugol solution (KI 25 mg every 6 h). The patient was found to have developed right hemiplegia several hours later. Brain MR diffusion-weighted images revealed multiple acute infarcts on both hemispheres (Figure 1). MR angiography showed stenosis of both distal internal carotid arteries, and both M1 portions of the middle cerebral arteries, consistent with Moyamoya disease (Figure 2). Electrocardiogram and echocardiogram showed no specific abnormality. Laboratory results indicated DIC and severe hepatopathy (Table 1). Antithrombin III and fresh frozen plasma were administered. Elevated levels of thyroid-stimulating immuno­ globulin (16.04 IU/L), anti-thyroperoxidase antibody (254.8 U/mL) and anti-glutamic acid decarboxylase antibody (215.72 U/mL) suggested autoimmune thyroiditis and type 1 diabetes mellitus. Other autoantibodies including antinuclear antibody, anti-double stranded DNA antibody, lupus anticoagulation antibody, anti-cardiolipin antibody, anti-phospholipid antibody, anti-LKM antibody and anti-mitochondrial antibody were all negative. The patient regained alertness in 3 days, and liver function and laboratory tests for DIC normalized after 1 week of treatment for thyroid storm and DKA. Figure 1: MR diffusion-weighted images. Signal changes are apparent on multiple foci of both hemispheres. Brought to you by | HEC Bibliotheque Maryriam ET J. Authenticated Download Date | 9/15/15 12:03 PM Noh et al.: Thyroid storm with diabetic ketoacidosis and multiple cerebral infarctions Discussion A B C Figure 2: Narrowing regions were found in both cerebral arteries (distal ICA and M1) on MR angiogram (A and B) and enhanced images (C). Table 1: Laboratory data during the critical period and after improvement. Critical period After 1 After 3 Reference month month range Initial Worst Free T4, ng/dL T3, ng/mL HbA1c, % AST, U/L ALT, U/L T. bilirubin, mg/dL Ammonia, μg/dL Prothrombin time, INR aPTT, s FDP, μg/mL Fbrinogen, mg/dL Antithrombin III, % LH, mIU/mL FSH, mIU/mL Estradiol, pg/mL 3 9 > 12 7.24 7.24 11.8 30 > 5500 35 > 5500 0.3 3.4 165 1.39 2.45 23.8 > 180 27.54 147 68 0.53 1.11 20.47 2.0 2.25 20 22 0.4 1.08 0.89–1.76 1.09 0.6–1.81 8.2 4–6 14 0–34 15 10–49 0.2 0.3–1.2 19–60 0.92–1.17 26–37 0.0–5.0 200–400 80–120 9.04 5.65 32 aPTT, activated partial thromboplastin time; FDP, fibrin degradation product; LH, luteinizing hormone; FSH, follicle-stimulating hormone. Neurological symptoms completely resolved in 1 month. The free T4 level normalized after 8 weeks of treatment, and menstruation restarted. Thyroid storm, or thyrotoxic crisis, is a life-threatening endocrine emergency. Patients in thyroid storm present with serious signs and symptoms of hyperthyroidism and multiple organ dysfunction. Multiple organ failure, congestive heart failure, arrhythmia, respiratory failure, sepsis and DIC are common causes of death (7, 8). As no laboratory abnormalities are specific to thyroid storm, diagnosis is based on clinical criteria such as the Burch-Wartofsky scoring system (9). Triggering factors for thyroid storm include thyroid or non-thyroid surgery, discontinuation of drug therapy, infection, parturition, major trauma, iodine exposure from radiocontrast dyes, myocardial infarction, cerebrovascular incidents and DKA (2). Autoimmune hyperthyroidism can be accompanied by various autoimmune diseases (10). The present patient had autoimmune thyroiditis combined with immunemediated diabetes mellitus, which are components of polyglandular autoimmune syndrome (PAS) and classified as PAS-3A. DKA is an important trigger for thyroid storm in hyperthyroidism. Because the coexistence of thyroid storm and DKA can potentially increase morbidity and mortality, early recognition and aggressive treatment are very important. The sudden cardiac arrest or death of patients with both thyroid storm and DKA has been reported in several cases (11, 12). Our patient experienced two episodes of sudden cardiac arrest on the first day of hospitalization. When altered level of consciousness, convulsion and respiratory insufficiency develop during the treatment of DKA, cerebral complications including cerebral edema, cerebral infarction, hemorrhage, and central pontine and extra pontine myelinolysis should be suspected. Cerebral infarction in DKA patient could be caused by not only thrombosis due to inflammation, dehydration, and hyperviscosity, but also vascular vulnerability owing to diffuse cerebral swelling during rehydration. Hyperthyroidism is also associated with thromboembolic events. Atrial fibrillation and ventricular dysrhythmias related to hyperthyroidism pose a high risk for developing cardioembolic stroke. Hypercoagulability and endothelial dysfunction in hyperthyroidism may increase the risk of venous thrombosis or pulmonary embolism (13–15). Therefore, if a cerebral infarction has occurred in a patient with hyperthyroidism, the possibility of thromboembolic obstruction should be ruled out, and thorough evaluation of the heart is needed. In this case, the patient had no evidence of thrombosis. Moyamoya disease is characterized by stenosis or occlusion of the internal carotid artery, extending to the Brought to you by | HEC Bibliotheque Maryriam ET J. Authenticated Download Date | 9/15/15 12:03 PM 4 Noh et al.: Thyroid storm with diabetic ketoacidosis and multiple cerebral infarctions middle and anterior cerebral arteries. Collateral vessels that have developed around occluded vessels are vulnerable to hemorrhage and thrombosis. Hyperthyroidism may also be related to cerebrovascular disease associated with Moyamoya disease, antiphospholipid syndrome, giant cell arteritis, Takayasu arteritis and cerebral venous thrombosis (16). The coexistence of Moyamoya disease and Graves’ disease has been reported (17–19). Although the pathogenesis of Moyamoya disease in patients with Graves’ disease is not well understood, it has been suggested that the autoimmune mechanisms causing Graves’ disease (20, 21) and hyperactivation of the sympathetic nervous system in a hyperthyroid state (18, 22) might play an important role in the development of steno-occlusive lesions in the intracranial arteries. Thyroid storm may trigger cerebral ischemia and lead to rapid progression of the cerebrovascular occlusion in Moyamoya disease (17). We speculate that the patient might have developed Graves’ disease and Moyamoya disease years prior, and DKA owing to recently developed type 1 diabetes mellitus most likely triggered the thyroid storm. The combination of DKA and thyroid storm might impose vascular vulnerability on cerebral arteries, thus provoking the series of multiple cerebral infarctions arising from Moyamoya disease. To our knowledge, this is the first reported case of the simultaneous occurrence of DKA, thyroid storm and multiple cerebral infarction caused by Moyamoya disease. The patient recovered dramatically from the multiple organ dysfunction and neurological disability without sequelae as thyroid function normalized. Her luteinizing hormone and follicle-stimulating hormone levels were elevated, and her menstrual cycle restarted after the recovery of thyroid function. In conclusion, an underlying thyroid disease should be suspected in patients with atypical symptoms or signs unexplainable by DKA alone. 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