THYROID STORM WITH COMA IN A PATIENT WITH METASTATIC THYROID CARCINOMA AND GRAVES DISEASE: WON THE BATTLE BUT LOST THE WAR

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1 Case Report THYROID STORM WITH COMA IN A PATIENT WITH METASTATIC THYROID CARCINOMA AND GRAVES DISEASE: WON THE BATTLE BUT LOST THE WAR Ashna Pinto, MBBS 1 ; Tyler Drake, MD 1,2 ; Zuzan Cayci, MD 3 ; Lynn A. Burmeister, MD 1 ABSTRACT Objective: To describe the background and events that may precipitate thyroid storm (TS) with coma as well as the course of treatment intervention and our patient s response to treatment. Methods: We present a case of TS with coma including precipitants, thyroid function tests, thyroid ultrasound, computed tomography findings, course, treatment, and outcome. Results: A 71-year-old woman was hospitalized with back pain and right leg weakness due to a newly diagnosed, 12.4-cm sacral tumor. The tumor had metastasized from poorly differentiated papillary thyroid carcinoma. The patient developed TS characterized by thyrotoxicosis with fever, tachycardia, and mental status change progressing to coma over several days. Treatment including antithyroid drugs, steroids, saturated solution of potassium iodide, L-carnitine, therapeutic plasma exchange, and thyroidectomy reversed the prolonged coma and TS, but left residual flaccid quadriplegia. The patient eventually died. Conclusion: This patient presented with multiple rare causes of TS (computed tomography contrast and Graves disease in the setting of high-volume thyroid cancer) and a rare manifestation of TS (coma). The TS included fever, tachycardia, and rapid onset of prolonged coma in the setting of thyrotoxicosis. Precipitants of the TS may have included enlarged thyroid tissue from goiter, distant metastasis, the operation, computed tomography contrast exposure, and high levels of thyroid-stimulating immunoglobulin. Multifaceted treatments, most importantly therapeutic plasma exchange, resolved the coma and TS, but the patient still succumbed to comorbidity. We agree with the Japan Thyroid Association recommendation for therapeutic plasma exchange in patients with TS, especially those in a coma who do not awaken within 24 to 48 hours of starting conventional TS treatment. (AACE Clinical Case Rep. 2019;5:e7-e12) Abbreviations: CT = computed tomography; GD = Graves disease; SSKI = saturated solution of potassium iodide; TS = thyroid storm; TSH = thyroid-stimulating hormone; TSI = thyroid-stimulating immunoglobulin; TT3 = total triiodothyronine; TT4 = total thyroxine Submitted for publication May 31, 2018 Accepted for publication July 13, 2018 From the 1 Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, 2 Division of Endocrinology, Department of Medicine, Minneapolis VA Health Care System, Minneapolis, Minnesota, and 3 Department of Radiology, University of Minnesota, Minneapolis, Minnesota. Address correspondence to Dr. Lynn A. Burmeister, 420 Delaware Street Southeast, MMC 101, Minneapolis, MN burme008@umn.edu. DOI: /ACCR To purchase reprints of this article, please visit: INTRODUCTION Thyroid storm (TS) is a rare, life-threatening state of extreme decompensated thyrotoxicosis (1-5). We report an unusual case of TS manifesting with prolonged coma, occurring in the setting of large-volume metastatic thyroid carcinoma and Graves disease (GD). Failure to respond to conventional drug treatment necessitated therapeutic plasma exchange and thyroidectomy, with reversal of coma but continued near quadriplegia. AACE CLINICAL CASE REPORTS Vol 5 No. 1 January/February 2019 e7

2 e8 Thyroid Storm with Coma, AACE Clinical Case Rep. 2019;5(No. 1) CASE REPORT A 71-year-old female with history of hypertension, atrial fibrillation, congestive heart failure, and chronic kidney disease presented with a 2-month history of lower back pain and progressive right lower extremity numbness and weakness, making her unable to walk. Lumbar imaging on the first hospital day (including both magnetic resonance imaging and computed tomography (CT) with contrast) showed a 12.4-cm sacral mass with extension into the sacral canal and involvement of right S1 through S5 sacral nerve roots (Fig. 1 A). Incisional biopsy of the sacral mass on the same day showed follicular variant papillary thyroid carcinoma. The CT results also showed multiple sub-centimeter pulmonary nodules indicating possible metastatic disease. One year prior to admission, thyroid-stimulating hormone (TSH) was 0.01 mu/l (normal range for this laboratory is 0.35 to 4.94 mu/l) and free thyroxine was 1.27 ng/dl (normal range for this laboratory is 0.70 to 1.8 ng/dl). She denied symptoms of thyrotoxicosis, personal or family history of thyroid disease, or history of radiation exposure. She was alert, oriented, afebrile, her heart rate was 77 beats per minute, and blood pressure was 148/66 mm Hg. Right foot drop and leg weakness were present. Admission labs, including liver function tests, were normal. High-dose dexamethasone was started for treatment of radiculopathy. Severe thyrotoxicosis was noted on day 3 with TSH <0.01 mu/l (at our laboratory, normal range is 0.40 to 4.00 mu/l), free thyroxine >8.00 ng/dl (at our laboratory, normal range is 0.76 to 1.46 ng/l), total thyroxine (TT4) >24.0 µg/dl (normal range is 4.5 to 13.9 µg/dl), total triiodothyronine (TT3) >460 ng/dl (normal range is 60 to 181 ng/dl), thyroglobulin 79,090 ng/ml (normal range is <40 ng/ml, thyroid intact), and bilirubin 1.9 mg/dl (normal range is 0.2 to 1.3 mg/dl). Despite this, she was alert, oriented, afebrile with hyperdynamic heart rate of 96 beats per minute, and normotensive. The thyroid was enlarged, somewhat fixed with right sided prominence. Pemberton sign was negative. Eye signs of GD were absent. A CT scan (with contrast) on day 3 showed a multinodular goiter with substernal extension, coarse calcifications, and mild tracheal compression (Fig. 1 B). A 3.4-cm, right sided thyroid nodule (Fig. 1 C) was later found to be positive for follicular variant papillary thyroid carcinoma on fineneedle aspiration cytology. Her treatments and thyroid hormone response are depicted in Figure 2. On day 4, cholestyramine was started to treat the lab abnormality in the context of a clinically euthyroid appearance and pending diagnostic tests. However, she later developed tachycardia, hypertension, and overnight delirium. By day 5 she became increasingly agitated and confused, lethargic, more tachycardic, hypertensive, tachypneic, and was transferred to the intensive care unit. TT4 returned µg/dl (normal range is 4.5 A B C Fig. 1. (A) axial post-gadolinium T1 fat suppressed images and sagittal T2-weighted magnetic resonance images demonstrate T2 intermediate signal, enhancing a cm, irregular mass (outlined by white arrows) involving the right hemi-sacrum and adjacent iliac bone. The mass extends into the sacral canal, right sacral neuraminal foramina, encasing S1 through S5 sacral nerve roots, and posteriorly into the gluteus and posterior paravertebral muscle. Incisional biopsy of the sacral mass showed follicular variant papillary thyroid carcinoma, with immunohistochemistry positive for thyroid transcription factor 1 and thyroglobulin. (B) post-contrast axial computed tomography scan of the chest and coronal reformatted images of the neck demonstrate enlarged right and left thyroid lobes. The gland is of heterogenous density with a nodular area of course calcifications (curved arrows). Left thyroid lobe extends into the superior mediastinum (star). The enlarged thyroid gland results in mild narrowing of the tracheal lumen (arrow). (C) grey-scale ultrasound of the thyroid demonstrates a cm, predominantly hypoechoic nodular mass in the right thyroid lobe. Linear hyperechoic area (star) with posterior shadowing represents calcification. Fine-needle aspiration cytology was positive for follicular variant papillary thyroid carcinoma.

3 Thyroid Storm with Coma, AACE Clinical Case Rep. 2019;5(No. 1) e9 to 13.9 µg/dl), TT3 >450 ng/dl (normal range is 60 to 181 ng/dl). Methimazole was started. By day 6 she was comatose, unresponsive to painful stimuli, and requiring intubation. Glascow coma score was recorded as 3 to 8 (6). Thyroid-stimulating immunoglobulin (TSI) index was high at 4.0 (normal range is <1.3). Her fever reached 101.2ºF on day 7, and infection with Clostridium difficile was diagnosed on day 8. She developed progressive renal insufficiency requiring continuous renal replacement therapy dialysis with intermittent norepinephrine starting on day 12. Unfortunately the treatments for hyperthyroid TS decompensation (Fig. 2), including antibiotics, produced no clinical improvement. Serial electroencephalograms performed on days 11, 12, and 13 showed delta theta slowing and diffuse encephalopathy that worsened over time. T2 hyperintensity visualized in the bilateral high parietal lobes on magnetic resonance imaging was interpreted as artifactual. Cerebrospinal fluid had 14 red cells, 0 white cells, glucose of 82 mg/dl, and protein of 31 mg/dl. Bilirubin peaked at 8.1 mg/dl on day 15. Due to continued coma, therapeutic plasma exchange was initiated on day 15 (Fig. 2). With this, the thyroid hormone levels greatly improved (Fig. 2 and Table 1), with corresponding improvement in vital signs and level of consciousness. By day 18, she opened and closed her eyes on command. On day 20, total thyroidectomy was performed, removing a 4.7-cm, poorly differentiated thyroid carcinoma with diffuse necrosis with a focal papillary and follicular pattern. Levothyroxine was started on day 25. Despite resolution of the TS and normalization in her mental status, she was severely weakened with near quadriplegia, achieving only a head nod by day 19 and a shoulder shrug by day 25. Neurologic consultation, spinal imaging, and electromyography concluded she had critical illness myopathy and polyneuropathy. Given the associated poor prognosis (7) and the metastatic cancer burden, she elected to stop aggressive medical cares. She was compassionately extubated and passed away shortly thereafter on day 30. DISCUSSION We present a patient with multiple rare causes of TS (CT contrast exposure, GD in the setting of goiter and high-volume thyroid cancer) as well as a rare manifestation of TS (coma). The patient had severe biochemical thyrotoxicosis, with thyroid hormone levels exceeding assay detection limits, but was not in TS at early presentation. Her status then deteriorated from normal mental status to TS with coma over a period of 3 days. Fig. 2. Serum total thyroxine (normal range is 4.5 to 13.9 µg/dl) and triiodothyronine (normal range is 60 to 181 ng/dl) concentrations over the 30-day hospital course. Methimazole was started day 5, changed to propylthiouracil on day 7, and then changed back to methimazole on day 18. A saturated solution of potassium iodide and L-carnitine were started on day 11. The dexamethasone dose was 4 mg every 6 hours on days 1 through 12, 2 mg every 6 hours starting on day 12, 2 mg every 12 hours starting on day 17, and 1 mg every 12 hours starting on day 26. exchange was performed on days 15, 16, 18 and 19. The patient was comatose from days 6 through 17.

4 e10 Thyroid Storm with Coma, AACE Clinical Case Rep. 2019;5(No. 1) Table 1 Thyroid Function Tests Before and After Therapeutic Plasma Exchange exchange 1 (day 15) exchange 2 (day 16) exchange 3 (day 18) exchange 4 (day 19) Reference range Before After Before After Before After Before After Free T ng/dl > Total T µg/dl Total T ng/dl TSH mu/l < < < Abbreviations: T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. The diagnosis of TS was based on her rapidly deteriorating clinical status with worsening tachycardia, fever, and mental status change. However, available scoring systems also support the diagnosis of TS. Burch-Wartofsky scores significantly increased from 20 to 70 between days 4 and 5 (Table 2), where a score of <25 is unlikely to represent TS and a score of >45 is highly suggestive of TS (1). She also met the Japan Thyroid Association criteria for TS on the evening of day 5 (19). Other causes of coma were not apparent. The clinical decline to TS with coma occurred despite being on beta blockers, high-dose dexamethasone, cholestyramine, and starting methimazole. Multiple factors likely participated in the pathogenesis of the TS, including the large volume of the thyroid and metastatic thyroid tissue driven by high TSI. Other precipitants including incisional biopsy operation on day 1 and iodine contrast exposure on both days 1 and 3 may also have contributed (3,8,9). Low TSH had been measured 1 year prior, suggesting preexisting toxic autonomy or GD. The large size of the substernal goiter, containing a 4.7-cm focus of poorly differentiated thyroid carcinoma and a large-volume (12.4- cm), distant metastasis further indicated a long duration of the thyroid conditions. High thyroglobulin reflected both the large thyroid volume (from both the goiter and the metastatic sites) as well as the hyperthyroid state. The high TSI levels supported the presence of coexistent GD. High TSI could have driven the TS process at both the level of the thyroid, and also by stimulation of metastatic thyroid hormone production. If the high TSI levels were longstanding, they may have also played a role in the aggressiveness of her thyroid cancer course (10). A thyroid uptake scan was not performed due to the expectation of interference from iodinated contrast exposure prior to the CT scan. Thyrotoxicosis in association with thyroid cancer may arise from several mechanisms, including autonomous production at differentiated metastatic sites (11), or by TSI stimulation (12-15). The latter may have been the case in our patient if the carcinoma was sufficiently differentiated to respond to TSI. TS has been even more rarely reported in the setting of thyroid cancer, including following treatment with radioactive iodine-131 (16) or burn (17) or trauma (18) to the metastatic sites. Indeed, our patient underwent incisional biopsy of the sacral metastasis on day 1, which we cannot exclude as a contributing precipitant of the TS. She developed hypothyroidism following thyroidectomy, despite continued presence of the metastatic tumor burden, Table 2 Burch-Wartofsky Point Scale for Thyrotoxicosis* Scores Day 3 Day 4 Day 5 Day 6 Day 7 Thermoregulatory Central nervous system Gastrointestinal-hepatic dysfunction Cardiovascular dysfunction a Precipitant b Total *Based on Burch and Wartofsky (1); a The patient had chronic atrial fibrillation preceding the hospitalization, for which 10 points were assigned on all days; b Computed tomography contrast exposure and incisional biopsy on day 1 were considered as precipitants, for which 10 points were assigned on all days.

5 Thyroid Storm with Coma, AACE Clinical Case Rep. 2019;5(No. 1) e11 speaking to the inefficiency of thyroid hormone production at those sites, if present. Because thyroid blood levels were above assay measurement limits, dilutions were used to follow the response of TT4 and TT3 to therapy. Multiple modalities of treatment were used to manage the TS, including beta blockers, dexamethasone, antithyroid drugs, a saturated solution of potassium iodide (SSKI), L-carnitine, therapeutic plasma exchange, and thyroidectomy (2,4,20). In our patient SSKI treatment was not started until day 11 out of concern that the TS had been precipitated by exposure to iodinated CT contrast. The largest drop in TT4 (12 fold) and TT3 occurred early in response to methimazole and propylthiouracil followed by SSKI. Once SSKI was given, the TT4 level dropped to 18.2 µg/dl and TT3 dropped to 250 ng/dl by day 15. Nonetheless, it appeared that therapeutic plasma exchange achieved the degree of thyroid hormone improvement necessary to resolve the coma (Table 1), as she began to awaken on day 18 (12 days after onset of coma and after 2 sessions of therapeutic plasma exchange). Others have also reported improvement in TS coma with therapeutic plasma exchange (4). Our patient s TS course had several features associated with higher risk of mortality, including coma, intubation, dialysis, therapeutic plasma exchange, and corticosteroid use (5,21). We believe she recovered from the TS and could have achieved long-term survival had she not had other critical comorbidities including disabling, unresectable metastatic cancer, as well as near quadriplegia. Flaccid quadriplegia has been reported in only 3 cases of thyroid myopathy (22,23). High doses of steroids, given for tumor radiculopathy, TS-related relative adrenal insufficiency, or to inhibit conversion of T4 to T3 could have also contributed to quadriplegia due to critical illness myopathy or neuropathy (7). It may be relevant to note that, for unclear reasons, steroid treatment was associated with higher mortality in a Japanese inpatient TS database (5,24). Therefore, we recommend minimizing prolonged high-dose steroid exposure during TS treatment. CONCLUSION We present a patient with multiple rare causes (CT contrast, GD in the setting of high-volume thyroid cancer) and a rare manifestation (coma) of TS. Multimodal treatment, most importantly therapeutic plasma exchange, resolved the coma and TS, but the patient still succumbed to comorbidity. 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