Hemiplegia after Thyrotropin Alfa in a Hypothyroid Patient with Thyroid Carcinoma Metastatic to the Brain

George E. Vargas, Harry Uy, Carlos Bazan, Theresa A. Guise and Jan M. Bruder

Department of Medicine, Division of Endocrinology (G.E.V., H.U., T.A.G., J.M.B.) and Department of Radiology (C.B.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7877

Address correspondence and requests for reprints to: Jan Bruder, M.D., University of Texas Health Science Center at San Antonio, Division of Endocrinology, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7877.


    Introduction
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 Introduction
 Case Report
 Measurements
 Discussion
 References
 
EFFECTIVE radioiodine treatment of thyroid cancer is dependent on an increase in serum TSH concentration in response to LT4 withdrawal. The major disadvantage to thyroid hormone withdrawal is the development of symptomatic hypothyroidism. More concerning, although not common, is the potential for accelerated tumor growth mediated by TSH (1, 2, 3, 4, 5, 6, 7, 8). The use of recombinant human TSH (TSH alfa) without LT4 withdrawal prevents the development of hypothyroidism and has been approved in diagnostic radioiodine scanning (9, 10). It is unknown whether short-term administration of TSH results in growth of thyroid cancer in patients. We report a patient with follicular thyroid cancer metastatic to the skeleton, brain, and clivus. Hypopituitarism resulted from a metastatic clival lesion that involved the pituitary gland. TSH alfa, in a compassionate use protocol, was administered before radioiodine treatment. Forty-eight h after TSH alfa administration, the patient developed hemiplegia.


    Case Report
 Top
 Introduction
 Case Report
 Measurements
 Discussion
 References
 
A 46-yr-old Hispanic female presented in 1980 to another institution in Mexico for evaluation of a thyroid mass. A right hemithyroidectomy revealed follicular thyroid cancer. The hospital records and details concerning the initial presentation are unavailable. Within an 8-yr period, she developed metastases to the brain and skull. In August 1988, she presented to our institution and underwent a left hemithyroidectomy with subsequent 210 mCi radioactive iodine (131I). Due to a mass effect and herniation, a subtotal resection of a skull mass with a craniectomy of the vault (Fig. 1Go, A and B) was performed in December 1988. A decrease marrow signal in the clivus was also observed on the magnetic resonance imaging (MRI). Pathology of the skull mass revealed follicular thyroid cancer. Between January 1989 and July 1989, she received two treatments of 131I (total 559 mCi) for metastatic involvement of the ribs and lumbosacral spine (Fig. 2AGo). In 1990, MRI of the spine revealed metastatic disease to the thoracic spine (T12), and computerized tomography scan of the head showed metastatic disease to the right orbit and clivus (scan not available). She was treated with external beam radiation (XRT) (4000 rads) to the thoracic and lumbar spine (T11–L3). In April 1992, MRI of the spine showed progression of the thoracic spine lesions to T2, T3, T12, and L1, and 3600 rads were given. In November 1993, she received XRT (4000 rads) for lytic lesions of the right shoulder and head. Her serum thyroglobulin (TG) concentration was 2000 (0–60 ng/mL) with a TSH concentration of less than 0.03 (0.35–5.50, uIU/mL). In December 1993, a month after LT4 withdrawal in preparation for 131I treatment, her TSH concentration increased to 57 uIU/mL with a concomitant TG concentration of 31,000 ng/mL. Two hundred fifty-four mCi of 131I was administered. Her posttherapy 131I whole body scan (WBS) in January 1994, showed multiple abnormal foci consistent with metastatic disease, and MRI of head showed ischemic changes with a clival mass close to the brainstem. Prednisone was started, and XRT (4000 rads) was given to the base of the skull and cervical spine.



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Figure 1. MRI (1988): A, Sagittal T1-weighted image with a large vertex metastasis (1 ), a normal-appearing sella (2 ), normal bright marrow signal in clivus (3 ), and an abnormal decreased marrow signal in clivus (4 ). B, Axial proton density image without metastasis.

 


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Figure 2. Total body 131I scan: A, 1989; B, 1997.

 
In July 1996, she developed a new pelvic lesion and extension of the clival mass into the cavernous sinus. In preparation for another treatment with 131I, her LT4 was discontinued in November 1996 and cytomel was administered for 4 weeks. Her TSH did not increase, although her serum-free thyroxine (FT4) concentration, off all thyroid hormone for 2 weeks, was 0.1 ng/dL (0.8–1.5 ng/dL). FSH and LH were also low, consistent with hypopituitarism. Cytomel was restarted pending approval for a compassionate use of TSH alfa. She later developed new onset tonic clonic seizures and was started on dexamethasone and phenytoin. A large mass extending from the clivus and involving the pituitary gland was noted on MRI (Fig. 3Go, A, B, andC). Cytomel was again discontinued for 2 weeks in preparation for 131I treatment. The TSH concentration again did not increase after cytomel withdrawal despite a low FT4. She received two intramuscular injections of 0.9 mg TSH alfa 24 hours apart in a compassionate use protocol. Serum TSH concentration increased to 572 uU/mL. Twenty-four h after the second injection, the patient developed right hemiplegia. A MRI of the brain revealed a hemorrhagic component of the left parietal and clival masses (Fig. 4Go, A, B, and C). She was treated with XRT to the head and lumbar spine. Four days after TSH alfa administration, 304 millicuries of 131I was administered. Her TSH was 214 uU/mL. The post-131I-treatment WBS revealed persistent metastases involving the head, neck, axilla, chest, pelvis, and lower extremity (Fig. 2BGo). Levothyroxine was resumed.



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Figure 3. MRI (1997) before TSH alfa administration. A, Sagittal T1-weighted image showing the site of the resected metastasis (1 ), a large mass involving the clivus, and pituitary gland (2 ). B, Axial T1-weighted image showing an abnormal decreased signal in the mesial posterior frontal lobe (arrow). C, Axial T2-weighted image showing an abnormal increased signal in the mesial posterior frontal lobe (arrow).

 


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Figure 4. MRI (1997) after TSH alfa administration. A, Sagittal T1-weighted image showing a large clival mass and hyperintense focus of hemorrhage (1 ). B, Axial T1-weighted image showing the hyperintense focus of hemorrhage within the metastatic lesion (arrow). C, Axial T2-weighted image showing a heterogenous mass with surrounding hyperintense edema (1 ) and hyperintense area of hemorrhage (arrow).

 
A year after this episode, the patient has partially recovered strength in her right upper extremity, but not in her lower extremity. Follow-up MRI in 1998 revealed a decrease in the size of the clival mass. The serum concentration of TG decreased on LT4 0.15 mg daily, suggesting a reduction in the tumor burden.


    Measurements
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 Introduction
 Case Report
 Measurements
 Discussion
 References
 
TSH

Two different methods for TSH determination were performed from 1987 through 1992. Between 1987 and 1992, a two-site immunoradiometric assay was used (Bio-Rad Laboratories, Inc., Hercules, CA). The normal values are 0.23–5.41 uU/ml (1987–1990) and 0.38–4.90 uU/ml (1990–1992). From 1992 to the present, a two-site chemiluminometric immunoassay was used (Ciba-Coming, Medfield, MA). The normal values are 0.35–5.50 uU/ml (0.35–5.50 mU/L).

Total Thyroxine (T4)

A solid-phase competitive RIA was used for total T4 determination between 1988 and 1991 (Nuclear Medical Lab, Durham, NC). The normal values are 5.5–11.5 ug/mL (70.8–148 nmol/L). A solid-phase competitive RIA with normal values of 4.4–12.5 ug/mL (56.5–160.9 nmol/L) was used from 1991 and 1992 (Ciba-Corning, Inc. Medfield, MA). From 1992 and 1994, a chemiluminescence competitive assay was utilized (Ciba-Corning, Inc.). The normal values are 4.5–10.9 ug/mL (57.9–140.3 nmol/L).

Free Thyroxine (FT4)

A chemiluminescent competitive immunoassay was used to determine FT4 concentrations (Ciba-Corning, Inc.). The normal values are 0.8–1.5 ng/dL (10.3–19.3 pmol/L; 1994–1997) and 0.9–1.8 ng/dL (11.6–23.2 pmol/L; 1997-Present).

TG

Between 1988 and 1996, a competitive binding RIA was used to determine TG concentrations (Kronus, San Clemente, CA). The normal values are 2.5–52.5 ng/mL. From 1996 to the present, a chemiluminescence sandwich immunoassay is used, with normal values between 0–60 ng/mL (ARUP Laboratories, Salt Lake City, UT).


    Discussion
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 Introduction
 Case Report
 Measurements
 Discussion
 References
 
Thyroid carcinoma occurs in an estimated 17,000 people each year in the United States (11, 12). Surgery, followed by radioiodine ablation and chronic thyroxine (LT4) suppressive therapy, is a commonly used and is an effective treatment (13). Effective radioiodine treatment, however, is dependent on an increase in serum TSH concentration in response to LT4 withdrawal, which allows for efficient tissue uptake of the iodine. Until recently, the methods to increase serum TSH concentration were LT4 withdrawal or bovine TSH (bTSH) administration. The major disadvantage to thyroid hormone withdrawal is the development of symptomatic hypothyroidism. In addition, some patients may not have a sufficient increase in endogenous TSH secretion for optimal imaging (14). More concerning, although not common, is the potential for accelerated tumor growth (1, 2, 3, 4, 5, 6, 7, 8). The use of bTSH has been limited by neutralizing antibody formation, decreasing its effectiveness with subsequent dosing (15, 16, 17). Allergic reactions, including anaphylaxis have also been reported with bTSH administration (18). A possible solution to the above problems is the use of recombinant human TSH, TSH alfa (9, 10, 19, 20, 21, 22, 23). TSH alfa has the properties and action of native TSH (19, 20, 21, 22, 23), and recent studies have reported the safety and efficacy of TSH alfa administration before radioiodine scanning (9, 10, 14). TSH alfa has been shown to stimulate the uptake of radioiodine for WBS in patients with thyroid cancer (9, 10). When compared with LT4 withdrawal, it is associated with fewer hypothyroid symptoms and dysphoric mood states, but is slightly less sensitive for body imaging (9, 10). TSH alfa has been approved by the Food and Drug Administration for use in scanning. There have been no reported studies on the use of TSH alfa in the treatment of thyroid cancer. It may be especially useful in patients who are unable to increase their endogenous TSH production secondary to pituitary or hypothalamic disease. Although brain metastases from thyroid carcinoma occurs with a frequency of 0.15–1.3% (2, 24, 25, 26), there were no medline reports of metastases to the pituitary gland from thyroid cancer that resulted in hypopituitarism. The use of TSH alfa may be useful in this situation for radioiodine scanning and treatment, as it was in a patient described by Ringel and Ladenson (14), with hypopituitarism resulting from a pituitary adenoma. We used TSH alfa in a compassionate use protocol to treat a patient with radioiodine who had hypopituitarism from a clival metastasis involving the pituitary gland.

The temporal association of right-side hemiplegia and administration of TSH alfa in this patient with follicular thyroid cancer metastatic to the brain is obvious and suggests a causal relationship. This is the first case report of hemorrhage in a brain metastasis causing hemiplegia after TSH alfa administration. Although prolonged exposure to increased endogenous concentrations of TSH during hypothyroidism have been linked with thyroid tumor growth (2, 3, 4, 5, 6, 7, 8) and hemorrhage (1, 2), this study suggest that brief increases induced by TSH alfa in the presence of hypothyroidism may be associated with this complication in patients with brain metastases. There are two case reports of patients with metastatic thyroid carcinoma to the brain that developed hemiplegia after 131I treatment (1, 2). In both cases, the cause was speculated to be secondary to 131I therapy and radiation-induced edema, under endogenous TSH stimulation. Our patient developed hemiplegia 48 h after TSH alfa administration, which resulted in an increase in TSH concentration to 572 uU/mL. This was 4 days before 131I therapy administration and suggests that the acute event was due to tumor growth stimulation by TSH alfa administration and not radiation-induced edema.

In addition to the direct effect of TSH stimulation, the patient’s hypothyroid state may have contributed to the event. Until now, TSH alfa has been administered to patients in a euthyroid state. It is speculated that hypothyroidism upregulates TSH receptors (27), alters drug metabolism (28), and causes minor bleeding tendencies (29), including easy bruising and menorrhagia. In euthyroid patients who receive TSH alfa before scanning, the TSH concentrations have been reported to be as high as 132 uU/mL (9). The TSH concentration in our hypothyroid patient was 5-fold higher and may be the result of a decrease in TSH metabolism. It has also been reported in vitro that TSH alfa up-regulates TSH receptors (30). In this case report, it is unclear if the higher TSH concentration and up-regulated TSH receptors accelerated tumor growth. TSH has also been reported to regulate vascular endothelium growth factor, which affects vascular permeability and blood flow (31). How this relates to the complication here is only speculative.

Furthermore, the hypothyroid state may have resulted in an increase in bleeding tendencies. In hypothyroid states, the platelet count is usually normal but the adhesiveness may be depressed. The prothrombin time is usually also normal, but the partial thromboplastin time may be prolonged and suggests a defect in the intrinsic clotting mechanism. However, operative blood loss has been reported to be similar in hypothyroid patients undergoing surgical procedures compared with normal patients (29). Taken together, the hemiplegia in our patient may have been a result of a direct TSH effect on tumor growth and increased vascular permeability in a previously quiescent metastatic lesion in combination with hypothyroid-induced coagulopathy. We caution the use of TSH alfa in patients who are hypothyroid with brain metastasis. The effect of TSH alfa on brain metastasis in euthyroid patients is still unknown.


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Table 1. Sequence of events

 

    Acknowledgments
 
We acknowledge Drs. Gregory Mundy and Bryan Haugen for their helpful discussions.

Received November 12, 1998.

Revised April 7, 1999.

Accepted August 13, 1999.


    References
 Top
 Introduction
 Case Report
 Measurements
 Discussion
 References
 

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