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.
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Introduction
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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.
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Case Report
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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. 1
, 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. 2A
). 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 (T11L3). 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 (060 ng/mL) with a TSH concentration of less
than 0.03 (0.355.50, 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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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 (0.81.5 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. 3
, 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. 4
, 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. 2B
). 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).
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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.
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Measurements
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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 0.235.41 uU/ml (19871990) and 0.384.90
uU/ml (19901992). From 1992 to the present, a two-site
chemiluminometric immunoassay was used (Ciba-Coming, Medfield, MA). The
normal values are 0.355.50 uU/ml (0.355.50 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 5.511.5 ug/mL (70.8148 nmol/L). A solid-phase
competitive RIA with normal values of 4.412.5 ug/mL (56.5160.9
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 4.510.9 ug/mL (57.9140.3 nmol/L).
Free Thyroxine (FT4)
A chemiluminescent competitive immunoassay was used to determine
FT4 concentrations (Ciba-Corning, Inc.). The normal values
are 0.81.5 ng/dL (10.319.3 pmol/L; 19941997) and 0.91.8 ng/dL
(11.623.2 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 2.552.5 ng/mL. From 1996 to the
present, a chemiluminescence sandwich immunoassay is used, with normal
values between 060 ng/mL (ARUP Laboratories, Salt Lake
City, UT).
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Discussion
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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 0.151.3% (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 patients
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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Acknowledgments
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We acknowledge Drs. Gregory Mundy and Bryan Haugen for their
helpful discussions.
Received November 12, 1998.
Revised April 7, 1999.
Accepted August 13, 1999.
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