Edited by: Pierrette Gaudreau, Université de Montréal, Canada
Reviewed by: Elisabetta Ferretti, Sapienza Università di Roma, Italy; Nils Lambrecht, University of California, Irvine, United States
This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology
†These authors have contributed equally to this work
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Ocular myasthenia gravis (Ocular MG, OMG) shares many clinical features with thyroid-associated orbitopathy or thyroid-associated ophthalmopathy (TAO). In the rare instance of their coexistence, clinicians may fail to diagnose ocular MG when TAO is also present. Here we report the case of a patient with both TAO and ocular MG, whose “hyperthyroidism”—most likely the hashitoxicosis variant of Hashimoto's thyroiditis—rapidly transformed to hypothyroidism after radioactive iodine therapy. This is reminiscent of a previous case of a patient with MG, in whom disease onset coincided with the methimazole-induced transformation from hyper- to hypothyroidism. It is possible that the same transformation from “hyper-” to hypothyroidism, which occurred after radioactive iodine therapy and was accompanied by hypothyroidism-associated orbitopathy (ophthalmopathy), may have induced the development of myasthenia gravis in our patient. The hypothyroidism may have been caused by the radioactive iodine therapy and/or it may simply reflect the natural course of the hashitoxicosis variant of Hashimoto's thyroiditis. The co-occurrence of hypothyroidism, hypothyroidism-associated orbitopathy (ophthalmopathy) and ocular MG has never been reported. Our case highlights the need for clinicians to focus on overlapping symptoms of hyperthyroidism and the hashitoxicosis variant of Hashimoto's thyroiditis, and to carefully differentiate between them, especially when deciding on radioactive iodine therapy. In addition, our case highlights that the possible co-occurrence of TAO should be considered when a patient with thyroid disease displays both ptosis and eye movement dysfunction, and when only the ptosis is dramatically resolved after treatment with pyridostigmine bromide.
Autoimmune diseases, which result from specific immune responses against self structures, include autoimmune thyroid diseases and myasthenia gravis (MG). In autoimmune thyroid diseases, which include Hashimoto's thyroiditis and Graves's disease (GD), the body mounts immune responses against thyroid antigens (
Ocular myasthenia gravis (Ocular MG, OMG) shares many clinical features with thyroid-associated orbitopathy or thyroid-associated ophthalmopathy (TAO) and is therefore difficult to diagnose when TAO is also present (
A 35-year-old Chinese man, employed at a bank, showed the following abnormal thyroid function results during a health examination at our hospital in November 2016: thyroid-stimulating hormone (TSH), < 0.005 mU/L (normal, 0.27–4.2); free triiodothyronine (FT3), 26.11 pmol/L (3.6–7.5); free thyroxine (FT4), 59.16 pmol/L (12.0–22.0); anti-thyroid peroxidase antibodies (TPO-Ab), >600 IU/ml (<34); and anti-thyroglobulin antibodies (TG-Ab), >4,000 IU/ml (<115).
The same man was admitted to a local hospital in March 2017 for further evaluation. He reported palpitations, sweating, heat intolerance, weakness, fatigue, polyphagia, tremors, and increased defecation lasting throughout the previous 6 months. A physical examination revealed no distinctive abnormalities except for a goiter. The results of thyroid function tests were as follows: TSH, < 0.0004 mIU/L (normal, 0.35-4.94); FT3, 17.74 pmol/L (2.63-5.70); FT4, 33.64 pmol/L (9.01-19.05); TPO-Ab, >400 IU/ml (<30); TG-Ab, >2,000 IU/ml (<75); and anti-thyroid-stimulating hormone receptor antibodies (TSHR-Ab), 38.89 IU/L (<1.22). Thyroid ultrasonography revealed an uneven echoic involvement of the parenchyma, with iso-echo nodules of regular shape and a clear boundary in the right lobe and isthmus. The 24-h rate of radioactive iodine uptake increased, with a peak appearing in advance. The patient was diagnosed with “hyperthyroidism” and given the anti-thyroid drug Tapazole orally (10 mg, three times daily). After treatment for 20 days, the patient complained of itchy skin and a red rash. This was interpreted as an allergic reaction, so Tapazole was discontinued, radioactive iodine therapy was then given, and the patient was discharged.
In May 2017, the patient displayed ptosis of the left eye, which grew worse by the end of the day or after exertion, and which improved upon rest. He also exhibited diplopia and limited eye movement in all directions, which at its worst meant that he could not move his eyes at all. In addition, the patient reported generalized muscle ache and weakness. Thyroid function tests at the local hospital gave the following results: TSH, < 47.8642 mIU/L; FT3, <1.54 pmol/L; FT4, <5.15 pmol/L; TPO-Ab, >400 IU/ml; and TG-Ab, >2,000 IU/ml. The patient was diagnosed with hypothyroidism and took levothyroxine (L-T4, 75 mg per day) replacement therapy. Two weeks later, the symptoms of fatigue, muscle weakness and myalgia had completely disappeared. However, after 2 months of L-T4 therapy, ocular symptoms persisted, and the patient was admitted to the neurology department in the same local hospital in July 2017. A physical and neurological examination found no abnormalities except for ptosis of the left eye and the limited movement of both eyes in all directions, without proptosis, periorbital or limb edema. TSH, FT3, and FT4 were normal. TPO-Ab was >400 IU/ml, TG-Ab was 1416.67 IU/ml, and serum lactic acid was 2.4 mmol/L (normal, 0.5–2.2). Complete blood count, tests of liver and kidney function, as well as levels of creatine kinase and serum tumor markers were normal. Magnetic resonance imaging of the brain, cervical vertebra, and the orbital cavity was normal, as were the electrocardiogram and echocardiography. Contrast-enhanced computed tomography of the chest was normal, revealing no obvious thymic hyperplasia or thymoma. Thyroid ultrasonography revealed uneven echoic involvement of the parenchyma, with iso-echo nodules in the right lobe. Low- and high-frequency repetitive nerve stimulation did not reveal abnormal decrease or increase in the amplitude of compound muscle action potential. The Ptosis was apparently alleviated, based on the positive response in the neostigmine test (
Eyelid symptoms before and after the neostigmine test.
In August 2017, the patient was admitted to our neurology department complaining of restricted eye movements. The following test results were obtained upon admission: serum lactic acid, 2.7 mmol/L (normal, 0.7-2.1); TSH, FT3, and FT4, normal; TPO-Ab, >600 IU/ml; and TG-Ab, >4,000 IU/ml. Normal findings were obtained for complete blood count, erythrocyte sedimentation rate, liver and kidney function, electrolytes, serum glucose, serum lipid, creatine kinase, and serum tumor markers. A thyroid ultrasonography revealed uneven hypoechoic involvement of the parenchyma, with mild hyper-echo nodules in the right lobe. Low- and high-frequency repetitive nerve stimulation did not reveal abnormal changes in the amplitude of compound muscle action potential. Nerve conduction tests and needle electromyography both provided normal findings. Contrast-enhanced magnetic resonance imaging of the orbital cavity revealed thickened extraocular muscles in both eyes, with an obvious uneven enhancement.
Given the possibility of a mitochondrial disease, such as chronic progressive external ophthalmoplegia, a muscle biopsy was conducted, and findings did not indicate any distinctive abnormalities. The patient was started on combination therapy of L-T4 and pyridostigmine bromide, which led to a stable condition of limited eye movement and mild diplopia. He stopped using pyridostigmine bromide in November 2017 when he began planning for a baby. A follow-up in December 2017 and February 2018 showed only mild abnormality in the left eyelid (
Eyelid symptoms after cessation of pyridostigmine bromide therapy.
Changes in thyroid function results from the beginning to the last follow-up.
1 | Nov. 2016 | < 0.005↓ (0.27–4.2 mU/L) | 26.11↑ (3.6–7.5 pmol/L) | 59.16↑ (12.0–22.0 pmol/L) | >600↑ (< 34 IU/ml) | >4000↑ (< 115 IU/ml) | ND | |
2 | Feb. 2017 | 0.0009↓ (0.35–4.94 mIU/L) | 17.96↑ (2.63–5.70 pmol/L) | 41.36↑ (9.01–19.05 pmol/L) | >400↑ (< 30 IU/ml) | 1823.86↑ (< 75 IU/ml) | 35.11↑ (< 1.22 IU/L) | |
3 | Mar. 2017 | 0.0004↓ | 17.74↑ | 33.64↑ | >400↑ | >2000↑ | 38.89↑ | |
4 | May 2017 | 47.8642↑ | < 1.54↓ | < 5.15↓ | >400↑ | >2000↑ | ND | |
5 | Jun. 2017 | 2.4451 | 4.05 | 13.04 | ND | ND | >40↑ | |
6 | Jul. 2017 | 1.8375 | 3.65 | 13.63 | >400↑ | 1416.67↑ | ND | |
7 | Aug. 2017 | 0.512 | 4.28 | 16.97 | >600↑ | >4000↑ | ND | |
8 | Dec. 2017 | 0.606 | 4.55 | 16.39 | >600↑ | >4000↑ | 22.28↑ (< 3 IU/L) |
Titers of anti-AChR and anti-MuSK antibodies assayed by ELISA or radioimmunoprecipitation assay.
Jul. 2017 | 0.39 | < 0.4 | ND | ND |
10 Dec. 2017 | ND | ND | 7.310 | 0.005 |
20 Dec. 2017 | 0.678 | ND | 1.864 | ND |
After the patient's first admission to a local hospital in March 2017, he was diagnosed with Graves's disease on the basis of abnormal thyroid function results with hyperthyroidism, increased titers of TPO-Ab, TG-Ab, and TSHR-Ab, and an increased 24-h rate of radioactive iodine uptake. However, a review of the initial ultrasound images of the thyroid gland and repeated ultrasonography which revealed uneven (nodular) hypoechoic areas, raises the possibility of the hashitoxicosis variant of Hashimoto's thyroiditis at the initial presentation rather than Grave's disease, which usually displays on ultrasound images as diffused hypoechogenicity without nodules (
The differential diagnosis of hyperthyroidism should include Grave's disease and the hashitoxicosis variant of Hashimoto's thyroiditis. The latter may show a hyperthyroid phase virtually indistinguishable from Graves's disease, including the elevated thyroid uptake of radioactive iodine and the presence of thyroid-stimulating immunoglobulins. However, hyperthyroidism is transient in the hashitoxicosis variant of Hashimoto's thyroiditis, and after 3–24 months evolves into permanent hypothyroidism (
Our patient showed elevated serum concentrations of anti-AChR antibodies (
In addition to hypothyroidism and ocular symptoms, our patient showed generalized muscle ache and weakness on May 2017, which disappeared after 2 weeks of levothyroxine therapy. Muscle ache and weakness are considered characteristics of hypothyroid myopathy (
Initially, our patient required anti-myasthenic medications to relieve ptosis. Subsequently, even at 1 or 3 months after cessation of pyridostigmine therapy, the left eyelid showed only mild abnormality (
Our patient displayed restricted eye movements and thickened extraocular muscles of both eyes, which are typical of TAO. The presence of ptosis in a patient with TAO should alert the clinician to the possible presence of MG, since the clinical features of TAO and ocular MG overlap substantially, and ptosis has been described as a rare feature of TAO (
TAO may occur more frequently among Graves' disease patients with ocular MG, than among Graves' disease patients without MG or with generalized MG. Euthyroid ophthalmopathy occurs more frequently among Graves' disease patients when they also have MG, suggesting a preferential association between the ocular manifestations of Graves' disease and MG (
Previous studies described a patient with MG in whom disease onset coincided with the methimazole-induced transformation from hyper- to hypothyroidism (
MG is usually reported in hyperthyroidic patients, rarely in patients with hypothyroidism. We present here a rare case of co-occurrence of MG, hypothyroidism and TAO after radioactive iodine therapy for “hyperthyroidism.” This case highlights the need for clinicians to be aware of the possible co-occurrence of such comorbidities, which have implications for treatment and management. Clinicians should carefully differentiate between hyperthyroidism and the hashitoxicosis variant of Hashimoto's thyroiditis, especially when considering radioactive iodine therapy. Our case further highlights the need to consider the co-occurrence of TAO if pyridostigmine bromide only partly resolves ocular MG symptoms in patients with thyroid disease. If necessary, magnetic resonance imaging of the orbit can be performed to guide diagnosis and therapy.
The study protocol was approved by the Ethics Committee of Sichuan University and written informed consent was obtained from participants.
RA, YL, BY, and HW collected patient data and wrote the manuscript. YX conducted the study and revised the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Written informed consent was obtained from the patient to participating in the study and for publication of this manuscript, including the images in