Anti-N-methyl-D-aspartate Receptor Encephalitis in a Patient with Thyroid Eye Disease.

Dear Editor,

Thyroid eye disease (TED) is a potentially sight-threatening ocular disease that can accompany hyperthyroidism or a history of hyperthyroidism due to Graves' disease [1]. Among patients with TED, 3% to 5% have severe disease with intense pain, inflammation, and sight-threatening corneal ulceration or compressive optic neuropathy [1]. Although the pathogenesis of TED is still under investigation, it is known to be caused by autoantibodies that bind to the thyroid-stimulating-hormone receptors expressed on orbital fibroblasts. These autoantibodies can bind to many other receptors in different organs, resulting in other forms of autoimmune disease. We report the first case of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, an autoimmune encephalitis caused by hypofunction due to autoantibodies against the NR1 subunit of the NMDAR [2], in a patient with TED. Anti-NMDAR encephalitis can mimic psychiatric disorders and result in significant residual disability or death without proper management.

A 27-year-old female presented with progressing exophthalmos for the previous 18 months (Fig. 1A). She had been diagnosed with Graves' disease 2 months prior to onset of exophthalmos, and her medication included methimazole 5 mg daily. Proptosis values (measured by Hertel's exophthalmometer) were 19 mm bilaterally. Examinations revealed a corrected visual acuity of 0.8 / 1.0, clinical activity score (CAS) of 4, and thyroid stimulating immunoglobulin of 643.6%. She had diplopia at primary gaze. Orbital computed tomography (CT) (Fig. 1B) revealed slight extraocular muscle hypertrophy, and the patient was given methylprednisolone 500 mg intravenous (IV) weekly for 4 weeks. Her proptosis values improved to 17 mm on both sides, with a CAS of 2. Treatment with methylprednisolone 500 mg IV weekly was continued for 5 more weeks. After completing the IV steroid, the patient underwent radiation therapy (20 Gy in 10 fractions). In the following months, TED relapsed, and CAS score remained at 3–4 despite IV and oral steroid therapy.

Fig. 1

Thyroid eye disease patient with anti-N-methyl-D-aspartate receptor encephalitis. Below are the axial views from orbital computed tomography. (A,B) Patient on the day of initial visit to the clinic. (C,D) Patient on the night of arrival to our emergency department. (E,F) Approximately 1 month after surgical orbital decompression and intravenous steroid and immunosuppressive therapy.

Eight months after the patient's initial visit, she presented at the emergency department with a corneal ulcer in her left eye and exposure keratopathy from lagophthalmos of both eyes (Fig. 1C, 1D). She had been admitted to a psychiatric unit at a local hospital for irritable mood and disorganized speech under the impression of steroid-induced psychosis. She was admitted to our psychiatric unit for general management and underwent emergency orbital decompression surgery. The operation, which involved 2-wall decompression with orbital fat removal, improved her proptosis. However, her mood symptoms did not improve. On postoperative day 3, she experienced myoclonic movements of her arms, sudden involuntary actions such as sitting up in bed, and loss of verbal communication. On postoperative day 4, the patient was not responsive to painful stimuli and showed catatonia, tremor, and rigidity. A systemic workup was performed and included brain magnetic resonance imaging, cerebrospinal fluid study, and abdominopelvic CT. The imaging studies were all normal, and electroencephalography showed a diffuse slowing pattern inconsistent with features of psychotic catatonia. Under the impression of anti-NMDAR encephalitis, she was transferred to the neurology unit. Serum and cerebrospinal fluid tests for NMDAR antibodies were positive, confirming the diagnosis of NMDAR encephalitis. The patient received IV methylprednisolone 1 g/day for 5 days, followed by IV immunoglobulin, IV rituximab, and oral mycophenolate mofetil. As her condition gradually improved, the patient was able to perform daily activities (Fig. 1E, 1F), and she was discharged from the hospital, remaining stable throughout follow-up appointments in the outpatient clinic.

To the best of our knowledge, this is the first report of anti-NMDAR encephalitis in a TED patient. Previously, two cases of anti-NMDAR encephalitis with uncontrolled Graves' hyperthyroidism without TED were reported [34]. In our patient, proptosis and orbital fat volume were significantly increased, even after high-dose steroid and radiation therapy. During anti-inflammatory treatment, the patient complained of retrobulbar pain and manifested congestive features, although the CT findings suggested minimal muscle enlargement. For this patient with progressive fat volume increase and ongoing autoimmunity, aggressive immunosuppression with combined steroid and radiation therapy was not effective. Surgical decompression of the orbit and rituximab were the most effective treatments for both TED and encephalitis.

Despite the rarity of TED complicated by anti-NMDAR encephalitis, recognizing anti-NMDAR encephalitis as a potential diagnosis for TED with severe neuropsychiatric manifestations can be life-saving knowledge in patient management.