Detection of Thyroid Abnormalities in Aquaporin-4 Antibody-Seropositive Optic Neuritis Patients

Objective: This study retrospectively analyzed the frequency of anti-thyroid antibodies (ATAs) and thyroid disease in patients with optic neuritis (ON). Methods: Tests of serum thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies and thyroid function were performed in 97 ON patients. Blood also was drawn to test for AQP4-Ab using cell-based and enzyme-linked immunosorbent assays. Comparisons of the frequencies of ATAs, thyroid diseases and thyroid function were performed based on AQP4-Ab status. Results: Seropositive AQP4-Ab was found in 47/97 (48.5%) patients. ATA was considered positive in 34/97 (35.1%) patients. The prevalence of ATA was two times higher (P = 0.019) in the AQP4-Ab+ group compared to the AQP4-Ab- group. AQP4-Ab+ ON patients exhibited lower FT3 (P = 0.006) and FT4 (P = 0.025) levels and a higher prevalence of definite Hashimoto thyroiditis (HT) (P = 0.005). Among AQP4-Ab+ patients, those with HT had a worse visual outcome than non-HT patients. Conclusion: A high prevalence of ATAs and HT was found in AQP4-Ab+ ON patients, and AQP4-Ab+ patients with HT exhibited worse visual outcomes than non-HT patients.

Original Contribution Detection of Thyroid Abnormalities in Aquaporin-4 Antibody-Seropositive Optic Neuritis Patients Shuo Zhao, MD, Huanfen Zhou, MD, Xudong Peng, MD, Shaoying Tan, PhD, MD, Zihao Liu, MD, Tingjun Chen, PhD, MD, Quangang Xu, PhD, MD, Shihui Wei, MD Objective: This study retrospectively analyzed the frequency of anti-thyroid antibodies (ATAs) and thyroid disease in patients with optic neuritis (ON). Methods: Tests of serum thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies and thyroid function were performed in 97 ON patients. Blood also was drawn to test for AQP4-Ab using cell-based and enzyme-linked immunosorbent assays. Comparisons of the frequencies of ATAs, thyroid diseases and thyroid function were performed based on AQP4-Ab status. Results: Seropositive AQP4-Ab was found in 47/97 (48.5%) patients. ATA was considered positive in 34/97 (35.1%) patients. The prevalence of ATA was two times higher (P = 0.019) in the AQP4-Ab+ group compared to the AQP4-Abgroup. AQP4-Ab+ ON patients exhibited lower FT3 (P = 0.006) and FT4 (P = 0.025) levels and a higher prevalence of definite Hashimoto thyroiditis (HT) (P = 0.005). Among AQP4-Ab+ patients, those with HT had a worse visual outcome than non-HT patients. Conclusion: A high prevalence of ATAs and HT was found in AQP4-Ab+ ON patients, and AQP4-Ab+ patients with HT exhibited worse visual outcomes than non-HT patients. Journal of Neuro-Ophthalmology 2017;37:24-29 doi: 10.1097/WNO.0000000000000454 © 2016 by North American Neuro-Ophthalmology Society Department of Ophthalmology (SZ), Beijing Hospital, Beijing, China; Department of Ophthalmology (HZ), The First Affiliated Hospital of Chinese People's Liberation Army General Hospital, Beijing, China; Department of Ophthalmology (ST, TC, QX, SW), The Chinese People's Liberation Army General Hospital, Beijing, China; Department of Health Care (XP), The Chinese People's Liberation Army General Staff Department Guard Bureau, Beijing, China; and Department of Ophthalmology (ZL), The Chinese Dongzhimen Hospital, Beijing, China. Supported by the National High Technology Research and Development Program of China (No. 2015AA020511) and the Hainan Technology and Society Development Program of China (No. SQ2014SHFZ0089). The authors report no conflicts of interest. S. Zhao, H. Zhou, and X. Peng contributed equally to this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Address correspondence to Shihui Wei, MD, Department of NeuroOphthalmology, The People's Liberation Army General Hospital, Beijing, China; E-mail: [e-mail] 24 INTRODUCTION O ptic neuritis (ON) is an inflammatory disorder of the optic nerve, which may be the first manifestation of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) (1). While NMOSD is a rare disease in Western countries and accounts for only 1%-2% of all central nervous system (CNS) inflammatory demyelinating disease among Caucasians, this percentage is as high as 20%-48% among Asians (2,3). ON in Caucasians typically presents as subacute monocular visual loss associated with pain during eye movement and recovery in several days or weeks (4). It is strongly associated with the development of MS. However, ON in Asian individuals often manifests as painless bilaterally simultaneous or persistent and progressive visual loss. It frequently is an early sign of NMO (5). The serum aquaporin-4 antibody (AQP4-AB) is highly specific for the diagnosis of NMOSD and distinguishes it from other causes of ON (6). The high frequency of autoantibodies and the coexistence of other autoimmune disorders in ON patients with AQP4-AB support the hypothesis of an autoimmune basis for this optic neuropathy (7). In the past, studies examined a possible link between autoimmune thyroid disease and MS, but none was found (8). Sakuma et al (9) demonstrated a higher prevalence of antithyroid antibodies (ATAs) in patients with optic-spinal MS (now known as NMOSD). Sellner et al (10) reported the frequency of autoimmune thyroid disease up to 17% in patients with NMOSD (11). Recent studies have included ATAs, notably antithyroid peroxidase antibody (TPO-AB), which correlate with longer segments of demyelination of the spinal cord, and ultrahigh titers of TPO-AB may accompany seropositivity of AQP4-AB (10,12,13). We investigated the prevalence of ATAs and autoimmune thyroid disease in AQP4-AB+ NMOSD patients who experienced ON. Consecutive AQP4-AB-negative ON patients were included as a control. Thyroid functions were compared based on AQP4-AB status and severity of NMOSD with or without autoimmune thyroid disease. Zhao et al: J Neuro-Ophthalmol 2017; 37: 24-29 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution METHODS Patients We retrospectively reviewed medical records of consecutive ON patients admitted to the neuro-ophthalmology department of the Chinese People Liberation Army General Hospital (PLAGH) from May 2014 through June 2015. Patients who were not screened for ATAs and thyroid functions were excluded. This study was approved by the PLAGH Ethics Committee. The diagnosis of ON followed the criteria of the Optic Neuritis Treatment Trial (14). A diagnosis of Hashimoto thyroiditis (HT) was made if the patient had any ATA positivity plus at least one of the following: 1) diffuse goiter on physical examination, 2) hypothyroidism on thyroid function tests, and 3) the presence of parenchymal heterogeneity of the thyroid gland with ultrasonography (15). The 2006 Wingerchuk criteria were used for the diagnosis of NMOSD (16). Laboratory Studies The concentrations of antithyroglobulin antibody (TG-AB) and TPO-AB and the levels of thyroxine (T4), triiodothyronine (T3), free T4 (FT4), free T3 (FT3), and thyroidstimulating hormone (TSH) were tested in the endocrinology research center of the PLAGH. An extracellular live cell- staining immunofluorescence approach using transiently transfected AQP4-expressing cells was used for the measurement of serum AQP4-AB, as previously described (17). Each serum sample was tested at least twice, and 2 independent masked evaluators scored the samples as positive (titer . 1:10) or negative. Quantitative AQP4-AB concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) (RSR Ltd, Cardiff, United Kingdom) (18). Sera also were drawn for testing of other non-organspecific (NOS) autoimmune antibodies in the rheumatologic research center in PLAGH, including antinuclear antibodies, autoantibodies against double-stranded DNA, extractable nuclear antigen, proliferating cell nuclear antigen, cardiolipin, and neutrophil cytoplasmic antigen. Cerebrospinal fluid was collected via lumbar puncture and tested for cell counts and levels of total protein, glucose, and chloride. Clinical evaluation included best-corrected visual acuity (VA), pupillary testing, slit lamp examination, and ophthalmoscopy. Automated perimetry (Humphrey SITA 30-2; Carl Zeiss Meditec Inc., Oberkochen, Germany) was performed when VA was better than 20/200. Peripapillary retinal nerve fiber layer circle scans and macular thickness measurements were obtained using spectral domain optic coherence tomography. Orbital and/or brain MRI was performed in all patients. Statistical Analyses Measurement data were analyzed using unpaired t tests or Mann-Whitney U tests. Categorical data were evaluated Zhao et al: J Neuro-Ophthalmol 2017; 37: 24-29 using the x 2 test or Fisher exact test, and P values ,0.05 were considered significant. Statistical power was determined using SPSS version 20.0 (IBM Corp, Armonk, NY). RESULTS Demographic and Clinical Characteristics Based on Serum AQP4-AB Results A total of 97 ON patients (168 involved eyes) were selected and reviewed. Forty-seven (48.4%) of these patients were AQP4-AB+. Among the AQP4-AB2 patients, 4 were diagnosed with hypothyroidism before presentation for ON and had been using oral levothyroxine for at least 1 year. Among AQP4-AB2 patients, one was diagnosed with hypothyroidism 8 months before and was given oral levothyroxine for 1 month. One additional patient had a history of hyperthyroidism 30 years ago. The demographic and clinical characteristics of the AQP4AB+ and AQP4-AB2 patients are shown in Table 1. Seropositivity of AQP4-AB was not associated with age at onset or annual relapse rate, but it was associated with female gender (P , 0.001), more recurrent episodes of ON (P = 0.006), and higher frequency of definite NMOSD (P , 0.001). VA at onset of ON and the proportion of favorable visual outcome (Snellen acuity better than 20/40) were not significantly different between the 2 groups. The proportion of severe visual loss (VA worse than 20/200) was significantly higher in AQP4-AB+ patients (P = 0.030), whereas the proportion of moderate visual loss (VA 20/40-20/200) was significantly lower in that group when compared with AQP4-AB2 patients (P = 0.006). Frequency of Antithyroid Antibodies and Thyroid Function Tests Based on Serum AQP4-AB Status Table 2 presents the comparisons of ATAs and autoimmune thyroid disease frequency and thyroid function between AQP4-AB+ and AQP4-AB2 patients. The prevalence of ATAs of 46.8% in patients with seropositive AQP4-AB was significantly higher than AQP4-AB2 patients (P = 0.019). With regard to ATAs, TG-AB (P = 0.004) and TPO-AB (P = 0.005) or dual-AB positivity (P = 0.001) was more frequent in AQP4-AB+ patients. Also, in this group, thyroid function measures of FT3 and FT4 were decreased significantly (P = 0.006 and P = 0.025, respectively), with lower T3 and T4 levels and higher TSH levels. A total of 13/47 (27.7%) AQP4-A+ patients were diagnosed with definite HT. This percentage was much higher than the AQP4-AB2 patients (6.0%, P = 0.005). Clinical Characteristics of AQP4-AB+ Optic Neuritis With and Without Antithyroid Antibodies The effect of ATAs on AQP4-AB+ ON patients is shown in Table 3. No significant differences were found in age at onset, disease duration, and annual relapse rates between 25 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographic and clinical features of patients with optic neuritis n Involved eyes Age at onset, yr, mean ± SD Gender (F:M) Disease duration, mo, mean ± SD Recurrent ON, n (%) Relapse times, mean ± SD ARR (median) VA at nadir, n (%) Worse than 20/200 20/80-20/200 Better than 20/40 VA outcome, n (%) Worse than 20/200 20/40-20/200 Better than 20/40 Definite NMOSD, n (%) Definite MS, n (%) AQP4-AB+ AQP4-AB2 P Value 47 80 36.6 ± 18.86 14.7:1 36.6 ± 16.57 37 (78.7) 5.2 ± 3.01 1.333 (n = 37) 50 86 36.7 ± 19.57 1.6:1 29.5 ± 45.15 26 (52.0) 4.0 ± 3.26 1.306 (n = 26) 0.995 ,0.001** 0.300 0.006** 0.001** 0.752 61 (76.3) 15 (18.8) 4 (4.9) 63 (73.3) 19 (22.1) 4 (4.6) 0.657 0.594 0.916 47 10 23 18 0 36 26 24 1 1 (58.8) (12.5) (28.7) (38.3) (0.0) (41.9) (30.2) (27.9) (2.0) (2.0) 0.030* 0.006** 0.904 ,0.001** NA *P , 0.05; **P , 0.01. AQP4-AB, aquaporin-4 autoantibody; ARR, annual relapse rate; MS, multiple sclerosis; NA, not available; NMOSD, neuromyelitis optica spectrum disorder; ON, optic neuritis; VA, visual acuity. the 2 groups. ATA+ ON patients tended to suffer more severe visual loss at onset and in follow-up compared with ATA2 ON patients. Patients with HT developed severe visual loss (worse than 20/200) more often than ATA2 ON patients (85.0% vs 50.0%; P = 0.012) (Fig. 1). Serum AQP4-AB concentration evaluated using ELISA did not differ between ATA+ and ATA2 patients (P = 0.516). Non-Organ-Specific Autoantibody Profiles and Autoimmune Disease Table 4 presents the frequency of NOS autoantibodies (auto-ABs) and autoimmune disease in the 2 ON groups. A total of 24/97 patients were seropositive for NOS autoABs. Notably, patients with ATAs but without AQP4-AB presented the highest prevalence of NOS auto-ABs among all the groups. The highest prevalence of HT (13/22, 59.1%) was detected in patients positive for ATAs and AQP4-AB, and HT was the only autoimmune disease detected in this subgroup. Other autoimmune disorders found in our patient cohort included Sjögren syndrome, systemic lupus erythematosus, ankylosing spondylitis, anaphylactoid purpura, and psoriasis. DISCUSSION In our study, 47/97 (48.4%) Chinese patients with ON were AQP4-AB+. These results are similar to those of Li et al (19) who found that approximately 40% of Chinese patients TABLE 2. Comparison of ATAs and thyroid function tests between AQP4-AB+ and AQP4-AB2 optic neuritis groups n ATA, n (%) TGI-AB TPO-AB Dual-ABs T3, nmol/L, mean ± SD T4, nmol/L, mean ± SD FT3, pmol/L, mean ± SD FT4, pmol/L, mean ± SD TSH, mU/L, mean ± SD Definite HT, n (%) AQP4-AB+ AQP4-AB2 P Value 47 22 (46.8) 20 (42.6) 17 (36.2) 15 (31.9) 1.2 ± 0.43 92.9 ± 22.99 3.8 ± 0.80 14.7 ± 2.59 3.1 ± 6.99 13 (27.7) 50 12 (24.0) 8 (16.0) 6 (12.0) 2 (4.0) 1.3 ± 0.57 95.8 ± 27.0 4.5 ± 1.54 16.5 ± 4.66 2.5 ± 4.36 3 (6.0) 0.019* 0.004** 0.005* 0.001** 0.102 0.564 0.006** 0.025* 0.593 0.005** *P , 0.05; **P , 0.01. AQP4-AB, aquaporin-4 antibody; ATAs, antithyroid antibodies; FT3, free T3; FT4, free T4; HT, Hashimoto thyroiditis; TPO-AB, thyroid peroxidase antibody; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone. 26 Zhao et al: J Neuro-Ophthalmol 2017; 37: 24-29 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Visual outcome of AQP4-AB+ patients with optic neuritis having ATAs and HT n Involved eyes (n) Age at onset, yr, mean ± SD Gender (F:M) Disease duration, mo, mean ± SD ARR (median) VA at nadir, n (%) Worse than 20/200 20/40-20/200 Better than 20/40 VA outcome, n (%) Worse than 20/200 20/40-20/200 Better than 20/40 ATA+ ATA2 HT P1 Value* P2 Value† 22 36 39.2 ± 18.19 21.0:1 59.0 ± 82.05 1.56 (n = 18) 25 44 34.4 ± 15.02 11.5:1 55.4 ± 65.07 1.00 (n = 19) 13 20 44.2 ± 13.92 All females 72.7 ± 103.87 1.60 (n = 9) 0.329 1.000 0.868 0.837 0.058 NA 0.591 0.632 29 (80.1) 7 (19.4) 0 (0.0) 32 (72.7) 8 (18.2) 4 (9.1) 17 (85.0) 3 (15.0) 0 (0.0) 0.413 0.886 NA 0.354 1.000 NA 25 (69.4) 3 (8.3) 8 (22.2) 22 (50.0) 7 (15.9) 15 (34.1) 17 (85.0) 1 (5.0) 2 (10.0) 0.079 0.308 0.243 0.012‡ 0.417 0.066 *ATA+ group vs ATA2 group. † HT group vs ATA2 group. ‡ P , 0.05. ARR, annual relapse rate; ATAs, antithyroid antibodies; HT, Hashimoto thyroiditis; NA, not available; VA, visual acuity. with ON were associated with NMOSD. This percentage is much higher than in Caucasians. In the Optic Neuritis Treatment Trial, which mostly enrolled Caucasians, almost all the patients presented with typical ON and approximately 40% progressed to MS over 15 years (4). Genetic heterogeneity may contribute to this phenomenon. The HLA-DPB1*0501 frequency in Asian NMOSD patients is much higher (44.9%-73.1%) than in Caucasian patients (2.6%-5.3%) (20) and is closely associated with AQP4 autoimmunity in Han Chinese and Japanese (21,22). However, no association has been found between the DPB1*0501 allele and NMOSD in Caucasian patients (23). Other HLA alleles for increased risk of NMOSD in Asians include increased DRB1*1602 and decreased DRB1*0901 (21,22), but these alleles have not been analyzed as a risk factor in Caucasians. We found a high frequency of ATAs and HT in Chinese with ON who were AQP4-AB+. Genetic factors also may be partially responsible for this finding, because DPB1*0501 is the risk allele for both NMO and autoimmune thyroid diseases in the Chinese population (24). We also found a significant difference in thyroid function between patients who were AQP4-AB+ vs those who were APQ4-AB2 (Table 2). This was apparent both in terms of ATAs (TG-AB, TPO-AB) and thyroid hormone levels (FT3, FT4). TG-AB and TPO-AB represent different aspects of the immune response. TPO-AB may lead to necrosis of thyroid cells via complement-dependent cytotoxicity, whereas TGAB is a reflection of disease activity (25). The literature is still evolving regarding the relationship of ATAs and NMOSD. Sellner et al (10) found a higher prevalence of ATAs in AQP4-AB+ CNS disease compared with FIG. 1. Postcontrast axial (A) and coronal (B) T1 MRI with fat suppression shows enhancement of the right optic nerve (arrows). C. Postcontrast sagittal T1 scan of the cervical spine reveals enlargement of the thyroid gland with heterogeneous enhancement (hatched arrow). Zhao et al: J Neuro-Ophthalmol 2017; 37: 24-29 27 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 4. Summary of NOS auto-ABs in patients both AQP4-AB+/AQP4-AB2 and ATA+/ATA2 AQP4-AB+ n Combined NOS auto-ABs, n (%) ANA SSA/SSB a-b2-GPI ACL PO AMA Ro-52 ANCA ACA CENP B APF Combined AD, n (%) HT SS SLE AS AP Psoriasis AQP4-AB2 ATA+ ATA2 ATA+ ATA2 22 7 (31.8) 6 (27.3) 4 (18.2) 3 (13.6) 2 (9.1) 0 0 1 (4.5) 0 0 0 0 25 8 (32.0) 7 (28.0) 4 (16.0) 2 (8.0) 0 2 (8.0) 0 0 0 1 (4.0) 1 (4.0) 1 (4.0) 12 5 (41.7) 3 (25) 0 1 (8.3) 1 (8.3) 0 2 (16.7) 0 1 (8.3) 0 0 0 38 4 (10.5) 2 (5.3) 3 (7.9) 1 (2.6) 0 0 0 0 0 0 0 0 13 (59.1) 0 0 0 0 0 0 2 (8.0) 1 (4.0) 0 1 (4.0) 0 3 (25.0) 0 0 1 (8.3) 1 (8.3) 0 0 0 0 1 (2.6) 0 0 ACA, anticentromere antibody; ACL, anticardiolipin antibody; AD, autoimmune disorders; AMA, antimitochondrial antibody; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; AP, anaphylactoid purpura; APF, antiperinuclear factor; AQP4-AB, aquaporin-4 antibody; AS, ankylosing spondylitis; ATAs, antithyroid antibodies; a-b2-GPI, anti-b2-glycoprotein I antibody; PO, antiribosomal P protein antibody; CENP B, anticentromere protein B antibody; HT, Hashimoto thyroiditis; NOS auto-ABs, non-organ-specific autoantibodies; SLE, systemic lupus erythematosus; SS, Sjögren syndrome; SSA/SSB, Sjögren syndrome A/B antibody. patients with MS and controls. Long et al (12) and Li et al (13) found the presence of ATAs to be an independent risk function for longitudinally extensive transverse myelitis. In contrast, a report from Japan found no difference in frequency of TPO-AB between NMOSD and MS patients (26). Our ON patients who were AQP4-AB+ and had HT experienced more severe vision loss compared with non-HT patients (Table 3). This has been reported previously (26,27). Two factors may contribute to this finding. First, astrocytic injury may be involved as it has been shown that sera from patients with Hashimoto encephalopathy bind to astrocytes of monkey cerebellum (28). Second, the thyroid hormone facilitates the process of remyelination by activation of oligodendrocyte precursor cells and upregulates myelin in mature oligodendrocytes (29). Thyroid hormones may play additional roles, including protein regulation of dendritic axonal growth, synaptogenesis, and astrocyte proliferation and differentiation (30). There are a number of limitations to our study. First, it was retrospective in design. Second, all our patients were Chinese; so, our results may not be generalizable to Caucasian patients with NMOSD. Third, we only analyzed ATAs qualitatively without quantitative evaluation because the levels of ATAs in many cases were above the detection range used in our electrochemiluminescence immunoassay method. Finally, we did not include normal controls in our study. However, our report is unique in examining the effects of thyroid function on ON patients who are AQP4-AB+. 28 Prospective studies with larger groups of patients and quantitative measures of thyroid activity are warranted. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Zhao, Q. Xu, and S. Wei; b. Acquisition of data: H. Zhou, S. Tan, and Z. Liu; c. Analysis and interpretation of data: X. Peng and T. Chen. Category 2: a. Drafting the manuscript: S. Zhao; b. Revising it for intellectual content: Q. Xu and S. Wei. 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