Objective: Previous studies have shown that functional abnormalities of the thyroid are associated with the pathogenesis of several neurological diseases. However, their relationship in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis remains to be defined. Methods: Forty-three patients with anti-NMDAR encephalitis were examined for thyroid function and autoimmune indications, in comparison with 225 healthy controls (CTL). Patients were further classified into 2 subgroups based on their free tri-iodothyronine (fT3) levels. Moreover, fT3 levels were also investigated after at least three months of follow-up. The clinical characteristics of the patients and CTL were described in detail. Results: Serum levels of fT3 and thyroid-stimulating hormone (TSH) were found to be relatively lower in patients with anti-NMDAR encephalitis than in CTL (both p < 0.001). Low T3 syndrome also occurred more frequently in anti- NMDAR encephalitis (25.6 vs. 0.4%, p < 0.001). However, no statistical differences were detected between patients and CTL in terms of the positive rate of thyroid antibodies and other types of thyroid dysfunction. Patients with low T3 levels tended to have a longer hospital stay (p = 0.006), a higher rate of abnormal brain magnetic resonance imaging (MRI) findings (p = 0.033), a higher frequency of consciousness declination (p = 0.029), and a higher modified Rankin scale (mRS) score during hospitalization. Low fT3 levels were also associated with abnormal MRI findings, a decline in consciousness, and the mRS score on admission. In addition, fT3 seemed to gradually return to normal levels upon improvement of the mRS score (r = –0.649, p = 0.002). Conclusions: Low T3 syndrome often copresents in anti-NMDAR encephalitis and indicates a longer hospitalization, abnormal MRI findings, consciousness declination, and a higher clinical severity. However, fT3 levels do not seem to influence the prognosis of anti-NMDAR encephalitis.

1.
Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J: Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12: 157–165.
2.
Niederwieser G, Buchinger W, Bonelli RM, Berghold A, Reisecker F, Koltringer P, Archelos JJ: Prevalence of autoimmune thyroiditis and non-immune thyroid disease in multiple sclerosis. J Neurol 2003; 250: 672–675.
3.
Wang X, Yi H, Liu J, Li M, Mao ZF, Xu L, Peng FH: Anti-thyroid antibodies and thyroid function in neuromyelitis optica spectrum disorders. J Neurol Sci 2016; 366: 3–7.
4.
Lai M, Hughes EG, Peng X, Zhou L, Gleichman AJ, Shu H, Mata S, Kremens D, Vitaliani R, Geschwind MD, Bataller L, Kalb RG, Davis R, Graus F, Lynch DR, Balice-Gordon R, Dalmau J: AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65: 424–434.
5.
Guan W, Fu Z, Zhang H, Jing L, Lu J, Zhang J, Lu H, Teng J, Jia Y: Non-tumor-associated anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis in Chinese girls with positive anti-thyroid antibodies. J Child Neurol 2015; 30: 1582–1585.
6.
Squizzato A, Gerdes VE, Brandjes DP, Buller HR, Stam J: Thyroid diseases and cerebrovascular disease. Stroke 2005; 36: 2302–2310.
7.
Meyer S, Schuetz P, Wieland M, Nusmaumer C, Mueller B, Christ-Crain M: Low triiodothyronine syndrome: a prognostic marker for outcome in sepsis? Endocrine 2011; 39: 167–174.
8.
Iervasi G, Pingitore A, Landi P, Raciti M, Ri-poli A, Scarlattini M, L’Abbate A, Donato L: Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003; 107: 708–713.
9.
Scoscia E, Baglioni S, Eslami A, Iervasi G, Monti S, Todisco T: Low triiodothyronine (T3) state: a predictor of outcome in respiratory failure? Results of a clinical pilot study. Eur J Endocrinol 2004; 151: 557–560.
10.
Suda S, Muraga K, Kanamaru T, Okubo S, Abe A, Aoki J, Suzuki K, Sakamoto Y, Shimoyama T, Nito C, Kimura K: Low free triiodothyronine predicts poor functional outcome after acute ischemic stroke. J Neurol Sci 2016; 368: 89–93.
11.
Tektonidou MG, Anapliotou M, Vlachoyiannopoulos P, Moutsopoulos HM: Presence of systemic autoimmune disorders in patients with autoimmune thyroid diseases. Ann Rheum Dis 2004; 63: 1159–1161.
12.
Cho EB, Min JH, Cho HJ, Seok JM, Lee HL, Shin HY, Lee KH, Kim BJ: Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability. J Neurol Sci 2016; 370: 214–218.
13.
De Vito P, Balducci V, Leone S, Percario Z, Mangino G, Davis PJ, Davis FB, Affabris E, Luly P, Pedersen JZ, Incerpi S: Nongenomic effects of thyroid hormones on the immune system cells: new targets, old players. Steroids 2012; 77: 988–995.
14.
van der Spek AH, Fliers E, Boelen A: Thyroid hormone metabolism in innate immune cells. J Endocrinol 2017; 232:R67–R81.
15.
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J: A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15: 391–404.
16.
Bernal J: Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 2007; 3: 249–259.
17.
Desouza LA, Ladiwala U, Daniel SM, Agashe S, Vaidya RA, Vaidya VA: Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain. Mol Cell Neurosci 2005; 29: 414–426.
18.
Surks MI, Sievert R: Drugs and thyroid function. N Engl J Med 1995; 333: 1688–1694.
19.
Wu YY, Feng Y, Huang Y, Zhang JW: Anti-N-methyl-D-aspartate receptor encephalitis in a patient with systemic lupus erythematosus. J Clin Neurol 2016; 12: 502–504.
20.
Titulaer MJ, Hoftberger R, Iizuka T, Leypoldt F, McCracken L, Cellucci T, Benson LA, Shu H, Irioka T, Hirano M, Singh G, Calvo AC, Kaida K, Morales PS, Wirtz PW, Yamanoto T, Reindl M, Rosenteld MR, Graus F, Saiz A, Dalmau J: Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol 2014; 75: 411–428.
21.
Zhou JY, Xu B, Lopes J, Blamoun J, Li L: Hashimoto encephalopathy: literature review. Acta Neurol Scand 2017; 135: 285–290.
22.
Plikat K, Langgartner J, Buettner R, Bollheimer LC, Woenckhaus U, Scholmerich J, Wrede CE: Frequency and outcome of patients with nonthyroidal illness syndrome in a medical intensive care unit. Metabolism 2007; 56: 239–244.
23.
Bunevicius A, Iervasi G, Bunevicius R: Neuroprotective actions of thyroid hormones and low-T3 syndrome as a biomarker in acute cerebrovascular disorders. Expert Rev Neurother 2015; 15: 315–326.
24.
Pappa TA, Vagenakis AG, Alevizaki M: The nonthyroidal illness syndrome in the non-critically ill patient. Eur J Clin Invest 2011; 41: 212–220.
25.
Jiao F, Zhang X, Bai T, Lin J, Cui W, Liu B: Clinical evaluation of the function of hypothalamo-pituitary-thyroid axis in children with central nervous system infections. Ital J Pediatr 2011; 37: 11.
26.
Jahagirdar V, McNay EC: Thyroid hormone’s role in regulating brain glucose metabolism and potentially modulating hippocampal cognitive processes. Metab Brain Dis 2012; 27: 101–111.
27.
Schraml FV, Goslar PW, Baxter L, Beason-Held LL: Thyroid stimulating hormone and cognition during severe, transient hypothyroidism. Neuro Endocrinol Lett 2011; 32: 279–285.
28.
Remaud S, Gothié JD, Morvan-Dubois G, Demeneix BA: Thyroid hormone signaling and adult neurogenesis in mammals. Front Endocrinol (Lausanne) 2014; 5: 62.
29.
Kramer CK, von Muhlen D, Kritz-Silverstein D, Barrett-Connor E: Treated hypothyroidism, cognitive function, and depressed mood in old age: the Rancho Bernardo Study. Eur J Endocrinol 2009; 161: 917–921.
30.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R: Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011; 10: 63–74.
31.
Wang R, Lai XH, Liu X, Li YJ, Chen C, Li C, Chi XS, Zhou D, Hong Z: Brain magnetic resonance-imaging findings of anti-N-methyl-D-aspartate receptor encephalitis: a cohort follow-up study in Chinese patients. J Neurol 2018; 265: 362–369.
32.
Cooke GE, Mullally S, Correia N, O’Mara SM, Gibney J: Hippocampal volume is decreased in adults with hypothyroidism. Thyroid 2014; 24: 433–440.
33.
Persani L: Clinical review – central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab 2012; 97: 3068–3078.
34.
Byun JI, Lee ST, Moon J, Jung KH, Sunwoo JS, Lim JA, Kim TJ, Shin YW, Lee KJ, Jun JS, Lee HS, Lee WJ, Kim YS, Kim S, Jeon D, Park KI, Jung KY, Kim M, Chu K, Lee SK: Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-D-aspartate receptor encephalitis. J Neuroimmunol 2016; 297: 141–147.
35.
Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A: IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol 1998; 28: 2178–2187.
36.
Wajner SM, Goemann IM, Bueno AL, Larsen PR, Maia AL: IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells. J Clin Invest 2011; 121: 1834–1845.
37.
Lee WJ, Lee ST, Moon J, Sunwoo JS, Byun JI, Lim JA, Kim TJ, Shin YW, Lee KJ, Jun JS, Lee HS, Kim S, Park KI, Jung KH, Jung KY, Kim M, Lee SK, Chu K: Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study. Neurotherapeutics 2016; 13: 824–832.
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