High prevalence of serum autoantibodies against the amino terminal of α-enolase in Hashimoto's encephalopathy
Introduction
Hashimoto's thyroiditis (HT) is the most common disorder affecting the thyroid gland. In 1966, Brain et al. reported the first case of encephalopathy associated with HT, who presented with recurrent neuropsychiatric symptoms accompanied by serum anti-thyroid antibodies in euthyroid states (Brain et al., 1966). Hashimoto's encephalopathy (HE) therefore was recognized as a nomenclature of new disease, distinct from myxoedema encephalopathy associated with hypothyroidism (Behan et al., 1988, Shaw et al., 1991, Chaudhuri and Behan, 2003, Chong et al., 2003).
Autoimmune mechanism has been proposed as an underlying pathogenesis (Brain et al., 1966, Chaudhuri and Behan, 2003, Chong et al., 2003), and immunotherapy such as steroids, immunosuppressants and/or intravenous injection of immunoglobulin (IVIg)/plasmapheresis was successfully administered (Shaw et al., 1991, Boers and Colebatch, 2001, Chaudhuri and Behan, 2003). Over 100 accumulated cases (Shaw et al., 1991, Chaudhuri and Behan, 2003, Chong et al., 2003) reported mainly by neurologists, emphasized this potentially treatable encephalopathy associated with HT in the differential diagnosis of unknown etiology of encephalopathy, and suggested the risk of under-diagnosis of HE (Ghika-Schmid et al., 1996, Maydell et al., 2002).
Several diagnostic criteria for HE have been proposed based on encephalopathy, the presence of anti-thyroid antibodies and/or responsiveness to immunotherapy including steroids (Shaw et al., 1991, Peschen-Rosin et al., 1999). Endocrinologists however argued against the terminology of HE because of the wide spectrum clinical features in patients with HE and the high prevalence of anti-thyroid antibodies in the normal population, which are usually subclinical (Sawka et al., 2002, Fatourechi, 2005).
To resolve such debates on the nomenclature and nature of HE, more specific diagnostic markers are needed (Chong et al., 2003, Fatourechi, 2005). Very recently, we discovered autoantibodies against the amino (NH2)-terminal of α-enolase (referred to as NAE) that were highly specific in sera from a limited number of HE patients (83%, 5 of 6 with HE; 11%, 2 of 17 with HT without any neuropsychiatric features; none of controls [50 individuals] including those with other neurological or immunological conditions involving encephalopathy [25 individuals]) (Fujii et al., 2005). Thus, the anti-NAE autoantibodies are a potential tool for the diagnosis of HE and resolving the debate over HE described above. We further investigated the prevalence and specificity of anti-NAE autoantibodies, and clarified the clinical features in a large number of patients with HE in this study.
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Patients
In this study, we selected 25 patients with HT, who presented with encephalopathy and fit the diagnostic criteria for HE, based on the presence of anti-thyroid antibodies and responsiveness to immunotherapy such as steroids, immunosuppressants and/or IVIg/plasmapheresis. These 25 patients included our own 8 cases and 17 cases from other institutions. Neurological specialists carefully excluded other possible causes of encephalopathy including infections, other autoimmune conditions, vitamin
Anti-NAE autoantibodies
The clinical profiles of patients and immunological characters were summarized in Table 1 and Fig. 1. Of the 25 patients with encephalopathy with HT examined here, 68% of them were NAE(+) (17 of 25) (p < 0.001, compared to patients with HT without encephalopathy [10%, 2 of 20], supplemented by additional data from 3 patients of HT without encephalopathy to our previous study) (Fujii et al., 2005). To our knowledge, there were no sera from 33 patients with 2 Basedow's disease, 4 post-infectious
Discussion
After Brain et al. reported the first case of encephalopathy associated with HT, there has been a debate on the nosology and nature on HE, despite the accumulation of over 100 reported cases (Behan et al., 1988, Chaudhuri and Behan, 2003, Chong et al., 2003). It is because of the wide spectrum clinical features in patients with HE, the high prevalence of anti-thyroid antibodies in the normal population (e.g. 5–10% in male, 10–25% in female in Japan), and the lack of specific diagnostic marker.
Acknowledgments
This work was supported in part by a Neuroimmunological Disease Research Committee grant (to M.Y.) from the Ministry of Health, Labor and Welfare of Japan. We would like to thank Tomomi Kame for technical assistance and the physicians supporting this study.
Attending physicians of patients in this study were as follows:
T Hamano, O Yamamura, K Kinomoto, M Sato, M Ikawa and R Nakachi, our institute; A Kimura, A Iwamura, T Yuasa, Konodai, National Center of Neurology and Psychiatry; H Higa, Naha
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