Hashimoto’s encephalopathy
Postmortem findings after fatal status epilepticus

I agree entirely with the points made by Dr. Perrot and am grateful to him for bringing to my attention an important case report that I had overlooked.

We read with great interest the article by Duffey et al [1], which describes a patient with fatal status epilepticus as part of Hashimoto's encephalopathy (HE). The brain postmortem examination found arteriovenous lymphocytic infiltrate and diffuse gliosis, suggesting an inflammatory factor in the pathogenesis of HE. The potential cytotoxic role of thyroid-related autoantibodies at the brain level was not addressed.

In 2002, we reported an anatomicoclinical observation of HE in a woman who died five months after the onset of an acute encephalopathy, including neuropsychiatric signs preceding coma, myoclonus and epileptic seizures. [2] Our neuropathological autopsy findings may provide some answers. We reported similar results to Duffey et al's including diffuse astrocytic gliosis and perivascular mononuclear cell infiltration by macrophages and T lymphocytes. We also disclosed: diffuse activation of microglia, with positive immunostainings for major histocompatibility complex class II antigens (HLA-DR, CR3/43) and for human macrophages (CD68, HAM56); expression of tumor necrosis factor-alpha (TNF-alpha) by perivascular macrophages and activated microglia; and negative immunostainings for thyroid peroxydase (ACM47) and for thyroglobulin.

If most of these findings are consistent with a brain aspecific vasculitic process, the absence of cross-antigenicity between brain and thyroid is not in favor of a common T-cell epitope and questions the autoimmune etiology. In addition, the clinical condition does not evolve parallel to anti-thyroid antibodies level [3]. This may be due to the existence of undetectable cytotoxic antibodies in blood, having a pathological effect on brain. Serum antimicrosomal antibodies may only represent a biological marker of a more generalized autoimmunological disorder, even if screening for other systemic autoantibodies is often negative. The pathological association between dysthyroidism and encephalopathy may be fortuitous. An alternative hypothesis could involve increased secretion of thyrotropin-releasing hormone (TRH) [4]. Since it is capable of modulating immune cells functions [5], TRH could have an indirect brain toxic effect through microglial activation.

Finally, from a unified perspective, a mixed but very speculative hypothesis might involve autoimmune mechanism together with TRH toxicity. In that case, the frequent euthyroidism or mild hypothyroidism present in this disease, might be due to deregulation of hypothalamo-hypophysial axis or change in the affinity of TRH receptors, related to autoantibodies activity [2, 4].

References

1. Duffey P, Yee S, Reid IA, Bridges LR. Hashimoto's encephalopathy. Postmortem findings after fatal status epilepticus. Neurology 2003;61:1124 -1126.

2. Perrot X, Giraud P, Biacabe AG, Perret-Liaudet A, Borson-Chazot F, Gray F, Kopp N, Boulliat J. [Encéphalopathie d'Hashimoto: une observation anatomo-clinique]. Rev Neurol (Paris) 2002;158:461-466.

3. Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW. Encephalopathy associated with Hashimoto thyroiditis : diagnosis and treatment. J Neurol 1996;243:585-593.

4. Ishii K, Hayashi A, Tamaoka A, Usuki S, Mizusawa H, Shoji S. Case report: thyrotropin-releasing hormone-induced myoclonus and tremor in a patient with Hashimoto's encephalopathy. Am J Med Sci 1995;310:202-205.

5. Reichlin S. Neuroendocrine-immune interactions. In: Epstein FH, ed. Mechanisms of disease. N Engl J Med 1993;329:1246-1253.