Hashimoto's Encephalopathy

Hashimoto encephalopathy (HE) is a rare sneurological condition associated with elevated antithyroid antibodies peroxidase (TPO) or thyroglobulin (TgAb). The terms "steroid-responsive encephalopathy associated with autoimmune thyroiditis" (SREAT) and the broader phrase "nonvasculitic autoimmune meningoencephalitis" are also used to describe this condition.

Initially described in 1966, it remains a controversial disorder. HE is most commonly characterized by subacute onset of confusion alongside altered levels of consciousness, seizures, and myoclonus. Unlike cognitive dysfunction related to hypothyroidism or hyperthyroidism, HE is considered an immune-mediated disorder rather than a direct consequence of an altered thyroid state in the central nervous system.

Due to a lack of awareness among many medical professionals, autoimmune encephalitis (AE) and HE are often underdiagnosed and undertreated. The exact cause of HE remains unclear. Unlike many other autoimmune encephalitis, no identified antibody or virus is responsible for the autoimmune response affecting the brain and nervous system.

Further research is necessary. High levels of thyroid antibodies, such as peroxidase (TPO) or thyroglobulin (TgAb), are currently used as diagnostic markers. Still, their role in causing brain and nervous system damage has not been established.

Currently there is no cure for Hashimoto encephalopathy. Treatments can help reduce its effects which involves a combination of immunosuppresents and othe medications to reduce inflammation and manage symptoms.

What is HE and Seronegative AE?

How Common is HE and Who is Effected

Hashimoto encephalopathy is a very rare disease. In 2006 a study estimated its prevalence was estimated at 2.1/100,000 in the adult population. The incidence of HE is probably much higher. The reason for the low recognition of HE is probably due to the limited knowledge of this disease among physicians and the lack of routine antithyroid antibody testing—especially in patients with thyroid diseases and cognitive impairment and dementia.

HE has been described in all age groups, including children. HE may be currently under-recognized in children. The disease is more frequently observed in women than in men (4:1 ratio), which probably results from the fact that Hashimoto’s thyroiditis is more common in females. In approximately 30% of described cases, HE coexisted with other autoimmune disorders, such as type I diabetes, systemic lupus erythematosus, and Sjögren’s syndrome. Despite the more frequent familial occurrence of Hashimoto’s thyroiditis, no cases of familial HE have been described.

Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment.

Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW

J Neurol. 1996;243(8):585.

Hashimoto's Encephalopathy and Hashimoto's Thyroiditis

Hashimoto encephalopathy involves the simultaneous occurrence of antithyroid antibodies and encephalopathy. It is not fully understood whether these two disorders are interconnected. There is no evidence that antithyroid antibodies in Hashimoto encephalopathy contribute to brain damage, and most affected individuals have normally functioning thyroids, suggesting these may be coincidental findings.

The mechanism of HE does not appear to be related to the thyroid status, which can vary greatly in patients with HE. In two recent reviews, 23% to 35% of patients had subclinical hypothyroidism, 17% to 20% had hypothyroidism, 7% had hyperthyroidism and 18% to 45% were euthyroid [1]. The development of neurologic symptoms may occur up to three years before the onset of autoimmune thyroiditis [2].

Given the belief among researchers that the initial correlation between Hashimoto's disease and Hashimoto's encephalopathy might be coincidental, some suggest using a term that better represents the disorder's primary cause.

Although some cases have identified antithyroid antibodies in the cerebrospinal fluid (CSF) of patients with HE, these antibodies neither appear to confer disease nor have clear antineuronal tissue binding.3 Most experts theorize that these antibody elevations represent a propensity for autoimmunity or are an indirect marker of autoimmunity affecting the brain.3

In the last ten years, alternative names for Hashimoto encephalopathy have been proposed, including steroid-responsive encephalopathy associated with thyroiditis (SREAT) and encephalopathy associated with autoimmune thyroid disease (EAATD) for a more accurate reflection of its autoimmune pathology.

Research indicates that autoimmune vasculitis or other inflammatory processes, potentially related to immune complex deposition and disruption of cerebral microvasculature, could be involved.

Ferracci F, Carnevale A. The neurological disorder associated with thyroid autoimmunity. J Neurol. 2006 Aug;253(8):975-84. doi: 10.1007/s00415-006-0170-7. Epub 2006 Jun 19. PMID: 16786216.

Peschen-Rosin R, Schabet M, Dichgans J. Manifestation of Hashimoto's encephalopathy years before onset of thyroid disease. Eur Neurol. 1999;41:79–84. doi: 10.1159/000008007

J. Zhou, B. Xu, J. Lopes, et al.

Hashimoto encephalopathy: literature review

Acta Neurol Scand, 135 (2017), pp. 285-290

Variations of HE

Hashimoto encephalopathy can be acute, subacute, chronic or relapsing–remitting. Two patterns of presentation are seen: a diffuse, progressive, cognitive impairment that can involve dementia, confusion, hallucination and drowsiness; and a stroke-like pattern of recurrent episodes of focal neurologic deficits, with varying degrees of cognitive impairment and altered consciousness.

Kothbauer-Margreiter, I., et al. "Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment." Journal of neurology 243.8 (1996): 585-593.

What is Seronegative AE?

What Is Seronegative AE?

Autoimmune encephalitis (AE) is an umbrella term for inflammatory disorders associated with central nervous system (CNS) neuronal autoantibodies or other CNS autoimmunity biomarkers.1 These antibodies inappropriately target important brain proteins, including neurotransmitter receptors, ion channels, and associated membrane proteins.2 This produces inflammation in the nervous system that can cause impairment or even death of brain tissue. The identification of specific antibodies to CNS proteins has transformed the understanding of AE and the ability to make precise diagnoses.2 Unfortunately, there are still antibodies that have yet to be identified. Patients who present with the typical clinical and imaging findings of AE with negative antibody testing are considered to have seronegative AE. 3,4,5

Seronegative autoimmune encephalitis (AE) has become a major subtype of AE. Seronegative AE can be categorized into the following three subtypes: autoimmune limbic encephalitis (LE), acute disseminated encephalomyelitis (ADEM), and antibody-negative probable AE (ANPRA).3,5

A significant portion of AE cases in children are seronegative. Children can present with a rapid onset of neuropsychiatric symptoms and are less likely to show well-defined neurologic symptoms. Complex behavioral changes during childhood and limited capacity to describe symptoms make diagnosing Seronegative AE difficult. 6

Antibody-mediated autoimmune encephalitis: A practical approach Justin R. Abbatemarco, Chen Yan, Amy Kunchok, Alexander Rae-Grant Cleveland Clinic Journal of Medicine Aug 2021, 88 (8) 459-471; DOI: 10.3949/ccjm.88a.20122
Graus F,Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15:391–404
Bhasin A, Haftka-George A (March 24, 2024) Diagnostic Challenges and Treatment Approach to Seronegative Autoimmune Encephalitis. Cureus 16(3): e56844. doi:10.7759/cureus.56844
Lee WJ, Lee HS, Kim DY, et al.: Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes. Brain. 2022, 145:3509-21. 10.1093/brain/awac166
Lee WJ, Lee HS, Kim DY, et al.: Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes. Brain. 2022, 145:3509-21. 10.1093/brain/awac166
99mTc-ECD-Brain SPECT findings in children with Autoimmune encephalitis: A retrospective review of cases Manishi L. Narayan, Sanisetty Sarath, Prateek Panda, Indar Sherawat Journal of Nuclear Medicine Jun 2023, 64 (supplement 1) P926;