Hashimoto thyroiditis (HT) is an autoimmune thyroid disease associated with antibodies against thyroid peroxidase enzyme (TPO) and thyroglobulin. The cause of HT remains elusive but is thought to result from a combination of environmental factors and genetic susceptibility. The disease often starts with a hyperthyroid state and progresses to euthyroidism and eventually to hypothyroidism.
In contrast to HT, Graves disease is also an autoimmune thyroid disease, but it often is associated with hyperthyroidism and goiter. Due to the autoimmune nature of both Graves disease and HT, both diseases can be associated with other autoimmune conditions and can affect other organ systems aside from the thyroid. One such organ system is the eye. Thyroid Eye Disease (TED) is thought to occur as a result of orbital fibroblast activation causing retro-orbital inflammation. TED has commonly been associated with hyperthyroid states, and only 10% of patients with TED have hypothyroidism. TED occurs in 25% of patients with Graves disease however, TED occurs less commonly in euthyroid states and in HT.
HT has also rarely been shown to affect the brain. Recently, case reports have described symptoms of encephalopathy in patients with Hashimotos, leading to the disease being coined “Hashimoto Encephalopathy (HE).” Experts have debated whether the encephalopathy and HT occur in patients as separate diseases or are linked as the same disease.
HE was first described in 1966 in a patient with “Hashimotos disease and encephalopathy.” It was then later described in 1991 when 5 patients were reported with encephalopathy and HT. Patients were described to have alteration in consciousness and seizures. Laboratory studies in HE often revealed anti-thyroid antibodies. CSF studies showed high protein without pleocytosis. Treatment of HE was successful with steroids. Since 1966, a number of patients have been noted in the literature to have different clinical presentations but similar responses to glucocorticoid treatment. Chong et al. conducted a review of 85 patients with HE, high serum anti-thyroid antibodies, and responsiveness to glucocorticoid therapy and concluded that HE was likely the single, unifying clinical syndrome.
Etiology & Pathogenesis
The pathogenesis of HE is not well-understood, but it is hypothesized that autoimmune vasculitis directed against thyroid antigens found in the brain could be a potential etiology. Despite cases being reported in the literature of HE, the etiology and clinical features of the HE remain ill defined.
The prevalence of HE is low and the estimated prevalence of HE is believed to be 2.1 per 100,000 individuals. Even fewer cases of HE with predominant cerebellar ataxia have been noted. A gender or age predominance has also not been reported in HE.
The diagnosis of HE is a clinical one supported by laboratory evidence of auto-thyroid antibodies.
A patient may report a history of HT or other thyroid problems. Rarely, patients will be euthyroid as described above. Nonspecific complaints such as fatigue may be stated. Other complaints could be neurologic manifestations of HE such as ataxia. The patient may state they have nonspecific eye complaints, such as double vision.
Signs & Symptoms
The most common symptoms of HE are seizures resistant to anti-convulsants, headaches, confusion, stroke-like episodes, cognitive impairment, focal neurologic deficits, and ataxia. Specifically, ataxia has been reported as the predominant symptom in one case of HE.
Physical Exam may show ataxia or wide based gait on neurologic examination. Patients may also have otherwise normal neurologic exam.
Complete eye exam should be performed on every patient with an eye complaint. On external examination, the patient may have exophthalmos or proptosis. Extra-ocular movement exam may show saccadic pursuit on horizontal gaze.
Diagnostic work up
Typical workup for HE includes both laboratory and imaging studies. Thyroid studies such as serum TSH, T4, T3, and anti-thyroid antibody levels could be performed. HE is associated with positive serum antibodies against the amino (NH2) terminal region of alpha enolase (NAE). Lumbar puncture with cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), electroencephalogram (EEG), and neuro-psychiatric evaluations could also be performed but are usually nonspecific and nondiagnostic. An MRI with and without contrast of the brain and orbit may show cerebellar atrophy if HE is ataxia predominant. Extraocular muscle enlargement may be visible as well on MRI in the case of TED with HE. An ultrasound of the orbit may show extra-ocular muscle enlargement in TED.
Diagnosis of HE has typically been made based on high serum anti-thyroid antibodies. However, one study found that the diagnosis should instead be made based on intrathecal synthesis of anti-thyroid antibodies found on CSF studies. Definitive diagnosis would be a brain biopsy; however, only a few cases have been reported results of a brain biopsy upon autopsy. In both cases, lymphocytic involvement was noted on biopsy. Lymphocytic infiltration in HE is consistent with histologic findings on thyroid biopsy in HT. Most cases of HE however do not require a brain biopsy and the diagnosis is typically made clinically and with positive anti-thyroid antibodies (e.g., thyroid peroxidase (TPO) antibody. Interestingly, thyroid function tests in HE are usually normal or slightly decreased.
The differential diagnosis for HE includes other causes for encephalopathy or ataxia (e.g., ischemic, inflammatory, infiltrative, infectious, traumatic, neoplastic, paraneoplastic, etc.). HE is a diagnosis of exclusion in this setting and there is no single diagnostic test for HE.
Medical management is the mainstay of treatment. Given the potentially disabling symptoms and consequences of HE, early diagnosis and treatment can optimize outcomes in patients. Treatment typically involves glucocorticoids, and intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) can serve as second and third line treatments.
In the review conducted by Chong et al., 98% of patients treated with glucocorticoids alone improved. However, the authors drew the conclusion that most patients improved in association with, not necessarily because of, steroid treatment. Improvement with glucocorticoid therapy can take over one year.
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