Anti-neuronal autoantibody in Hashimoto's encephalopathy: neuropathological, immunohistochemical, and biochemical analysis of two patients

doi:10.1016/j.jns.2003.08.005

Journal of the Neurological Sciences

Volume 217, Issue 1, 15 January 2004, Pages 7-12

https://doi.org/10.1016/j.jns.2003.08.005 Get rights and content

Abstract

Hashimoto's encephalopathy (HE) is thought to be caused by disorders of immune mechanisms. Although immunologically mediated central nervous system vasculitis or unidentified anti-neuronal autoantibodies have been suspected of causing HE, its pathogenesis is still unclear. For the study presented here, two patients with typical clinical and laboratory/electrophysiological findings of HE were analyzed to clarify the role of anti-neuronal autoantibodies in the pathogenesis of HE. The autopsied brain of one of the patients was histopathologically examined. For Western blotting analysis and immunohistochemistry, serum and purified immunoglobulin G obtained from the other patient were used. Autopsy revealed no evidence of central nervous system vasculitis or other abnormal findings in the brain. The patient's serum contained an anti-neuronal autoantibody that immunohistochemically labeled neurons of mouse and human cerebral cortices and reacted with the 36-kDa antigenic protein present in a soluble fraction obtained from human cerebral cortex. Our results indicate that anti-neuronal autoantibodies may be associated with the pathogenesis of HE.

Introduction

Hashimoto's thyroiditis (HT), an autoimmune-mediated, organ-specific, chronic lymphocytic inflammation of the thyroid gland, occasionally complicates neurological symptoms [1]. Neurological manifestations associated with hypothyroidism constitute a relatively common clinical symptom known as “myxedema coma/psychosis” [1], while HT-associated neurological symptoms without endocrine abnormalities are very rare. This uncommon clinical condition was first reported by Brain et al. [2] in 1966, and has since been recognized as Hashimoto's encephalopathy (HE) [3]. HE is characterized by various neuropsychological symptoms, including cognition/consciousness deterioration, personality changes, seizures and myoclonus, and by diffuse abnormalities on electroencephalograms (EEG) and elevated protein levels in cerebrospinal fluid (CSF) [4], [5], [6], [7], [8]. Recently, this entity has attracted growing attention because it is included in the group of treatable dementias [6], [9], and it has also been recognized as one of the most important items for differential diagnosis of Creuzfeldt–Jakob disease [10], [11], [12]. Although autoimmune mechanisms are thought to play a pathogenetic role in HE, the etiology of the disease is still incompletely understood. We here report the results of a clinicopathological, immunohistochemical, and biochemical study of two patients with HE presenting with typical clinical and laboratory/neurophysiological findings. Our aim was to clarify the role of anti-neuronal autoantibodies in the etiology of HE.

Section snippets

Patient 1

Beginning in August 1994, family members of a 51-year-old Japanese man started to notice that he was becoming depressive. In the subsequent weeks, he showed signs of progressive slowing down of thought processes and reduced psychomotor activity. He also developed paranoia and both visual and auditory hallucination, and was startled by noises. The symptoms fluctuated, but slowly became worse. He was admitted to the psychiatric department of our institution on April 21, 1995. In June of the same

Autopsy materials

An autopsy was performed 7 h after the death of patient 1 on March 27, 1996, 20 days after the initiation of the corticosteroid treatment. The tissue materials were fixed in 10% formalin solution and embedded in paraffin. General tissues including the thyroid gland were cut to 6μm thickness and stained with hematoxylin and eosin (H&E). Cerebral cortices (frontal, parietal, temporal with hippocampus, and occipital regions), basal ganglia, cerebellum, and brainstem were cut to 6μm thickness and

Autopsy findings

Patient 1 showed multiple injuries due to his suicide, i.e., multiple fractures, bilateral hemopneumothorax, diffuse pulmonary hemorrhages, multiple ruptures of the liver, and subarachnoid/subdural hemorrhages. The thyroid gland was normal in size without nodular lesions. Microscopic examination of the thyroid gland revealed slight focal infiltration of the parenchyma by lymphocytes, but no lymphoid follicles were observed. The thyroid follicles were focally atrophic and the interstitial

Discussion

This study disclosed that serum from a patient with HE contained an anti-neuronal autoantibody that immunohistochemically labeled neurons of mouse and human brains and reacted with the 36-kDa antigenic protein present in the human cerebral cortex. The immunoreactive band at 36 kDa was also detected with the purified/biotinylated IgG from the patient's serum, but not with that from the control or the HT patient without encephalopathy. We also confirmed the absence of central nervous system (CNS)

Acknowledgments

We would like to thank Dr. Jun Tsuyuzaki, Department of Neurology, Komoro Kousei General Hospital for his helpful comments.

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Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis
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A few patients with Hashimoto’s thyroiditis or Graves’ disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto’s encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis.
Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases.
Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.
Hashimoto Encephalopathy in Pediatrics: Report of 3 Cases
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Citation Excerpt :
Autoimmune processes most likely play a major role, possibly autoimmune cerebral vasculitis. A recent thought also favors inflammatory responses to antineural antibodies.10,11 Other sources point to hormonal dysregulation as a possible etiology.9
To describe the rare occurrence of pediatric Hashimoto encephalopathy in 3 patients.
The patients, 9 to 13 years of age, presented with new-onset seizures and other neurologic symptoms, including hemiplegia, aphasia, and memory loss. Thyroid function tests and thyroid antibodies were measured. Magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid analysis, and electroencephalography were also performed.
The first patient had a thyroid-stimulating hormone (TSH) level of 60 μIU/mL (range, 0.4-4.5), free T4 of 0.28 ng/dL (range, 0.7-1.6), and thyroid peroxidase antibody (TPO Ab) of 1243 IU/mL (range < 9). The MRI results indicated a hyperintense signal along the gyri and sulci with diffuse leptomeningeal enhancement bilaterally. The second patient had a TSH level of 25 μIU/mL, free T4 level of 0.7 ng/dL, and TPO Ab level of 3340 IU/mL. The MRI result was normal. The third patient, who was already on levothyroxine, had a TSH level of 17 μIU/mL, free T4 level of 0.81 ng/dL, and TPO Ab level of 1200 IU/mL. The MRI result was normal. All patients had significant elevation of protein in the cerebrospinal fluid and background slowing on electroencephalography. All patients were treated with high doses of intravenous methylprednisolone followed by oral prednisone and thyroid hormone replacement.
These cases underscore the importance of thyroid function tests with antibodies in children presenting with acute neuropsychiatric manifestations, especially new-onset seizures without any identifiable cause. We believe that this condition is underdiagnosed in children, and a high index of suspicion is recommended.
Thyroid gland and brain: Enigma of Hashimoto's encephalopathy
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The versatile clinical manifestations of the Hashimoto's chronic autoimmune thyroiditis often include psycho-neurological disorders. Although hypothyroidism disturbs significantly the ontogenesis and functions of central nervous system, causing in severe cases of myxedema profound impairment of cognitive abilities and even psychosis, the behavioral, motor and other psychoneurological disorders accompany euthyroid and slightly hypothyroid cases and periods of Hashimoto's disease as well, thus constituting the picture of so called “Hashimoto's encephalopathy”. The entity, although discussed and explored for more than 50 years since its initial descriptions, remains an enigma of thyroidology and psychiatry, because its etiology and pathogenesis are obscure. The paper describes the development of current views on the role of thyroid in ontogeny and functions of brain, as well as classical and newest ideas on the etiology and pathogenesis of Hashimot's encephalopathy. The synopsis of the world case reports and research literature on this disorder is added with authors' own results obtained by study of 17 cases of Hashimoto's thyroiditis with schizophrenia-like clinical manifestations. The relation of the disease to adjuvant-like etiological factors is discussed. Three major mechanistic concepts of Hashimoto's encephalopathy are detailed, namely cerebral vasculitis theory, hormone dysregulation theory and concept, explaining the disease via direct action of the autoantibodies against various thyroid (thyroperoxidase, thyroglobulin, and TSH-receptor) and several extrathyroid antigens (alpha-enolase and other enzymes, gangliosides and MOG-protein, onconeuronal antigens) – all of them expressed in the brain. The article demonstrates that all above mentioned concepts intermingle and prone to unification, suggesting the unified scheme of pathogenesis for the Hashimoto's encephalopathy. The clinical manifestations, criteria, forms, course, treatment and prognosis of Hashimoto's encephalopathy and its comorbidity to other diseases – are also discussed in brief. The relation between Hashimoto's encephalopathy and non-vasculitis autoimmune encephalomyelitides of paraneoplastic and non-paraneoplastic origin is emphasized [1 figure, bibliography – 200 references].
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Hashimoto's encephalopathy (HE) is a rare not well understood, progressive and relapsing multiform disease, characterized by seizures, movement disorders, subacute cognitive dysfunction, psychiatric symptoms and responsiveness to steroid therapy. The disorder is generally associated with thyroid diseases and the most common feature is the presence of anti-thyroperoxidase antibodies (TPOAb). Patients are usually euthyroid or mildly hypothyroid at presentation. All age groups can be affected. The pathophysiology is still unclear, especially the link between elevated serum TPOAb and the encephalopathy. Most reported cases occurred in women and girls. Unspecific symptoms, non-pathognomonic laboratory neurophysiology and neuroimaging features make its diagnosis a real challenge for clinicians.
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Both severe thyrotoxicosis and hypothyroidism may affect brain function and cause a change in consciousness, as seen with a thyroid storm or myxedema coma. However, encephalopathy may also develop in patients with autoimmune thyroid diseases independent of actual thyroid function level, and this is known as Hashimoto's encephalopathy. Although most patients are found to have Hashimoto's thyroiditis, less frequently they have Graves' disease. Clinical manifestations include epilepsy, disturbance of consciousness, cognitive impairment, memory loss, myoclonus, hallucinations, stroke-like episodes, tremor, involuntary movements, language impairment, and gait impairment. Hashimoto's encephalopathy is a relatively rare disease. As a good response can be obtained with corticosteroid therapy, early diagnosis and treatment is very beneficial for patients. Here we report three patients with Hashimoto's encephalopathy with typical manifestations of hallucinations that were associated with hypothyroidism, hyperthyroidism, and euthyroid status, respectively. They all showed a dramatic response to methylprednisolone pulse therapy.

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Anti-neuronal autoantibody in Hashimoto's encephalopathy: neuropathological, immunohistochemical, and biochemical analysis of two patients

Abstract

Introduction

Section snippets

Patient 1

Autopsy materials

Autopsy findings

Discussion

Acknowledgments

Brain Dev.

Pediatr. Neurol.

Am. J. Med.

FEBS Lett.

Neurologic manifestations of myxedema

N. Engl. J. Med.

Hashimoto's disease and encephalopathy

Lancet

Hashimoto's encephalopathy: a new neuroimmunological syndrome

Ann. Neurol.

Cartlidge NEF. Hashimoto's encephalopathy: a steroid responsive disorder associated with high anti-thyroid antibody titers. Report of 5 cases

Neurology

Electroencephalographic findings in Hashimoto's encephalopathy

Neurology

Hashimoto's myoclonic encephalopathy: an underdiagnosed treatable condition?

Mov. Disord.

Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment

J. Neurol.

Manifestation of Hashimoto's encephalopathy years before onset of thyroid disease

Eur. Neurol.

Hashimoto's encephalopathy in the elderly: relationship to cognitive impairment

J. Geriatr. Psychiatry Neurol.

Autoimmune thyroiditis and a rapidly progressive dementia: global hypoperfusion on SPECT scanning suggests a possible mechanism

Neurology

Hashimoto's encephalitis as a differential diagnosis of Creutzfeldt–Jakob disease

J. Neurol. Neurosurg. Psychiatry

Hashimoto's encephalopathy mimicking Creutzfeldt–Jakob disease: brain biopsy findings

J. Neurol. Neurosurg. Psychiatry