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Abstract A case of presumed Hashimoto’s encephalopathy (HE) is presented. The presentation included memory loss, delusions, functional decline and culminated in a generalized seizure. Anti-thyroid antibodies were detected and symptoms resolved with prednisolone. Patients with HE may present with prominent neuropsychiatric symptoms, attract psychiatric diagnoses and present to psychiatric services. Primarily a diagnosis of exclusion, HE should be considered in cases of encephalopathy in which standard investigations are negative.
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- CASE HISTORY
The patient was a previously well, retired, 66-year old, high-functioning woman. Over 3–4 months she began to find it difficult to drive, write in her diary and also made frequent paraphrasic errors when speaking. This was associated with general malaise, fatigue, reduced appetite and 10 kg (13% of her premorbid weight) weight loss. She also described a generalized tremor and had developed a delusional belief that her husband wished to harm her. She was not on medication, did not abuse alcohol or other substances and there was no significant family history.
Initially she was admitted to a smaller regional hospital where she presented with a restricted and irritable affect and poor oral intake. She became agitated and disoriented, particularly at night, and also described visual hallucinations of small animals in her room. No neurological features, including myoclonus, were described. At this time all routine blood investigations (including complete blood count, serum urea, electrolytes, creatinine, liver enzymes, thyroid hormone assays, folate and B12 level) were normal. A non-contrast CT of the brain was reported as demonstrating mild atrophy, but no focal lesion.
Although a diagnosis of a depressive illness with psychotic features was made, a differential diagnosis of dementia with psychotic features was also considered. Treatment with paroxetine and risperidone resulted in some improvement.
One month after discharge she suffered a generalized tonic–clonic seizure requiring intubation and admission to the intensive care unit of a metropolitan teaching hospital. After extubation she was noted to have significant short-term memory deficits but no focal neurological signs.
Routine blood investigations were normal. Examination of the cerebrospinal fluid (CSF) was normal apart from mildly elevated protein (1.45 g/L). 14-3-3 protein was not detected. CSF or serum testing for herpes simplex virus, Varicella-zoster virus, cytomegalovirus and human immunodeficiency virus were negative. Complement screening was negative and rheumatoid factor, antinuclear antibodies, extractable nuclear antigens and cytoplasmic and perinuclear antineutrophil cytoplasmic antibodies were not detected. Urine and serum protein electrophoresis was negative. Tumor markers were not detected and syphilis serology was non-reactive. Computed tomography (CT) of the brain was normal. Angiography of the anterior and posterior cerebral circulation was normal. Magnetic resonance imaging (MRI) scan was normal and electroencephalogram (EEG) was unremarkable.
The patient was transferred to the Neuropsychiatry Unit at the Royal Melbourne Hospital. She presented as a well-kempt but fatuous woman. She was disoriented with impaired attention and markedly poor short-term memory (particularly non-verbal memory). Her speech was characterized by impaired verbal fluency and word-finding problems. There was a concrete thinking style with reduced abstract reasoning as well as poor judgement. There were no depressive or psychotic features at this time.
Further investigations, including repeated blood investigations, were normal. Repeat CSF examination demonstrated only elevated CSF protein. EEG showed evidence of primary generalized seizure disorder. CT of chest and abdomen revealed a fracture dislocation of the left humeral head and a wedge fracture of the T6/T7 lumbar vertebrae consistent with an osteoporotic process. A normal bone marrow biopsy excluded underlying malignancy.
A diagnosis of encephalopathy of uncertain origin was made and repair of the humeral fracture was arranged. However, her mental state rapidly deteriorated. She was virtually mute, with poor concentration and attention and required assistance with all aspects of personal care. She had bilateral grasp and pout reflexes as well as diffuse hyperreflexia. She also had bilateral and multifocal myoclonus. In the face of previously normal investigations, the diagnosis of Hashimoto’s encephalopathy (HE) was considered.
Thyroid hormone (thyroid-stimulating hormone, T4, T3) levels were within normal limits. Anti-thyroid peroxidase antibodies (anti-TPO) were raised in titer (640 IU/mL, normal < 100 IU/mL), consistent with this diagnosis.
A course of prednisolone 60 mg was commenced with marked improvement in her mental state. The neurological signs improved before the cognitive changes and she was able to be discharged within 2 weeks. The patient suffered a relapse in her symptoms (confusion, disorientation reduced conscious state and impaired gait) when the prednisolone dose was decreased to 10 mg some 2 months after her recovery. At this time the anti-TPO antibody titer was 320 IU/mL. After exclusion of another underlying medical cause the patient again responded rapidly to prednisolone 60 mg. This was tapered to 40 mg and at last review she remained well, with complete return to previous functioning, on a dose of 20 mg daily.
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- CASE HISTORY
Hashimoto’s encephalopathy is best defined as a steroid-responsive encephalopathy of unknown etiology associated with high titers of serum antithyroid (usually anti-TPO) antibodies. HE was first described by Brain et al. in a patient with thyroiditis and hypothyroidism.1 Since that time there have been more than 120 case reports cited. Unlike the first described case, patients are frequently clinically and biochemically euthyroid.
Hashimoto’s encephalopathy is more common in women (female : male, 4–5:1) with a mean age of onset between 45 and 50 years. There may be a history of other autoimmune disease. The clinical picture is one of encephalopathy with progressive cognitive decline, although the course may also be relapsing and remitting. Seizures are common (>95% of cases) and predominately of the generalized type, although focal and myoclonic seizures are also reported. The course of HE can also be characterized by stroke-like episodes (>65% of cases).2,3 Myoclonus, tremor and ataxia have also been described. Cognitive difficulties may be protean, but severe memory deficits are frequent.
Neuropsychiatric features may suggest a psychiatric diagnosis. These include agitation and restlessness, apathy, social isolation and subtle personality changes. Visual hallucinations are frequently reported (>90%), as are other disorders of perception3 and delusions.
Routine investigations are often normal. Thyroid hormone levels can also be normal. Inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) may be elevated. CSF protein is often moderately elevated and oligoclonal bands may be detected. Diagnosis is made when high titers of antithyroid antibodies are detected.2
The EEG can be normal, but often demonstrates a non-specific encephalopathic pattern with generalized slowing. Neuroimaging is generally normal, but subtle diffuse subcortical signal intensities on MRI fluid attenuated inversion recovery images have been reported.4
It is important to note that antithyroid antibodies are detected in 3–4% of the population; hence high titers of these antibodies in conjunction with the clinical features of HE are necessary before a diagnosis can be made.
The majority of patients respond to corticosteroid treatment. Most authors refer to an initial dose of prednisolone of 1 mg/kg, which is then slowly tapered over a 12-month period.5 Relapse during tapering is common, but the symptoms remain highly steroid responsive. If thyroid abnormalities are present, treatment of these changes has little effect on the encephalopathy.
The etiology of HE is unknown. Association with other autoimmune disorders, high titers of antithyroid antibodies, elevated CSF protein and detection of oligoclonal bands in the CSF are suggestive of an autoimmune process. In addition, circulating immune complexes are detected in some patients with HE6 and some postmortem studies have demonstrated cerebral vasculitis.7
Limbic encephalitis should be considered in the differential diagnosis. Paraneoplastic limbic encephalitis is a subacute encephalopathic process also presenting with progressive cognitive and behavioral change. Seizures and focal neurological deficits are less common than in HE. It is most commonly associated with small cell carcinoma of the lung (associated with anti-Hu, Ma1,2, CRMP/CV2 antibodies), testicular cancer (anti-Ma 2 antibodies) and thymoma (anti-voltage-gated potassium channel [anti-VGKC] antibodies).8 Autoimmune limbic encephalitis is associated with anti-VGKC antibodies.
Because HE frequently presents with neuropsychiatric symptoms and a number of normal investigations, these patients may well be referred for a psychiatric opinion. HE is steroid responsive and has a good prognosis despite a high risk of relapse. It is suggested that measuring antithyroid (anti-TPO) antibodies is worthwhile in such cases, particularly if there is a history of memory loss and seizures.