Author: Chong, C S Y
Date published: March 1, 2011
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Presenile dementia (onset of illness < 65 years) affects approximately 40 per 100,000 population.1 The aetiology of presenile dementia is diverse, but more than 80% of cases are accounted for by the 5 commonest causes of Alzheimer's disease (AD), vascular dementia, frontotemporal dementia (FTD), head injury, and dementia of Parkinson's disease / Lewy body disease.1,2 Hashimoto's encephalopathy (HE) is a rare but important differential diagnosis of early-onset dementia, because the condition is highly treatable and the associated dementia is potentially reversible.
Hashimoto's encephalopathy is the term used to describe a steroid-responsive encephalopathy of presumed autoimmune origin characterised by high serum antithyroid antibody titres. Hashimoto's encephalopathy is more common in women than in men (female-to-male ratio = 4:1) and it has been reported among paediatric, adult, and elderly populations throughout the world.3,4 Two types of initial clinical presentation can occur: a vasculitic type with stroke-like episodes and mild cognitive impairment; and a diffuse progressive type with predominant dementia.5 The clinical presentation may also involve a relapsing and remitting course, and is associated with other neurological features such as seizures, ataxia, psychosis, neuropsychiatric symptoms, stupor, or myoclonus.6,7 Thyroid function is usually clinically and biochemically normal. The high antithyroid antibody titres, in particular antithyroid peroxidase antibodies, are diagnostic. When the other toxic, metabolic, and infectious causes of encephalopathy are excluded, the common differential diagnoses of HE are Creutzfeldt-Jakob disease (CJD), rapidly progressive dementias, and limbic encephalitis.6,8
This report is of a patient with HE; the differential diagnosis, aetiology and pathogenesis, and treatment options are discussed.
A 57-year-old woman presented in 2007 with generalised seizure. She had a medical history of thyroid disease, for which she was taking thyroxine supplement after radioactive iodine treatment, and an insidious onset of dementia from the age of 51 years, resulting in her early retirement 2 years later due to deterioration in work performance. Her family history was notable as her elderly mother also had dementia.
At the age of 53 years, she received medical attention for cognitive impairment, and scored 22 of 30 in the Mini- Mental State Examination (MMSE). Dementia workup revealed normal blood test results, including thyroidstimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4). Computed tomography (CT) of the brain showed atrophic changes over the frontal region (Fig 1), while electroencephalogram revealed non-specific findings. She was diagnosed with AD and was treated with rivastigmine 3 mg twice a day. However, her global cognitive function continued to decline rapidly, with a decrease in MMSE score to 19 in 6 months, and her dependency for activities of daily living and self-care increased. She also demonstrated gradual personality changes from outgoing and sociable to withdrawn and apathetic.
About 6 months prior to the index hospital admission, her motor function and activities of daily living became disturbed, with gait abnormality that confined her to a wheelchair and she was mentally dull with akinetic mutism. Her feeding was poor and she became incontinent of urine.
The patient was admitted to the Department of Psychiatry, United Christian Hospital after the generalised seizure, and a thorough examination and investigations for encephalopathy were started. Magnetic resonance imaging (MRI) revealed deep white matter ischaemic changes and mild cortical atrophy (Fig 2). The high thyroid autoantibody titres (antithyroglobulin, 1:1280; antimicrosomal, 1:1600) supported the diagnosis of HE, even though the patient was clinically and biochemically euthyroid. The detailed investigation results are shown in Table 1. She started steroid therapy (Table 2) and showed a satisfactory response in subsequent weeks, being seizure-free and regaining ambulation and better interaction and awareness of her surroundings. Longer follow-up is needed for longitudinal observation on the progress of her cognitive function.
This patient was initially diagnosed with early-onset AD for its compatible manifestations, including insidious pattern of onset, progressive deterioration over time, clinical presentation of cortical dementia, and the unremarkable findings of the preliminary organic workup (Table 1, Figs 1 and 2). The emergence of motor impairment (gait abnormality), change in consciousness level (mental dullness and akinetic mutism), and the episode of seizure showed the clinical picture of encephalopathy, which initiated further investigations.
Early-onset AD often runs in families.9 For this patient, the absence of a family history of early-onset dementia, plus the lack of response to the cholinesterase inhibitor, complicated the diagnosis of early-onset AD.
This patient's symptoms also mimicked FTD, with the typical onset in the 50s, progressive downhill course over time, presence of a family history of dementia, and atrophic changes over frontal region of the brain shown by CT scan. However, the relatively late involvement of behavioural and personality changes and language disorder during the course of the illness were not typical of FTD. The MRI performed after the seizure did not support FTD. The classical description of 'knife-blade atrophy' (bilateral atrophy of the frontal and anterior temporal lobes) is characteristic of FTD. Reñé et al10 found that MRI showed frontal and / or temporal atrophy in 62% of patients with FTD, and single-photon emission CT showed frontal and / or temporal hypoperfusion in 75%. There is no definitive test available for FTD,11 except for genetic mutation of the progranulin and tau genes in some families, and its diagnosis is often attained by excluding other conditions that might be causing the signs and symptoms.
Vascular dementia was one of the differential diagnoses given the MRI finding of deep white matter ischaemia. However, the degree of vascular involvement could not fully account for the severe and diverse clinical manifestations of the patient.
Hashimoto's encephalopathy can sometimes mimic CJD.8 However, a patient with CJD would have progressed to end-stage within months (the median duration of illness of classic CJD is 4-5 months and that of variant CJD is 13-14 months12) instead of years as for this patient. The absence of periodic sharp wave complexes also excluded a diagnosis of classic CJD. Owing to the lack of clinical indication, cerebrospinal fluid 14-3-3 protein was not checked.
Thyroid disease has a well-known detrimental effect on the neurological system,13 and hypothyroidism is a cause of reversible dementia. In this patient, thyroid screening (TSH, T3, and T4) was performed as part of the routine dementia workup,14 but the results were normal. Such negative findings might lower the index of suspicion for biochemical euthyroid conditions, resulting in a delay to investigation for HE. Given the links between past history of thyroiditis,8 female sex,6 and HE with investigationnegative early-onset dementia, these authors suggest performing antithyroid antibody assay to include or exclude HE at an earlier stage of illness.
The aetiology and pathogenesis of HE remain unclear. There is no evidence to suggest that the antithyroid antibodies have a pathogenic role and their levels do not correlate with the clinical course or response to treatment. Several different hypotheses have been suggested, including localised cerebral oedema, autoimmune vasculitis, toxic effect of thyrotropin-releasing hormone, and an immunopathological basis similar to relapsing acute disseminated encephalomyelitis.6 In retrospect, the atypical features of rapid progression and motor involvement could have indicated HE at an earlier stage of illness.
Most patients respond to treatment with steroids. Initial treatment with high-dose steroids in the form of oral prednisolone 1 mg/kg or intravenous (IV) methylprednisolone 1 g/day has been suggested. Adjunctive therapies with thyroid-acting agents and antiepileptic drugs have also been mentioned.15 For refractory disease, long-term treatment with prednisone, azathioprine, cyclophosphamide, plaquenil, methotrexate, periodic IV immunoglobulin, plasma exchange, and various combinations of these treatments may be helpful.16,17 This patient was diagnosed to have HE which, despite delayed treatment for some years since the onset of neuropsychiatric symptoms, has shown some reversion of cognitive impairment.
In conclusion, HE should be considered a differential diagnosis in female patients presenting with presenile dementia, especially in the presence of a history of thyroid disorder.
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Dr Catherine Shiu-yin Chong, MBBS, Department of Psychiatry, United Christian Hospital, Hong Kong SAR, China.
Dr Jess Lam-ming Leung, MBChB, MRCPsych, FHKAM (Psychiatry), Department of Psychiatry, United Christian Hospital, Hong Kong SAR, China.
Dr Isaac Ho-hon Wong, MBBS, MRCPsych, FHKAM (Psychiatry), Department of Psychiatry, United Christian Hospital, Hong Kong SAR, China.
Dr Ping-wing Ng, MBBS, MRCP, FRCP, FHKAM (Medicine), Department of Medicine, United Christian Hospital, Hong Kong SAR, China.
Dr May Yin-king Miao, MBBS, MRCPsych, FHKAM (Psychiatry), Department of Psychiatry, United Christian Hospital, Hong Kong SAR, China.
Address for correspondence: Dr May YK Miao, Department of Psychiatry, United Christian Hospital, Kwun Tong, Hong Kong SAR, China.
Tel: (852) 2727 8350;
Fax: (852) 3513 5505;
Submitted: 14 July 2010; Accepted: 16 September 2010