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Hashimoto's Encephalopathy

Hubert C. Chen, MD, Umesh Masharani, MD, Division of Endocrinology, University of California at San Francisco

South Med J. 2000;93(5)

Abstract and Introduction

Abstract

Hashimoto's encephalopathy is a subacute condition associated with autoimmune thyroiditis. Its presentation varies from focal neurologic deficits to global confusion. Unlike encephalopathy associated with hypothyroidism, Hashimoto's encephalopathy responds to steroid therapy and not thyroxine replacement.

Introduction

The neurologic complications of hypothyroidism, such as dementia, psychosis, ataxia, and seizure, are well-established and invariably resolve when thyroxine replacement is started. However, encephalopathy associated with autoimmune thyroiditis occasionally persists even after thyroid function normalizes, sometimes responding only to immunosuppression. Only a handful of such cases has been reported, and this clinical entity, also known as Hashimoto's encephalopathy, is not widely known. It is debated at times whether Hashimoto's encephalopathy is a distinct clinical condition. We report a case that illustrates the efficacy of steroid therapy for encephalopathy in the setting of autoimmune thyroiditis and review the literature.

Case Report

A 55-year-old man was hospitalized due to increasing confusion, paranoia, and stuttering speech for 3 weeks. His medical history was notable for mild depression not requiring pharmacotherapy and idiopathic-dilated cardiomyopathy treated with angiotensin-converting enzyme inhibitor and diuretics. He had no history of seizures, strokes, or head traumas. Physical examination revealed mild thyromegaly (40 to 50 g), normal tendon reflexes, and no focal neurologic deficits or ataxia.

Laboratory results showed normal electrolyte values and renal and liver functions. Results of a urine toxicology screen were negative. Lumbar puncture revealed no red or white blood cells, with normal protein and glucose levels. Antinuclear antibody titer was undetectable. Because of the thyromegaly, a thyroid peroxidase antibody titer was measured, and the result was positive at 8,000 U/L. Thyrotropin and free thyroxine (FT4) levels were normal at 1.76 µIU/L and 15 pmol/L, respectively.

Magnetic resonance imaging (MRI) showed only mild cerebral volume loss within both frontal and parietal lobes. Electroencephalography (EEG) showed near-continuous bilateral temporal and frontal spikes. With this finding, carbamazepine therapy was initiated. No clinical or EEG changes were observed after 3 days. Prednisone (100 mg/day) was then started, with significant improvement in the patient's mental status and EEG abnormalities within 48 hours. The steroid therapy was gradually tapered over 3 months, and the patient remained symptom-free and euthyroid after 9 months.

Discussion

Encephalopathy associated with autoimmune thyroiditis was first described in 1966 by Brain and colleagues.[1] Also referred to as Hashimoto's encephalopathy, it is a subacute process that responds to immunosuppression and not to thyroxine replacement. Hashimoto's encephalopathy is rare. Approximately 30 cases have been reported,[2-10] mostly in the neurology literature ( ).

The pathogenesis of this encephalopathy is unknown. Hypothyroidism can be excluded, since Hashimoto's encephalopathy is seen in the euthyroid state or after the correction of hypothyroidism.[2,5] Current evidence suggests that the encephalopathy results from an autoimmune process, though the exact mechanism has not been elucidated. Some findings suggest acute disseminated encephalomyelitis as a potential model,[6] while others favor cerebral angiitis as a paradigm.[5]

The antithyroid antibodies are unlikely to be the culprit in the central nervous system, since no shared antigen between the thyroid gland and the brain has been identified. Also, antithyroid antibody titers do not correlate with disease severity.[4] More likely, the thyroiditis and the encephalopathy both represent the casualty of an overly aggressive immune system.

The average age of onset in reported cases[2-10] is 47 years (range, 14 to 78 years). Approximately 85% of the patients are women. Two types of clinical presentation can be observed. The first type is characterized by acute stroke-like episodes with transient focal neurologic deficits and even epileptic seizures. The second form has a more insidious onset, progressing to dementia, psychosis, and coma over several weeks. No focal neurologic deficits are seen in the latter type, but neuropsychologic testing reveals severe cognitive deficits.

No specific diagnostic test exists for Hashimoto's encephalopathy. Thyrotropin and FT4 levels should be relatively normal. A positive antithyroid antibody titer is necessary but not sufficient in making the diagnosis of Hashimoto's encephalopathy. The presence of other autoantibodies, such as anti-parietal cell antibody or anti-intrinsic factor antibody, has been reported.[10] Although nondiagnostic, these additional autoantibodies can signify an increased likelihood of an immune-mediated form of encephalopathy.

In about 75% of reported cases, the cerebrospinal fluid reveals an elevated protein level (range, 0.48 to 2.98 g/L [48 to 298 mg/dL]). Of these, 25% also have mononuclear pleocytosis (range, 8 to 169 cells). Oligoclonal bands are detected in 4 of 15 patients for whom such a result is reported. Glucose level is always normal. Therefore, while cerebrospinal fluid abnormalities are usually seen in Hashimoto's encephalopathy, a normal examination may be present in up to 25% of cases and does not rule out the condition.

Electroencephalography is abnormal in more than 90% of cases. Typically, the EEG shows nonspecific, intermittent slow wave activity. Epileptic activity has been documented in several cases. These abnormalities do not improve and even worsen after the initiation of anticonvulsant therapy.[10]

Neuroradiology studies frequently reveal nonspecific findings, such as bilateral subcortical high signal lesions on T2-weighted images,[11] or mild cerebral atrophy with temporal predominance.[10] Cerebral angiograms (reported in 10 cases) and Doppler sonograms of cerebral vasculatures (reported in 5 cases) are normal.

Patients with Hashimoto's encephalopathy respond dramatically to steroid therapy. The initial dose of steroids varies between 50 mg and 150 mg of prednisone daily, usually slowly decreased over weeks to months, depending on the clinical course. While rapid improvement can be observed within 1 to 3 days, as in the case of our patient, the average time from start of therapy to significant clinical improvement is 4 to 6 weeks.[11] Most patients (90%) stay in remission even after treatment has been discontinued (with follow-up periods of up to 10 years).

When should the diagnosis of Hashimoto's encephalopathy be entertained? Any neuropsychiatric condition that is not responding to conventional therapy, especially in the setting of probable or known autoimmune thyroiditis, should raise suspicion for Hashimoto's encephalopathy. The presence of goiter on physical examination or a positive family history for thyroid dysfunction, in the proper clinical setting, warrants testing for thyroid function and antithyroid antibody titer. Additional studies such as EEG, MRI, and lumbar puncture should be done not only to look for supporting evidence for Hashimoto's encephalopathy, but also to rule out other etiologies of encephalopathy. Clearly, more common causes of encephalopathy, such as infections, electrolyte imbalance, toxins, and neoplasms must be reasonably excluded before steroid therapy is initiated.

Conclusion

Hashimoto's encephalopathy, while rare, may have been underrecognized, since its clinical presentation overlaps several more common disorders, such as depression, seizures, or anxiety. Increased awareness is the first step in clarifying the nature of this condition. The diagnosis should be considered in patients with potential or known autoimmune thyroiditis with atypical neuropsychiatric manifestations not responding to conventional therapy.

References

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  2. Thrush DC, Boddie HG: Episodic encephalopathy associated with thyroid disorders. J Neurol Neurosurg Psychiatry 1974; 37:696-700
  3. Mauriac L, Roger P, Kern AM, et al: Thyroidite de Hashimoto et encephalopathie. Rev Franc Endocrinol Clin 1982; 23:147-150
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