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

Although the neurologic manifestations of chronic hypothyroidism and myxedema are easily recognizable, the cerebral complications of Hashimoto's thyroiditis (HT) may precede systemic signs of hypothyroidism, making the diagnosis difficult.¹ Illnesses associated with HT may include rheumatoid arthritis, pernicious anemia, Addison's disease, systemic lupus erythematosus, ulcerative colitis, and glomerulonephritis.¹ Prior to 1996, however, myasthenia gravis was the only neurologic condition known to be associated with HT. In that year, Brain et al. described a patient with episodic encephalopathy associated with thyroiditis.² Subsequent communications have presented cases with similar clinical features, including depressed consciousness, seizures, pyramidal signs, involuntary movements, and multiple strokes.^3-7 Diagnostic testing usually reveals a euthyroid state with elevated thyrotropin (TSH) and thyroid autoantibodies, increased CSF protein, and EEG abnormalities. Neuroimaging, including CT, MRI and angiography, are typically normal except for abnormal uptake on isotope brain scan.

We report a case of undiagnosed thyroiditis presenting as a subacute progressive dementia.

Case report. A 59-year-old right-handed woman, a high school graduate who worked as a nurse's aide, presented to our institution from an outside hospital with progressive dementia. Her family first noticed mental changes about 5 months earlier during a vacation. They reported mildly depressed mood and mildly diminished verbal fluency and activity at that time. A month later, work colleagues noted apathy, inability to recall schedules and duties, and decreased productivity. Just prior to admission to our hospital she was asked to take a leave of absence because of impaired memory and unsteadiness on her feet. The family added that she was progressively more confused and tremulous, with decreasing speech and impaired comprehension. Her primary physician considered a diagnosis of depression and admitted her to an outside hospital for further work-up; serum chemistry, blood count, rheumatoid factor, antinuclear antibody, autoimmune profile, vitamin B12, and folate were all normal. MRI of the brain, echocardiogram, carotid Doppler, mammogram, and CT of the abdomen and pelvis were also normal. TSH was elevated at 19.7 mU/L with a normal T4 of 5.2 µg/dL (66.9 nmol/L). CSF analysis, including cultures, Venereal Disease Research Laboratory (VDRL) test, and cytology, was remarkable only for an elevated protein of 180 mg/dL (1.8 g/L). Thyroid ultrasound showed a diffusely hypoechoic gland. The patient began taking sertaline for depression and levothyroxine 75 µg/day replacement therapy.

She was then transferred to our institution for further work-up, with a provisional diagnosis of Creutzfeldt-Jakob disease (CJD) because of her progressive cognitive decline. Further review of history and symptoms indicated no prior medical or surgical history, and she denied use of tobacco and alcohol; a family history of thyroid problems was reported, as well as a 30-lb weight loss during the previous 5 months.

On physical examination the patient was pleasant, cooperative, and afebrile and had a blood pressure of 125/60; general physical examination was normal. On neurologic examination her speech was fluent with occasional hesitation secondary to word-finding difficulties. She had difficulty recalling her age and date of birth, failed at serial subtraction, but she was not agraphic and could copy figures; her Mini-Mental State Examination (MMSE) score was 20/30, with inability to spell backwards and carry out three-step commands. Cranial nerve examination revealed only a lack of smooth pursuit, a glabellar sign, and a slightly flattened left nasolabial fold. Motor examination revealed a mild left upper extremity pronator drift, a non-persistent large action tremor minimally present at rest, mildly bradykinetic gait, absence of associated arm movements, and slight dysmetria on cerebellar testing. Sensory examination, deep tendon reflexes, and plantar responses were unremarkable.

Serum chemistries, complete blood count, autoimmune profile, protein electrophoresis, erythrocyte sedimentation rate, antiparaneoplastic antibodies, and PPD were all normal. CSF analysis again showed an elevated protein of 127 mg/dL (1.27 g/L), with normal glucose, cell count, IgG/albumin ratio, and cultures. There was no evidence of oligoclonal banding or myelin basic protein. Chest CT was normal. Brain MRI showed mild generalized atrophy, but brain SPECT showed global decreased perfusion(figure 1). EEG showed a diffuse slowing of background activity (figure 2). After 2 weeks of levothyroxine therapy, TSH remained elevated, but had improved to a level of 12.66 mU/L with normal T4 and T3 uptake.

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Figure 1. Brain SPECT using technetium-labeled HMPAO obtained 90 minutes after injection. Selected SPECT images during the height of the patient's deterioration showing expected increased activity in the occipital lobes bilaterally (top row), with markedly diminished perfusion of the temporal, parietal, and frontal lobes bilaterally (top row). SPECT images after the patient's clinical improvement demonstrating symmetric distribution of radiopharmaceutical in both cerebral and cerebellar hemispheres, showing significant improvement from the previous study (bottom row).

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Figure 2. EEG during initial evaluation showing mild, intermittent, diffuse slowing of the background activity (A). EEG at the height of deterioration showing an exacerbation of slowing of the background activity and the appearance of intermittent runs of triphasic waves maximal bifrontally seen throughout the recording (B).

Serial neuropsychological testing during her stay revealed rapid decline in all aspects of cognition, with particularly impaired concentration, anomia, amnesia with confabulation, and inappropriate affect without insight.

Within a week of admission, she had clear myoclonus in all extremities, her action tremor and finger-to-nose dysmetria was worse, and a repeated EEG showed severe slowing of background activity with discontinuous triphasic waves maximal bifrontally (see figure 2). She was easily distractable, unable to follow two-step commands, was severely anomic and unable to speak in sentences, and was apparently hallucinating; her MMSE score was 0/30. She was discharged with a clinical diagnosis of CJD, and remained on thyroid replacement therapy.

One month later her family reported improvement. Improvement in mental status was confirmed with a MMSE of 27/30. Neurologic examination had also improved, with only a mild decrease in the speed and amplitude of fine motor movements and minimal apraxia of the left upper extremity. Anti-microsomal antibodies were elevated at 1:400 with negative anti-thyroglobulin antibodies. A repeat brain SPECT (see figure 1) and EEG were normal.

Discussion. The diagnosis of Hashimoto's encephalopathy is challenging because the manifestations can mimic other neurologic syndromes and thyroiditis often remains subclinical. The clinical progression of acute or subacute confusion, altered consciousness, myoclonus or tremulousness, seizures and stroke-like attacks may take a relapsing course, and should raise suspicions about this diagnosis. Studies typically reveal diagnostically nonspecific but mildly elevated CSF protein and EEG abnormalities. However, thyroiditis should be suspected, and T4, TSH, and antithyroid antibodies titers measured.

Our patient had subclinical hypothyroidism and an elevated antimicrosomal antibody titer similar to other described cases.⁷ Unlike other reported cases of recovery, our patient was not treated with steroids but rather with levothyroxine alone. Her improvement may be attributed to modulation of autoimmunity by thyroid hormone replacement.⁸ Previous reviews note patchy uptake on isotope brain scan.⁵ In our case, brain SPECT showed markedly diminished perfusion of the entire frontal, temporal, and parietal lobe regions bilaterally (seefigure 1). On clinical recovery, brain SPECT normalized dramatically.

There are many theories about the pathogenesis of Hashimoto's encephalopathy, but there are no pathologic studies. Shaw et al. hypothesize an autoimmune cerebral vasculitis based on the response to steroids.⁵ In the review by Shaw et al., many of the patients had either normal or slightly elevated ESR and normal cerebral angiogram.⁵ These findings would not rule out a vasculitis, since capillary or small vessel pathology, or both, would be missed on cerebral angiogram. Our patient demonstrated such a diffuse and homogenous hypoperfusion that we hypothesize a disruption of cerebral microvasculature secondary to autoantibody or immune complex deposition, as previously described in glomerulonephritis.⁹ This autoimmune mechanism, directed against the endothelium, could alter vascular reactivity and be responsible for global or focal hypoperfusion, or both.

Although the clinical presentation of Hashimoto's encephalopathy is heterogeneous, patients with a progressive encephalopathy should be evaluated for evidence of chronic autoimmune thyroiditis with T4, TSH, and antithyroid antibodies. Recent reviews have described chronic autoimmune thyroiditis in 40 to 45% of women and 20% of men at autopsy.¹⁰ Despite numerous descriptions in the neurologic literature, this disorder remains largely unrecognized. The availability of highly sensitive tests for thyroid antibodies easily allows recognition of subclinical disease in cases in which the complications of chronic autoimmune thyroiditis are suspected. In patients with a clinical presentation of rapid cognitive deterioration and suspicion of CJD, we strongly recommend thyroid testing. Prompt treatment with steroids and thyroid hormone usually results in complete recovery. Further work is needed to determine the etiology of this neurologic syndrome.

Acknowledgments

We would like to thank Dr. Christopher Goetz and Dr. David Baldwin, Jr. for their critical review of the manuscript.