Hashimoto's encephalopathy

Did You Know?

• Duration of treatment is usually between 2 and 25 years.
• Earlier reports suggested 90% of cases stay in remission after treatment discontinuation, but more recent studies indicate relapse is common after initial high-dose steroids.
• Left untreated, the condition can result in coma and death.

Pathogenesis

The mechanism underlying Hashimoto's encephalopathy remains unknown, though it is thought to be autoimmune in nature, akin to Hashimoto's thyroiditis. Autoantibodies targeting alpha-enolase have been associated with the condition; if these antibodies inhibit enolase, the penultimate enzyme in glycolysis, cellular energy production would decline, potentially causing organ atrophy. This atrophy could result from cell shrinkage due to energy deficit or from cell death via apoptosis or necrosis. Insufficient ATP may impair the Na/K ATPase, disrupting the sodium gradient needed for the Na/Ca antiporter, allowing calcium to accumulate to toxic levels and trigger lysosomal rupture and apoptosis. Low energy states also compromise axonal transport mediated by dynein and kinesin ATPases, leading to neuronal injury. Autopsy findings in some cases have revealed lymphocytic vasculitis of venules and veins in the brainstem and diffuse gliosis predominantly in gray matter.

Diagnosis

Diagnostic evaluation often reveals increased liver enzyme levels (55% of cases), elevated thyroid-stimulating hormone (55%), and raised erythrocyte sedimentation rate (25%). Cerebrospinal fluid may show elevated protein (25%) and contain antithyroid antibodies, but is negative for 14–3–3 protein. Magnetic resonance imaging demonstrates abnormalities consistent with encephalopathy in 26% of cases, while single photon emission computed tomography shows focal and global hypoperfusion in 75%. Cerebral angiography is normal. Thyroid hormone abnormalities occur in over 80% of cases, including subclinical hypothyroidism (35%), overt hypothyroidism (20%), hyperthyroidism (5%), euthyroidism on levothyroxine (10%), and euthyroidism not on levothyroxine (20%). Antithyroid peroxidase and antithyroglobulin antibodies are elevated but do not correlate with severity. Electroencephalography is almost always abnormal (98%), typically showing diffuse slowing or frontal intermittent rhythmic delta activity. Proposed diagnostic criteria include encephalopathy with cognitive impairment plus neuropsychiatric symptoms, myoclonus, seizures, or focal deficits; elevated thyroid antibodies; euthyroidism or mild hypothyroidism; exclusion of infectious, toxic, metabolic, neoplastic, or paraneoplastic causes; and complete or near-complete remission with glucocorticoids.

Treatment

Initial therapy typically involves oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days, with thyroid hormone replacement added if needed. For patients who do not respond, alternative treatments include azathioprine, cyclophosphamide, chloroquine, methotrexate, periodic intravenous immunoglobulin, and plasma exchange. No controlled trials have determined the optimal regimen. Seizures are managed with standard antiepileptic agents.