on 13-Jan-2021 (Wed)

HE is most often characterized by a subacute onset of confusion with altered level of consciousness, seizures, and myoclonus

The nature of the relationship between Hashimoto thyroiditis (HT) and HE is unclear. Some argue that the association is entirely spurious [8]. Elevated antithyroid antibodies in the serum correlate well with pathologic thyroiditis. However, elevated titers are prevalent in the general healthy population, occurring in 2 to 10 percent of young adults and 5 to 20 percent of older adults. It is possible, therefore, that elevated titers are a coincidental finding.

HT itself is associated with neurologic and systemic autoimmune diseases including myasthenia gravis, systemic lupus erythematosus, and type 1 diabetes mellitus [7]. Support for this argument includes the observation that the symptoms of HE are not paralleled by symptoms of thyroiditis. In addition, changes in antithyroid autoantibody levels do not consistently correspond with neurologic symptoms or improvement with treatment. These findings lead some to propose that steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a more appropriate designation for this disorder [9-11]

A hospital-based epidemiologic study aggressively screened for HE in patients with unexplained neurologic symptoms consistent with HE and estimated the prevalence of HE to be 2.1 per 100,000 [22].

Among reported cases, the mean age of onset of initial symptoms is 41 to 44 years (range 9 to 78) [2-4,21,23]. Women are more commonly affected than men, at a ratio of approximately four to one.

Clinical manifestations of HE most often include an acute to subacute onset of confusion with alteration of consciousness [2,5]. Two patterns of presentation have been described:

● A stroke-like pattern of multiple, recurrent, acute to subacute episodes of focal neurologic deficits with a variable degree of cognitive dysfunction and alteration of consciousness. Approximately 25 percent of patients follow this course [3].

● A diffuse, progressive pattern, characterized by slowly progressive cognitive impairment with dementia, confusion, hallucinations, or somnolence [2,24]. Some cases have a more fulminant presentation in which rapid deterioration to coma occurs [2,7]

In addition to confusion and mental status changes, other neurologic signs are common in both groups:

● Approximately two-thirds of patients experience focal or generalized tonic-clonic seizures [3,21,25,26]. Status epilepticus has been reported in 12 percent.

● Myoclonus or tremor is seen in up to 38 percent of patients [3,21]. Myoclonus may be focal or multifocal.

● Diffuse hyperreflexia and other pyramidal tract signs are present in 85 percent of patients [2].

● Psychosis, particularly visual hallucinations, but also paranoid delusions, have been reported in 25 to 36 percent of patients [3,21].

The long-term course of illness may be self-limited, relapsing-remitting, or progressive [27,28]

Rare syndromes associated with HE include a cerebellopathy with or without encephalopathy, isolated myelopathy, and chorea [23,29-33]. Peripheral nervous system involvement with electrophysiological evidence of a sensory ganglionopathy, demyelinating polyneuropathy, and/or amyotrophy has been described in individual cases of HE [34-36]

There are no systemic symptoms, including fever, with rare exceptions [7]. Neurologic symptoms can occur in patients with a known diagnosis of Hashimoto thyroiditis (HT) or in patients without a previous diagnosis. The development of clinical HT may occur up to three years after presentation with HE [4]

Thyroid status varies among patients with reported HE, ranging from overt hypothyroidism to overt hyperthyroidism. In systematic reviews, 23 to 35 percent of patients with HE have subclinical hypothyroidism and 17 to 20 percent have overt hypothyroidism [3,21]. Approximately 7 percent are hyperthyroid; the remainder are euthyroid.

Antithyroid antibodies are infrequently measured in the cerebrospinal fluid (CSF). One case series found that 9 of 12 patients with encephalopathy and elevated serum antithyroid antibodies had elevated CSF autoantibody titers [22]. The authors suggested that serum antibody titers were overly sensitive. However, other investigators did not find antithyroid antibodies in the CSF of patients with HE [5]

CSF analysis is abnormal in approximately 80 percent of patients [2]. The following findings have been noted [2]:

● The most common abnormality is an elevated protein concentration (reported range 48 to 298 mg/dL), which occurs in approximately 75 percent of patients. Levels greater than 100 mg/dL are uncommon, occurring in approximately 20 percent.

● A lymphocytic pleocytosis (8 to 169 cells) is present in 10 to 25 percent of patients [2,21].

● The glucose concentration is normal.

● Both the presence and absence of oligoclonal bands are reported [2].

● Elevated 14-3-3 protein, a finding associated with Creutzfeldt-Jakob disease, has been reported in HE but is not a universal finding [21,28,37]

Nonspecific electroencephalographic (EEG) abnormalities are seen in 90 to 98 percent of patients, usually demonstrating nonspecific slowing of background activity [2,7,9,38]

C-reactive protein and the erythrocyte sedimentation rate are elevated in some patients [41]. In one series, mild elevations of liver enzymes were found in 12 of 20 patients [41]

Magnetic resonance imaging (MRI) in patients with HE is usually normal, but may demonstrate cerebral atrophy or nonspecific T2 signal abnormalities in the subcortical white matter [3]. The latter have been described in approximately one-half of patients and do not enhance with gadolinium [2,3,7]. This may be an incidental finding, although a few reports have described regression or resolution of these findings with treatment [3].

One study examined the clinical features of 32 patients presenting with progressive encephalopathy associated with elevated antithyroid antibody titers [41]. Of the 12 patients who did not respond to steroids, four with autopsy data were later proven to have alternative diagnoses: Creutzfeldt-Jakob disease, frontotemporal dementia, and dementia with Lewy bodies. Notably, these are all untreatable conditions

The finding of elevated antithyroid peroxidase antibody (TPOAb) or antithyroglobulin antibody (TgAb) in patients with a compatible clinical presentation is required for the diagnosis of HE. These findings and a response to corticosteroids generally define this syndrome. Thyroid hormone levels should be measured but, as noted above, thyroid status is variable in HE.