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HE is most often characterized by a subacute onset of confusion with altered level of consciousness, seizures, and myoclonus
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INTRODUCTION — Hashimoto encephalopathy (HE) is an uncommon syndrome associated with Hashimoto thyroiditis (HT). Originally described in 1966, it remains a somewhat controversial disorder [1]. <span>HE is most often characterized by a subacute onset of confusion with altered level of consciousness, seizures, and myoclonus. In contrast with the cognitive dysfunction associated with hypothyroidism or hyperthyroidism, HE is believed to be an immune-mediated disorder rather than representing the direct effec




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.
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cess. ●In one series, seven of eight patients had HLA B8 DRw3 haplotypes compared with 30 percent of a control population [7]. This profile is common to other patients with autoimmune diseases. <span>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. Others argue that the relationship between HT and HE is just that seen among autoimmune disorders in general [3]. HT itself is associated with neurologic and systemic autoimmune disease




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]
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ts. It is possible, therefore, that elevated titers are a coincidental finding. Others argue that the relationship between HT and HE is just that seen among autoimmune disorders in general [3]. <span>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]. The nature of the putative autoimmune response in HE is speculative. A number of observations and investigations in small numbers of patients have elicited different theories: ●HE may




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.

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associated with other autoimmune diseases. EPIDEMIOLOGY — A systematic review published in 2006 identified only 121 published cases of HE [21]. However, the syndrome may be underrecognized [2]. <span>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 FEATURES — 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 be




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]

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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 FEATURES — <span>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]. These clinical patterns can overlap. In addition to confusion and mental status changes, other neurologic signs are common in both groups: ●Approximately two-thirds of patients experie




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]

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dementia, confusion, hallucinations, or somnolence [2,24]. Some cases have a more fulminant presentation in which rapid deterioration to coma occurs [2,7]. These clinical patterns can overlap. <span>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 electr




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]
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ations, 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]. <span>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




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]
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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]. <span>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]. LABORATORY FEATURES Antithyroid antibodies — An elevated serum level of antithyroid peroxidase antibody (TPOAb) and/or antithyroglobulin antibody (TgAb) is an essential laboratory feat




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.
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investigators did not find antithyroid antibodies in the CSF of patients with HE [5]. The specificity and sensitivity of antithyroid antibodies in the CSF are unclear. Thyroid hormone levels — <span>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. Cerebrospinal fluid — 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 prote




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]
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ase following treatment [3,7,11,21,22]. Given the prevalence of these antibodies in the general healthy population of 2 to 20 percent, this cannot be considered to be a specific finding for HE. <span>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]. The specificity and sensitivity of antithyroid antibodies in the CSF are unclear. Thyroid hormone levels — Thyroid status varies among patients with reported HE, ranging from overt hyp




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]

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ients with HE have subclinical hypothyroidism and 17 to 20 percent have overt hypothyroidism [3,21]. Approximately 7 percent are hyperthyroid; the remainder are euthyroid. Cerebrospinal fluid — <span>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]. Electroencephalography — Nonspecific electroencephalographic (EEG) abnormalities are seen in 90 to 98 percent of patients, usually demonstrating nonspecific slowing of background activ




Nonspecific electroencephalographic (EEG) abnormalities are seen in 90 to 98 percent of patients, usually demonstrating nonspecific slowing of background activity [2,7,9,38]
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ands 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]. Electroencephalography — <span>Nonspecific electroencephalographic (EEG) abnormalities are seen in 90 to 98 percent of patients, usually demonstrating nonspecific slowing of background activity [2,7,9,38]. Focal spikes or sharp waves and transient epileptic activity are less common. Triphasic waves and frontal intermittent rhythmic delta activity (FIRDA) have also been described. Some re




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]
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nspecific findings. Cerebral angiography, when performed, is normal [2]. Single-photon emission computed tomography (SPECT) may show focal, multifocal, or global hypoperfusion [3,7,13]. Other — <span>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]. DIFFERENTIAL DIAGNOSIS — Any disease associated with a syndrome of delirium or rapidly progressive dementia may be confused with HE. These include: ●Creutzfeldt-Jakob disease ●Acute di




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].
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n described. Some report that EEG abnormalities recover rapidly with steroid administration [9], whereas others note that EEG improvement lags behind clinical improvement [7,39]. Neuroimaging — <span>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]. In exceptional cases of HE, MRI findings of diffuse or focal white matter changes suggesting primary demyelination have been described [3,15,40,41]. Other findings noted in individual c




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
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ischemic attack ●Basilar or hemiplegic migraine ●Cerebral vasculitis The essential testing required to exclude these conditions is discussed in the subsequent section. (See 'Diagnosis' below.) <span>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. DIAGNOSIS — The finding of elevated antithyroid peroxidase antibody (TPOAb) or antithyroglobulin antibody (TgAb) in patients with a compatible clinical presentation is required for the




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.
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ta were later proven to have alternative diagnoses: Creutzfeldt-Jakob disease, frontotemporal dementia, and dementia with Lewy bodies. Notably, these are all untreatable conditions. DIAGNOSIS — <span>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. (See 'Thyroid hormone levels' above.) Essential testing to exclude other diagnoses includes: ●Lumbar puncture to include cultures for bacteria, viruses, fungi, and mycobacterium ●Electr