Clinical manifestations

Presentation and course

	• The clinical presentation of Hashimoto encephalopathy is heterogeneous, ranging from encephalopathy with psychiatric features to stroke-like events or seizure episodes in the context of positive antithyroid antibodies.
	• Imaging features and neuropsychological testing are often nonspecific, further complicating the diagnosis for the clinician.
	• A good response to corticosteroids, formerly considered as diagnostic, has been shown to be variably present and unpredictable in most cases.

Hashimoto encephalopathy has been described with a variety of nonspecific clinical presentations, making a typical diagnosis challenging for clinicians (35; 48).

A review by Figgie and colleagues screened the literature for patients with positive anti-thyroid antibodies and found a total of 227 out of 2717 patients with associated neurologic symptoms (15). Of these, 153 patients had unrelated neurologic conditions; 32 had unexplained neurologic symptoms not fulfilling diagnosis criteria for Hashimoto encephalitis, mostly due to incomplete workup; 30 had other neuroimmunological disorders; and only 12 patients fulfilled the diagnosis criteria for Hashimoto encephalitis. Of these, 11 presented with cognitive impairment, nine with altered sensorium, eight with new-onset seizures, eight with psychosis, five with movement disorders, five with sensory symptoms, four with stroke-like symptoms, four with ataxia, three with language impairment, and three with sleep disorders. Symptom onset was acute for seven patients, subacute for one, and chronic for four.

Onset of acute-subacute (days to weeks) encephalopathic features, such as progressive cognitive decline, should alert the clinician to pursue prompt evaluation (08; 13). Typical associated features are psychiatric manifestations (personality changes, mood disorders, hallucinations, delusions, mood disorders, mania, or catatonia), altered sensorium, and seizures. Up to 25% of patients present with stroke-like episodes (13). Other reported features are extrapyramidal symptoms, other types of tremors, myoclonus, cerebellar involvement, language impairment, akathisia, and autonomic features (09; 27; 35; 48; 33; 08; 13; 39). Cranial neuropathies, ophthalmopathy, headaches, and sleep disorders are less discriminant for Hashimoto encephalopathy (15). Patients present no associated fever (44).

Seizures occur in 47% to 70% of patients and are either focal or generalized and are often refractory to common antiepileptic drugs (46; 44; 08). They can occur at any point in the disease course, and they are a common form of presentation in children (28; 05). Some may even present with new-onset status epilepticus or nonconvulsive status epilepticus (46; 08).

Although nonspecific, headaches have also been described as part of the presentation (16). The most common type of headaches are hypothyroidism-related headaches followed by migraines, new daily persistent headaches, and tension headaches.

Some authors have attempted to classify different phenotypes, with the most common one being a limbic-like presentation of the disease with cognitive decline associated with psychosis or hallucinations and seizures (08). Others have identified a subgroup of patients presenting with ataxia as the main complaint, with or without encephalopathy, proposing a cerebellar subtype of Hashimoto encephalopathy (23; 14; 45; 13).

Two main patterns of presentation have been described: one presenting with recurrent episodes, such as stroke-like focal symptoms, and the other presenting as a more progressive indolent course of altered consciousness and psychiatric features (44; 08; 39).

Patients typically begin to improve within days to a few weeks after starting corticosteroids or other immunosuppressive therapy, but maximal improvement may take weeks to months. Patients may relapse during corticosteroid taper or much later after completing a course of immunosuppressive therapy. Relapses generally involve symptoms similar to the initial attack.

Prognosis and complications

Prognosis is usually good, with reports of spontaneous recovery and generally favorable outcomes with corticosteroid therapy (08). Patients usually have a full recovery and remain disease-free thereafter.

Clinical vignette

A previously well 26-year-old man with a prior history of Addison disease and Hashimoto thyroiditis presented with a series of three unprovoked nocturnal generalized convulsions over 5 days for which he was started on levetiracetam. Over a 2-month period he then developed progressive cognitive impairment with disorientation, working memory issues, and fatigue. After a cluster of three additional generalized convulsions, he was admitted to the hospital.

Brain MRI showed increased T2 signal in the medial temporal lobes. Malignancy screening with testicular ultrasound and with CT of the chest, abdomen, and pelvis was negative. EEG showed intermittent diffuse slowing. Anti-TG were mildly elevated and anti-TPO were highly elevated. Thyroid hormone levels and TSH were normal. CSF analysis showed normal cell counts and normal protein but had 17 oligoclonal bands. Infectious studies and studies for antibodies associated with autoimmune encephalitis (NMDAR, LGI1, Caspr2, AMPAR, GABA-B receptor, GABA-A receptor, GAD65, Ma2, etc.) were negative.

Treatment with intravenous methylprednisolone (1 g daily for 5 days) followed by a slow taper of oral prednisone was initiated. His mental status began to improve within days of starting treatment. Over the following 8 months, his seizures were gradually controlled, and his cognition and energy returned to normal except for a mild deficit in learning new information. He returned to work. During corticosteroid taper, he had two periods with an increase in seizures, which responded to an increase in prednisone followed by a slower taper. Follow-up brain MRI studies showed resolution of the abnormal changes.

Biological basis

	• Hashimoto encephalopathy is thought to be an autoimmune disorder but its etiology has not been elucidated.
	• Proposed mechanisms include antibody-mediated encephalitis and cerebral vasculitis.

Etiology and pathogenesis

The exact cause of Hashimoto encephalopathy remains unknown, but it is thought to be autoimmune in etiology. This is based on the observations that the disease has a female predominance, CSF analysis often shows indirect signs of inflammation (elevated cell counts, proteins oligoclonal bands, and IgG index), a relapsing and remitting course is often observed, it frequently occurs in the context of Hashimoto thyroiditis and other autoimmune disorders, and generally responds to immunosuppressants (23).

There has been increased interest in a new and more aggressive phenotype of Hashimoto thyroiditis accompanied with elevated serum IgG4 levels (08; 39). The exact pathophysiology of IgG4-related disease remains unknown but is thought to result from aberrant immunity. The infiltration of IgG4-secreting plasma cells in the thyroid tissue could cause chronic inflammation and immune targeting of thyroid cells eventually leading to Hashimoto thyroiditis (39). Some speculate that the production of IgG4 could be linked to the neurologic features of Hashimoto encephalopathy, but more studies are needed for elucidation (44).

Through the years, many questions have been raised debating whether Hashimoto encephalitis is a form of T-mediated seronegative autoimmune encephalitis or is related to a neuronal antibody that we are not able to detect with current technologies (15). Three main mechanisms have been proposed for the underlying pathophysiology of Hashimoto encephalopathy: immune complex deposits in the CNS vasculature, autoantibodies exhibiting molecular-mimicry, and cytotoxic effects of various mediators expressed in response to hypothyroidism (39).

Immunology. Antithyroid antibodies are not thought to directly interact with brain tissues. Indeed, antithyroid antibodies are rather nonspecific, as they are found in 13% of the general population (21), they are detected in much lower levels in CSF than in serum in patients with and without autoimmune thyroid disease (22), and their titers do not correlate with the severity of neurologic disease (19). These factors make a direct effect of the antithyroid antibodies on brain tissue unlikely. Nonetheless, antithyroid antibodies could represent a bystander for pathological antibodies that have yet to be discovered. Mane-Damas and colleagues described a case of pediatric Hashimoto encephalopathy where the patient’s serum applied on rat brain resulted in a hippocampal staining pattern (31). This pattern persisted after the washout of anti-TPO antibodies, suggesting the presence of other unspecified antibodies targeting a neuronal antigen. Blanchin and colleagues, on the other hand, observed direct binding of anti-TPO antibodies to human astrocytes (04), suggesting a pathogenic role for antithyroid antibodies in the disease. More recently, Benvenga and his colleagues found 27 and 47 CNS-expressed proteins that share homology with Tg and TPO, respectively, further supporting this hypothesis (03).

The discovery of defined CNS autoantibodies to NMDAR, AMPAR, LGI1, and other targets has provided convincing explanations for additional patients who might previously have been diagnosed with Hashimoto encephalopathy. Additional specific brain autoantibodies have been discovered since then (26). Other cell-based autoimmune mechanisms may also exist. See Dalmau and Graus’ article on autoimmune encephalitis for discussion of these disorders (10).

Autoantibodies to the amino terminus of alpha-enolase have been reported by some authors to be present in the sera of patients with Hashimoto encephalopathy but not in healthy controls (47; 25; 32). A minority of patients with Hashimoto thyroiditis also had these antibodies. However, Mattozzi and colleagues argued that antibodies to alpha-enolase are not specific to Hashimoto encephalopathy because they have also been detected in patients with limbic encephalitis (due to known neuronal antibodies and in cases of Creutzfeld-Jakob disease) (18; 25; 33).

Furthermore, using flow cytometry in a cohort of 22 patients with Hashimoto encephalopathy, Pfeuffer and colleagues found a persistent increase in CD4+ T cell activation and CD4/CD8 T cell ratio in the patients with a relapsing disease course, but not in those with a monophasic illness (38). They suggested that persistent intrathecal CD4 T cell expression could be considered as a potential biomarker to identify patients at risk for refractory disease.

Pathology. Though the literature on the pathology of Hashimoto encephalopathy is scant, the few available pathology reports point toward a vasculitic process. Indeed, a “mild lymphocytic infiltrate around venules and arterioles” and “perivascular cuffs of lymphocytic cells” were observed in two patients with suspected Hashimoto encephalopathy (12; 09). Diffuse gliosis and perivascular lymphocytic infiltration were found in the brain biopsy of a tumor-like lesion in a patient with suspected Hashimoto encephalopathy and on autopsy of a pediatric case of graft-versus-host-disease with suspected Hashimoto encephalopathy (41; 43). In our opinion, most of these cases did not meet all diagnostic criteria for Hashimoto encephalopathy and, therefore, their true correlation with the disease remains uncertain.

Epidemiology

The estimated prevalence of the disease is around 2.1 per 100 000 (44; 08; 39). In an epidemiological study, where presumably false-positive cases of Hashimoto encephalopathy were correctly classified by the detection of neuronal antibodies such as anti-NMDAR, the prevalence decreased to 0.6 per 100,000 population (11).

This disease is estimated to be four to five times more common in women, probably resulting from a higher prevalence of autoimmune disease, including Hashimoto thyroiditis in women (44; 08, 39). In the largest series, most (70% to 80%) patients were female (09; 27). It usually occurs in the fourth to sixth decade of life, with a mean age of onset ranging from 41 to 48 years (08; 39; 15). Although rare, some cases have been reported in the pediatric population as well, with cases even below the age of 3 (05).

Prevention

Hashimoto encephalopathy is extremely rare, and there are no known forms of primary prevention. Patients who have had Hashimoto encephalopathy may be at risk for relapses. The duration and nature of immunosuppressive therapy that may decrease the risk of relapse is not known. Patients with repeated attacks of Hashimoto encephalopathy may be treated with longer-lasting or stronger immunosuppressive therapies.

Differential diagnosis

Confusing conditions

Hashimoto encephalopathy is a diagnosis of exclusion and should only be considered after completing a thorough diagnostic workup. Owing to its wide spectrum of subacute clinical manifestations, careful evaluation should be carried out to exclude other forms of encephalopathies and encephalitis that may have a clinical overlap, such as any of the following toxic, metabolic, infectious, neoplastic, inflammatory, and psychiatric forms:

• CNS infections (herpes simplex virus encephalitis, neurosyphilis, HIV-associated opportunistic infections, etc.) • Prion diseases, including Creutzfeldt-Jakob disease • Atypical dementia (Alzheimer, Lewy body dementia, frontotemporal dementia, corticobasal degeneration, vascular dementia) • Delirium • CNS malignancy • Hepatic or uremic encephalopathy • Neurologic manifestations of severe hyperthyroidism or hypothyroidism • Illicit substance and medication intoxication and withdrawal (eg, alcohol withdrawal, Wernicke encephalopathy) • CNS vasculitis • Atypical neuromyelitis optica spectrum disorder • Neurologic presentation of systemic disease (sarcoidosis, lupus, Sjogren) • Psychiatric conditions

The diagnosis of autoimmune encephalitis should be considered in the presence of specific elements, as previously described by Graus and colleagues (17). These include a subacute onset of working memory deficits, altered mental status or neuropsychiatric symptoms, AND at least one of the following: new focal CNS findings, seizures not explained by a previously known seizure disorder, CSF pleocytosis, oligoclonal bands or elevated IgG index, or MRI features suggestive of encephalitis. Then, specific etiologies of autoimmune encephalitis should be ruled out by using accepted sets of diagnostic criteria and testing serum and CSF for onconeuronal and neuronal cell-surface antibodies (eg, anti-NMDA receptor encephalitis, anti-LGI1 encephalitis, Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, etc.). In a series of 144 cases referred to the Mayo Clinic between 2006 and 2019 with suspected Hashimoto encephalopathy, 73% had an alternative nonimmune disorder, and a majority did not have evidence of an underlying neurologic condition (42). These results have been replicated in a recent review of the literature by Figgie and colleagues showing that more than half of patients with thyroid antibodies did not have an underlying neurologic disorder (15).

Associated or underlying disorders

Coexisting thyroid disease is very common. For example, Chong and colleagues found 35% of patients with subclinical hypothyroidism, 22% with euthyroid state, and 20% with overt hypothyroidism.

Comorbid autoimmune conditions are also common (15). The prevalence of other comorbid autoimmune disorders was estimated at 30% in a series (07). The most common autoimmune disorder is Hashimoto thyroiditis (44). Hashimoto encephalopathy may be mistaken for an autoimmune encephalitis as both presentations closely resemble one another (44; 29).

Diagnostic workup

	• The diagnosis of Hashimoto encephalopathy should be considered in acute-subacute presentations of encephalopathy and compatible neurologic symptoms.
	• Workup should include assessment of thyroid function and thyroid antibodies, but it should be noted that the same findings may also be found in autoimmune encephalitis.
	• Neuroimaging, electrodiagnostic studies, and lumbar puncture should be considered and oriented as to exclude other alternative diagnoses, such as autoimmune encephalitis.

Diagnostic criteria. Graus and colleagues have proposed the most recent diagnostic criteria for Hashimoto encephalopathy based on those previously proposed by Castillo and colleagues (07; 17):

(1) Encephalopathy with seizures, myoclonus, or stroke-like episodes (2) Subclinical or mild overt thyroid disease (3) Normal or nonspecific abnormalities on brain MRI (4) Positive serum anti-TPO or anti-TG antibodies (5) Absence of well-characterized neuronal antibodies in CSF and serum (6) Reasonable exclusion of alternative causes

To meet the diagnosis, patients must meet all six criteria. Inclusion of a good response to corticosteroid therapy as a diagnosis criterion remains controversial in the literature. Mattozzi and colleagues found that only a minority of patients who fulfilled their inclusion criteria for the diagnosis of Hashimoto encephalopathy fully responded to corticosteroids (33). If present, it may confirm the diagnosis of Hashimoto encephalopathy, but if absent, it should not exclude the diagnosis.

Workup. Hashimoto encephalopathy mostly remains a diagnosis of exclusion. The differential diagnosis includes several autoimmune and nonautoimmune causes of encephalopathy, and, as such, appropriate diagnostic workup for these conditions should be performed in the appropriate clinical settings. Complete blood counts, metabolic workup, and renal and liver function tests should be performed. Infectious workup such as blood cultures and urinalysis should be considered. If there is a concern for malnutrition, vitamin B12 and thiamine levels should be checked, and empiric repletion should be considered. Patients should have negative inflammatory markers (44). Thyroid function should also be assessed and severe hypo- or hyperthyroidism excluded before making a diagnosis of Hashimoto encephalopathy. If a diagnosis of autoimmune thyroiditis is confirmed, special attention should be paid to exclude neurologic manifestations associated with malabsorption of vitamins or minerals as these patients could present with associated gastrointestinal disease (34).

Lumbar puncture with oligoclonal bands and IgG index, brain MRI with gadolinium, baseline EEG or EEG polyvideo monitoring, as well as serum antibodies to thyroglobulin (anti-TG) and thyroperoxidase (anti-TPO) are recommended for all patients. Cancer screening should be considered on a case-by-case basis, considering patient age and sex, clinical presentation, and other risk factors for malignancy.

Thyroid testing. Most patients will present with an euthyroid state or with mild hypothyroidism (09; 33; 08; 13; 15). It should also be noted that patients with autoimmune encephalitis also demonstrated lower thyroid hormones compared to controls (30). Antithyroid antibodies (anti-TPO and anti-TG) will be positive and are a key feature to making the diagnosis. It is important, however, to keep in mind that about 10% of the population may have positive antithyroid antibodies, making their finding nonspecific. Interestingly, some neurologic conditions, such as multiple sclerosis, myasthenia gravis, autoimmune encephalitis, and chronic inflammatory demyelinating neuropathies, have been reported to have incidental elevated anti-thyroid antibodies (15). One study showed that the prevalence of anti-thyroid antibodies in autoimmune encephalitis is double that found in controls (30). To date, there is no correlation with the antibodies’ titer and severity or prognosis of the disease (39). Antibodies are detected by various methods, including radioimmunoassay and chemiluminescent assay. Importantly, administration of IVIG may cause false-positive results (40).

Lumbar puncture. Most patients will have a nonspecific CSF finding of elevated proteins and mild lymphocytic pleocytosis (09; 27; 08; 13; 15). If a marked pleocytosis is present, other diagnoses should be entertained, such as an infectious etiology. Testing for known causes of autoimmune encephalitis (eg, antibodies to NMDAR, AMPAR, LGI1, GABA-B) should be performed, particularly if the clinical presentation is consistent with limbic encephalitis or shows characteristic features of those disorders. For some of these entities, such as anti-NMDAR encephalitis, CSF testing is preferred as this is more sensitive and specific than serum testing.

Brain MRI with gadolinium. Most patients will have a normal or nonspecific MRI (09; 27; 44; 08; 15). When abnormal, the most common finding is bilateral patchy or confluent subcortical and periventricular white matter leukoencephalopathy (29). Other findings include migratory cortical or medial temporal T2/FLAIR hyperintensities. For all patients, there was no diffusion restriction nor contrast enhancement (15). If restriction, contrast enhancement, or diffuse white matter changes are present, other CNS inflammatory or infectious conditions should be considered.

EEG. Most patients will present with normal EEG or background slowing (09; 27; 44; 08; 15). Other features are nonspecific and include epileptiform discharges and intermittent rhythmic delta activity. EEG is especially useful in eliminating other conditions that may present with a specific pattern, such as certain types of autoimmune encephalitis (eg, extreme delta brush in anti-NMDA receptor encephalitis). Continuous EEG monitoring could also be considered to rule out known seizure syndromes and psychogenic nonepileptic seizures, depending on the presentation.

Pathology. Although not part of a routine workup, more glandular fibrosis on thyroid pathology has been associated with anti-TPO. Although interesting, the role of this marker in predicting central nervous system damage remains unclear (08).

New potential biomarkers. Some reports have suggested measuring antithyroid antibodies and antibodies against the amino terminal domain of alpha enolase in the CSF, but the sensitivity and specificity of these markers have not yet been validated (44; 08; 13). Abnormal antithyroid antibodies have been found in the CSF of 62% to 75% of patients with Hashimoto encephalopathy (48; 37). Although their level doesn’t seem to be correlated to severity of the disease, it is believed that their decrease might be related to a favorable outcome (35; 37). High titers of amino (NH2)-terminal of alpha-enolase have been detected in patients with Hashimoto encephalopathy but may also be found in other autoimmune diseases and infections (13). Some have even found a decrease in the N-acetylaspartate/creatinine ratio in the posterior cingulate regions in patients with Hashimoto thyroiditis without neurologic involvement (44). This advanced neuroimaging technique requires further validation and elucidation of its clinical relevance and feasibility before it can be applied to practice.

Management

	• There is currently no validated treatment for Hashimoto encephalopathy.
	• Although response to corticosteroids was previously considered diagnostic, some studies have shown a variable effect, with complete response in only 32% of patients.
	• A trial of corticosteroid therapy is reasonable in most cases.

To this day, there are no large trials or validated guidelines on the treatment of Hashimoto encephalopathy (44; 08). Current data rely on case series and expert opinions. The mainstay of treatment relies on corticosteroid therapy and correction of thyroid dysfunction. Although steroid responsiveness has sometimes been considered a key element of Hashimoto encephalopathy, it is not always the case, and this may have led to a bias in how cases have been identified for case series. There are no guidelines regarding steroid dose and duration, but the most common treatment protocols involve corticosteroids given as intravenous pulses of methylprednisolone or prolonged oral prednisone tapers over weeks to months (44; 09; 36; 27; 33). It is unclear if a taper should be used thereafter. In their case series, Mattozzi and colleagues found that only 32% of patients who fulfilled pretreatment criteria for Hashimoto encephalopathy completely responded to corticosteroids (33).

Some patients (16% to 33% in various case series) present relapses and may require escalation of immunosuppressive therapy (33; 13). Most relapses were also treated with another course of corticosteroids (15). Individual patient characteristics and side effects of corticosteroids or other immunosuppressive therapies, such as increased risk of infections, decreased bone density, fertility concerns, and psychiatric and ophthalmologic comorbidities, should be considered when making treatment decisions.

IVIG or plasmapheresis are reasonable alternatives for patients for whom corticosteroids are contraindicated (24; 02). The use of plasmapheresis and steroid-sparing agents, such as cyclosporine and azathioprine, has also been reported in patients who either cannot tolerate steroids, don’t respond, or relapse during tapering (08). In patients with severe encephalitis, stronger forms of immunosuppressive therapy, such as rituximab and cyclophosphamide, may be considered.

As for the treatment of seizures, no specific antiepileptic drug has shown superiority. However, some authors suggest an effect of levetiracetam on inflammatory cytokines, making it an enticing option (46). As always, treatment choice should be oriented according to patient’s characteristics and seizure type.

Importantly, it should be noted that thyroiditis may be associated with other autoimmune conditions. Autoimmune gastric conditions have been reported in 10% to 40% of patients with Hashimoto thyroiditis (34). This can lead to malabsorption of vitamins and minerals and can tint the neurologic presentation. These should be taken into consideration and repeated when indicated.

Outcomes

Predictive prognostic factors are difficult to identify due to the various discrepancies in the literature on Hashimoto (33). Many published cases report patients who do not fully meet the accepted diagnostic criteria or who haven’t had a complete workup excluding other autoimmune or paraneoplastic confounding etiologies. Truthful prognosis and predictive prognostic factors, therefore, remain unknown.

Data from case reports or case series report an improvement with corticosteroid therapy in 36% to 93% of patients, with a marked improvement in 75% according to one study from Thailand and complete recovery in 32% in another study from Spain (09; 27; 33; 13).

Some studies suggest a more aggressive form of Hashimoto thyroiditis in younger males, with serum IgG4 elevation and very high levels of thyroid antibodies (44; 08). These patients can present fibrosis, sclerosis, and even inflammatory tumors. Literature on this pathology is still in early development, but such patients should be classified into the IgG4-related disorders. Further studies are needed to elucidate the link between this presentation and Hashimoto encephalopathy.