Neuroimmunology
Anti-IgLON5 disease
Oct. 10, 2024
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Hashimoto encephalopathy …
- Updated 04.11.2024
- Released 05.10.2018
- Expires For CME 04.11.2027
Hashimoto encephalopathy
Introduction
Overview
Hashimoto encephalopathy is a controversial and poorly defined entity usually recognized as a steroid-responsive encephalopathy associated with thyroid autoimmunity. The key features are: (1) altered level of consciousness, (2) presence of anti-thyroid peroxidase (anti-TPO) or anti-thyroglobulin (anti-TG) antibodies. It is distinct from sensorium alterations occurring in the context of severe dysthyroidism, and severe abnormalities in thyroid hormone levels should be excluded when making the diagnosis. Symptoms can vary considerably but commonly include cognitive deficits, behavioral changes, myoclonus, stroke-like episodes, and seizures. Patients with suspected Hashimoto encephalopathy require careful evaluation in order to rule out autoimmune and nonautoimmune causes of encephalopathy.
Key points
|
• Hashimoto encephalopathy is a poorly understood syndrome of reversible cognitive impairment in the setting of positive antithyroid autoantibodies. | |
|
• There are no validated criteria for the diagnosis of the disease but proposed diagnostic criteria include: (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. | |
|
• The literature on Hashimoto encephalopathy is highly heterogenous and most reports did not adequately exclude alternative diagnoses, such as other causes of autoimmune encephalitis. | |
|
• Antithyroid antibodies are relatively common in the general population and may also be found in patients with other, better-defined types of autoimmune encephalitis. | |
|
• The existence of the disease has been seriously questioned in recent years owing to its nonspecific diagnostic criteria and to a lack of distinct biomarkers. | |
|
• There is no class 1 evidence for treatment of Hashimoto encephalopathy. |
Historical note and terminology
In 1966, Brain and colleagues reported the initial case of Hashimoto encephalopathy, a 40-year-old man with antithyroid antibodies who had multiple stroke-like episodes and periods of profound confusion (06). He eventually had excellent recovery (although he did not obviously respond to corticosteroids). Though he had thyroid disease, this was well controlled during most of his clinical course. The authors concluded that he may have had an autoimmune disease but doubted that the antithyroid antibodies were directly pathogenic.
In the last decade, alternative names for Hashimoto encephalopathy have been proposed, including steroid-responsive encephalopathy associated with thyroiditis (SREAT) and encephalopathy associated with autoimmune thyroid disease (EAATD).
Hashimoto encephalopathy should not be confused with Hashimoto thyroiditis. Hashimoto thyroiditis was first described in 1912 as a form of thyroid disease with lymphomatous infiltrates (20). Unlike Hashimoto encephalopathy, humoral factors such as antibodies to thyroid peroxidase, thyroglobulin, and other antithyroid antibodies are thought to directly contribute to the pathogenesis of Hashimoto thyroiditis, along with cellular immunity, genetic risk, and other factors (01). The diagnosis of Hashimoto thyroiditis is based on the presence of primary hypothyroidism (elevated TSH, low T4), goitrous or atrophic thyroid changes, and can be confirmed by the presence of positive anti-TPO or anti-TG antibodies.
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.) |
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 |
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.
References
- 01
- Ajjan RA, Weetman AP. The pathogenesis of Hashimoto's thyroiditis: further developments in our understanding. Horm Metab Res 2015;47(10):702-10. PMID 26361257
- 02
- Barrett LD, Ballew M, Ewers E. Hashimoto’s encephalopathy with use of intravenous immunoglobulin as first-line therapy. Mil Med 2023;188(9-10):e3276-9. PMID 37428510
- 03
- Benvenga S, Antonelli A, Fallahi P, Bonanno C, Rodolico C, Guarneri F. Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis. J Clin Transl Endocrinol 2021;26:100274. PMID 34849350
- 04
- Blanchin S, Coffin C, Viader F, et al. Anti-thyroperoxidase antibodies from patients with Hashimoto's encephalopathy bind to cerebellar astrocytes. J Neuroimmunol 2007;192(1-2):13-20. PMID 17963848
- 05
- Boelen R, de Vries T. Clinical characteristics of paediatric Hashimoto's encephalopathy. Eur J Paediatr Neurol 2021;32:122-7. PMID: 33964645. PMID 33964645
- 06
- Brain L, Jellinek EH, Ball K. Hashimoto's disease and encephalopathy. Lancet 1966;2(7462):512-4.** PMID 4161638
- 07
- Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol 2006;63(2):197-202. PMID 16476807
- 08
- Chaudhuri J, Mukherjee A, Chakravarty A. Hashimoto's encephalopathy: case series and literature review. Curr Neurol Neurosci Rep 2023;23(4):167-75. PMID 36853554
- 09
- Chong JY, Rowland LP, Utiger RD. Hashimoto encephalopathy: syndrome or myth? Arch Neurol 2003;60(2):164-71.** PMID 12580699
- 10
- Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018;378(9):840-51. PMID 29490181
- 11
- Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83(1):166-77. PMID 29293273
- 12
- Duffey P, Yee S, Reid IN, Bridges LR. Hashimoto's encephalopathy: postmortem findings after fatal status epilepticus. Neurology 2003;61(8):1124-6. PMID 14581677
- 13
- Dumrikarnlert C, Thakolwiboon S, Senanarong V. Clinical presentations and treatment outcomes of Hashimoto encephalopathy at Siriraj Hospital - Thailand's largest national tertiary referral center. BMC Neurol 2023;23(1):334. PMID 37737161
- 14
- Ercoli T, Defazio G, Muroni A. Cerebellar syndrome associated with thyroid disorders. Cerebellum 2019;18(5):932-40. PMID 31388971
- 15
- Figgie MP Jr, Kelly H, Pyatka N, Chu C, Abboud H. Characterization of neurological morbidity associated with thyroid antibodies: Hashimoto's encephalopathy and beyond. J Neurol Sci 2024;458:122908. PMID 38309249
- 16
- Gozubatik Celik RG, Uludüz Ulu D, Hatipoğlu E, et al. The frequency and related factors of primary headaches in patients with Hashimoto thyroiditis. Agri 2022;34(4):292-7. PMID 36300741
- 17
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15(4):391-404.** PMID 26906964
- 18
- Hayashi Y, Yamada M, Kimura A, et al. Clinical findings of a probable case of MM2-cortical-type sporadic Creutzfeldt-Jakob disease with antibodies to anti-N-terminus of α-enolase. Prion 2017;11(6):454-64. PMID 28967811
- 19
- Hernan Martinez J, Torres O, Mangual MM, et al. Hashimoto's encephalopathy: an underdiagnosed clinical entity. Bol Asoc Med P R 2013;105:57-61. PMID 23767389
- 20
- Hiromatsu Y, Satoh H, Amino N. Hashimoto's thyroiditis: history and future outlook. Hormones (Athens) 2013;12(1):12-8. PMID 23624127
- 21
- Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87(2):489-99. PMID 11836274
- 22
- Ilias I, Karagiorga V, Paraskevas G, et al. Thyroid autoantibodies in the cerebrospinal fluid of subjects with and without thyroid disease: implications for Hashimoto's encephalopathy. J Thyroid Res 2015:819072. PMID 26798549
- 23
- Joubert B, Rostasy K, Honnorat J. Immune-mediated ataxias. Handb Clin Neurol 2018;155:313-32. PMID 29891069
- 24
- Karan A, Nuthulaganti SR, Zhang Y, Kandah F, Gutierrez M, Reddy P. Two PerPLEXing cases of Hashimoto's encephalopathy unresponsive to steroid and intravenous immunoglobulin therapy. Cureus 2022;14(7):e26853. PMID 35974865
- 25
- Kishitani T, Matsunaga A, Ikawa M, et al. Limbic encephalitis associated with anti-NH2-terminal of alpha-enolase antibodies: a clinical subtype of Hashimoto encephalopathy. Medicine (Baltimore) 2017;96(10):e6181. PMID 28272206
- 26
- Lancaster E. The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol 2016;12(1):1-13. PMID 26754777
- 27
- Laurent C, Capron J, Quillerou B, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): characteristics, treatment and outcome in 251 cases from the literature. Autoimmun Rev 2016;15(12):1129-33. PMID 27639840
- 28
- Lee J, Yu HJ, Lee J. Hashimoto encephalopathy in pediatric patients: homogeneity in clinical presentation and heterogeneity in antibody titers. Brain Dev 2018;40(1):42-8. PMID 28784301
- 29
- Liang C, Chu E, Kuoy E, Soun JE. Autoimmune-mediated encephalitis and mimics: a neuroimaging review. J Neuroimaging 2023;33(1):19-34. PMID 36217010
- 30
- Lin JF, Wang JR, Wang JQ. Li JM. The detection of up-regulated anti-thyroid antibodies and autoimmune thyroid diseases in patients with autoimmune encephalitis: a retrospective study of 221 patients. Neurol Sci 2022;43(6):3901-10. PMID 35137351
- 31
- Mane-Damas M, Vinke A, Hoffmann C, et al. Unidentified neuronal surface IgG autoantibodies in a case of Hashimoto's encephalopathy. Front Immunol 2020;11:1358.** PMID 32733453
- 32
- Matsunaga A, Ikawa M, Kawamura Y, et al. Serial brain MRI changes related to autoimmune pathophysiology in Hashimoto encephalopathy with anti-NAE antibodies: a case-series study. J Neurol Sci 2019;406:116453. PMID 31525528
- 33
- Mattozzi S, Sabater L, Escudero D, et al. Hashimoto encephalopathy in the 21st century. Neurology 2020;94(2):e217-24.** PMID 31882532
- 34
- Mincer DL, Jialal I. Hashimoto thyroiditis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing, 2024.
- 35
- Montagna G, Imperiali M, Agazzi P, et al. Hashimoto's encephalopathy: a rare proteiform disorder. Autoimmun Rev 2016;15(5):466-76. PMID 26849953
- 36
- Patnaik SK, Upreti V, Dhull P. Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) in childhood. J Pediatr Endocrinol Metab 2014;27(7-8):737-44. PMID 24598831
- 37
- Petithomme-Nanrocki M, Brunet A, Didier K, et al. Disappearance of anti-thyroglobulin antibodies from the cerebrospinal fluid in parallel with neurological improvement during treatment for Hashimoto's encephalopathy. Ann Biol Clin (Paris) 2022;80(5):464-5. PMID 36453744
- 38
- Pfeuffer S, Ruck T, Rolfes L, et al. Patients with a relapsing course of steroid-responsive encephalopathy associated with autoimmune thyroiditis exhibit persistent intrathecal CD4 T-cell activation. Eur J of Neurol 2020;28(4):1284-91. PMID 33230897
- 39
- Sorodoc V, Constantin M, Asaftei A, et al. The use of intravenous immunoglobulin in the treatment of Hashimoto's encephalopathy: case based review. Front Neurol 2023;14:1243787. PMID 37745658
- 40
- Uchida Y, Kato D, Adachi K, Toyoda T, Matsukawa N. Passively acquired thyroid autoantibodies from intravenous immunoglobulin in autoimmune encephalitis: two case reports. J Neurol Sci 2017;383:116-7. PMID 29246597
- 41
- Uwatoko H, Yabe I, Sato S, et al. Hashimoto's encephalopathy mimicking a brain tumor and its pathological findings: a case report. J Neurol Sci 2018;394:141-3. PMID 30266017
- 42
- Valencia-Sanchez C, Pittock SJ, Mead-Harvey C, et al. Brain dysfunction and thyroid antibodies: autoimmune diagnosis and misdiagnosis. Brain Commun 2021;3(2):fcaa233. PMID 34061124
- 43
- Vicent MG, Cantarín V, Guerrero C, et al. Hashimoto encephalopathy as manifestation of central nervous system chronic graft-versus-host disease after hematopoietic stem cell transplantation. Pediatr Blood Cancer 2019;66(12):e28008. PMID 31535441
- 44
- Waliszewska-Prosol M, Ejma M. Hashimoto encephalopathy-still more questions than answers. Cells 2022;11(18):2873. PMID 36139446
- 45
- Wei C, Shen Y, Zhai W, et al. Hashimoto's encephalopathy with cerebellar ataxia as the main symptom: a case report and literature review. Front Neurol 2022;13:970141. PMID 36081870
- 46
- Xu X, Lin A, Wang X. Seizures in steroid-responsive encephalopathy. Neurol Sci 2021;42(2):521-30. PMID 33219869
- 47
- Yoneda M, Fujii A, Ito A, Yokoyama H, Nakagawa H, Kuriyama M. High prevalence of serum autoantibodies against the amino terminal of alpha-enolase in Hashimoto's encephalopathy. J Neuroimmunol 2007;185(1-2):195-200. PMID 17335908
- 48
- Zhou JY, Xu B, Lopes J, Blamoun J, Li L. Hashimoto encephalopathy: literature review. Acta Neurol Scand 2017;135(3):285-90. PMID 27324276
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Eugenie Girouard
Dr. Girouard of Centre Hospitalier Universitaire de Montréal has no relevant financial relationships to disclose.
See Profile -
Sarah Lapointe MD
Dr. Lapointe of the University of Montreal received an honorarium from Novocure as a consultant.
See Profile
Editor
-
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
See Profile
Former Authors
- Kristina Patterson MD PhD
- Eric Lancaster MD PhD
- Julien Rousseau MDCM
Patient Profile
- Age range of presentation
-
- Generally between the fourth to sixth decade of life, but may be found in pediatric populations
- Sex preponderance
-
- Female to male ratio of 4:1
- Heredity
-
- Heredity may be a factor.
- Population groups selectively affected
-
- No population group selectively affected
- Occupation groups selectively affected
-
- No occupation group selectively affected
ICD & OMIM codes
- ICD-9
-
- Other causes of encephalitis and encephalomyelitis: 323.81
- ICD-10
-
- Other encephalitis, myelitis and encephalomyelitis: G04.8
- Encephalitis, myelitis, and encephalomyelitis, unspecified: G04.9
- Encephalitis, and encephalomyelitis in diseases classified elsewhere: G05.3
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
Neuro-Oncology
Anti-LGI1 encephalitis
Oct. 03, 2024
-
Neuro-Ophthalmology & Neuro-Otology
Giant cell arteritis
Sep. 25, 2024
-
Neuroimmunology
Chronic inflammatory demyelinating polyradiculoneuropathy
Sep. 07, 2024
-
Neuroimmunology
Autoimmune autonomic neuropathy
Aug. 31, 2024
-
Neuroimmunology
HTLV-1 associated myelopathy
Aug. 29, 2024
-
Neuroimmunology
Myositis and cancer
Aug. 29, 2024
-
Neuro-Oncology
Paraneoplastic retinopathy
Aug. 20, 2024