Abstract
The condition "Hashimoto's encephalopathy" (HE) refers to a cerebral dysfunction syndrome with elevated antithyroid peroxidase antibody titers that is thought to have an autoimmune cause. Similar to autoimmune thyroid illness, women are more likely than men to develop HE. It has been documented in adult, geriatric, and pediatric populations worldwide. The clinical appearance may be recurrent and remitting, with myriad symptoms involving myoclonus, seizures, episodes resembling strokes, cognitive deterioration, and neuropsychiatric symptoms. Clinically and biochemically, thyroid function is often normal. Although HE seems to be a rare disorder, it should be taken into consideration when treating "investigation negative encephalopathies" because it responds to corticosteroid treatment. The results of neuroimaging frequently do not help to clarify the diagnosis. High titers of antithyroid antibodies, specifically antithyroid peroxidase antibodies, are diagnosed in the setting of the usual clinical picture. Corticosteroid treatment is nearly always successful, although relapses are common. Other immunomodulatory treatments, like intravenous immunoglobulin and plasma exchange, are often effective as well. Despite a statistical correlation to autoimmune thyroid illness, the cause of HE is not well understood. Research is still needed to fully understand the connections between clinical images, thyroid disease, auto-antibody pattern, and brain pathology. It's possible that over time, a class of nonvasculitic autoimmune inflammatory meningoencephalopathies will include HE. Some writers have proposed severing all connections to Hashimoto and calling the illness, SREAT - "steroid responsive encephalopathy associated with autoimmune thyroiditis".
Keywords
Cerebrospinal fluid, Computed tomography, Electroencephalography, Hashimoto’s encephalopathy, Hashimoto’s thyroiditis, Lumbar puncture, Magnetic resonance imaging, Positron emission tomography
Abbreviations
HE: Hashimoto’s Encephalopathy; CT: Computed Tomography; MRI: Magnetic Resonance Imaging; EEG: Electroencephalography; CSF: Cerebrospinal Fluid; LP: Lumbar Puncture; PET: Positron Emission Tomography; HT: Hashimoto’s Thyroiditis; EAE: Experimental Allergic Encephalomyelitis; ADEM: Acute Disseminated Encephalomyelitis
Introduction
The clinically heterogeneous illness known as Hashimoto's encephalopathy (HE) is characterized by a corticosteroid-responsive encephalopathy with elevated blood antithyroid antibody titers that do not include aberrant thyroid hormone levels. Hashimoto's encephalopathy is the name given to a condition that Lord Brain and associates reported in 1966 [1]. This concerned a 49-year-old man who had episodes of stroke-like symptoms involving several vascular regions, hallucinations, fluctuating awareness, and cognitive impairment. His diagnosis of Hashimoto's autoimmune thyroiditis (HT) was confirmed. There was an increase in CSF protein as well as high titers of anti-thyroglobulin (anti-TG) and antithyroid microsomal antibodies. This patient, however, was clinically hypothyroid, did not react to prednisolone treatment, and ultimately seemed to heal with thyroxine treatment alone, demonstrating the heterogeneity of HE. Since then, there has been a lot of interest in the connection between antithyroid antibodies, autoimmune thyroid illness, and corticosteroid-responsive encephalopathy. As a result, over 175 instances have been documented in the literature. In consideration of the historical and case report bias in the literature, the term "Hashimoto's encephalopathy" will be used to refer to the present state of knowledge on this type of encephalopathy, as this article aims to provide an overview of it. Future directions for nosology will be discussed in the conclusion section.
Inclusion and Exclusion Criteria
To identify articles and reviews and journals pertaining to Hashimoto’s encephalopathy, we used two sources of information: PubMed (National library of medicine) and Google scholar. We limited candidate articles, reviews, and journals to those having the term Hashimoto’s encephalopathy in their titles. No specific time period was followed as our understanding of the disease is quite limited and we wanted to encompass as much information as possible in this review. We excluded articles that were not written in English.
|
Criteria |
Inclusion |
Exclusion |
|
Publication type |
Original research, Reviews, Case reports, full text articles |
Letters, editorials |
|
Language |
English |
Any other language |
|
Time period |
Every year |
- |
Epidemiology
Since HE is an uncommon disorder, it might be challenging to estimate its incidence and prevalence. According to one prospective investigation, the incidence of detectable antithyroid antibodies in patients of unexplained encephalopathy was estimated to be 2.1/100,000 participants [2]. Cases in adult [3], elderly [4], and pediatric populations have been recorded globally [5]. The average age of onset is between 45 and 55 years old, with ages ranging from 9 to 86 years old, as shown in Table 1. With a female to male ratio of almost 5 to 1, there is a definite female majority in the adult population [3,6]. Pediatric samples typically show similar gender distribution, despite their tiny size [3,7]. HE is linked to other autoimmune illnesses. In a study of 20 patients with HE, 30% had a co-morbid autoimmune condition, including type 1 diabetes, systemic lupus erythematosus, and Sjogren's syndrome [8]. A bigger, literature-based analysis identified fewer connections of this sort, although only a few of the 85 cases had thorough antibody testing for connective tissue illnesses [3]. While there is evidence that autoimmune thyroid illness can run in families, no examples of familial HE has been described [9,10].
|
Prevalence Approximately |
2/100 000 |
|
Mean age of onset |
45–55y |
|
Age range |
9–86y |
|
Female to male ratio |
5 : 1 |
|
Associated autoimmune disorders |
Autoimmune thyroid disease, systemic lupus erythematosus, type 1 diabetes mellitus, Sjogren’s syndrome |
Pathophysiology
It is uncertain what causes HE. There is little evidence to support a common mechanism at the microscopic level between patients with HE. The pathological findings in vivo are varied and have only been obtained from a limited number of patients; the most common result is mild lymphocytic infiltration of tiny capillaries [11,12]. The brain biopsy taken from animal models after inducing experimental allergic encephalomyelitis by sensitization to myelin basic proteins also showed intense perivascular round cell infiltrates in white matter [13]. It is debatable whether these characteristics indicate intracerebral vasculitis, especially as the CNS and other organs do not appear to exhibit vessel wall damage and transmural infiltration typical of vasculitis [3].
In contrast to other autoimmune neurological disorders like myasthenia gravis or paraneoplastic syndromes, where antibodies play a role in pathogenic mechanisms by disrupting cell signaling pathways (e.g., anti-Hu antibodies) or blocking specific neurotransmission functions (e.g., anti-acetylcholine receptor antibodies) [14], the role of thyroid antibodies in the pathogenesis of HE is still unknown. Antithyroid antibodies may indicate genuine etiopathogenic variables that cause such encephalopathies by functional or cytotoxic effects, or they may simply be an autoimmune epiphenomenon in the context of encephalopathic processes of various etiologies. The existence of antithyroid antibodies designates a group of neurological illnesses under the name Hashimoto's encephalopathy, regardless of the part that these antibodies may play in the pathophysiology of CNS problems.
Autoimmune reaction to antigens shared by the thyroid gland and CNS
There is no empirical evidence to support the theory that the pathogenicity of antithyroid antibodies may be attributed to the cross-reactivity of CNS and thyroid gland epitopes. No proteins found in the central nervous system have been shown to share structural similarities with thyroglobulin and thyroperoxidase proteins. Although there is little evidence to support a shared thyroid/brain antigen, a recent study found that anti-TPO antibodies bind specifically to cerebellar astrocytes in HE patients but not in HT patients [15]. This finding may lend credence to the theory that antibodies that affect neuroglial function may be responsible for neuronal dysfunction. Paradoxically, seroepidemiological research has revealed that antithyroid antibodies are present in 10–20% of the healthy population and rise with age >65 [16], particularly in women [17]. Antithyroid antibodies have also been linked to peripheral neuropathy, myopathy, chronic fatigue syndrome, fibromyalgia, mood and anxiety disorders, depression, borderline personality disorder, Alzheimer's disease, Wegener's granulomatosis, juvenile idiopathic arthritis, and 34%–41% of patients with fibromyalgia [18]. Given that thyroid antibodies have been associated with a wide range of disorders and have been observed in the general healthy population, it is unlikely that there is a distinct antigen in the brain that thyroid antibodies share and are therefore not necessarily disease-specific.
Autoimmune vasculitis
Neuroimaging SPECT results that typically demonstrate focal or global hypoperfusion [3] and the identification of anti-α-enolase antibodies—which are highly expressed in endothelial cells and have been linked to other vasculitic disorders including Kawasaki disease—support this theory [19]. Like the antibodies, it is unclear if the perivascular lymphocytic infiltration detected in five out of seven pathology reports is a nonspecific finding or indicative of the onset of a "true vasculitis”. Perivascular cuffing, however, is also frequently observed as a neuropathological "fingerprint" of neuroinflammatory conditions such encephalitis, multiple sclerosis, and uncommon types of epilepsy like Rasmussen's syndrome [20,21].
Toxic effects of thyrotropin-releasing hormone
The theory behind the toxic effects of thyrotropin-releasing hormone (TRH) is that elevated cerebral TRH is the source of the encephalopathic symptoms of Huntington's disease (HE), including myoclonic and ataxic symptoms. The hypothalamus releases TRH, which causes the pituitary to produce more TSH, which in turn causes the thyroid to produce more thyroid hormone [22]. There has only been a single trial where TRH infusion successfully caused myoclonus and tremor that resembled the patient's symptoms during an exacerbation in a patient with HE.
Clinical Presentation/Symptomatology
Behavioral abnormalities, disorientation, cognitive decline, stroke-like episodes, amnestic syndrome, ataxia, seizures, myoclonus [23,24] and psychiatric manifestations are only a few of the many symptoms that can accompany HE [25-27]. Epilepsy, encompassing focal and focalized seizures [3,28] and myoclonus are the most common manifestations in adulthood, accounting for 60–66% of affected patients, according to reports [22]. The most frequent type of seizures in children are generalized tonic-clonic seizures, which are followed by partial complex seizures. Additional prevalent symptoms have been documented to include cognitive impairment (84.6% of affected patients) and psychiatric symptoms (38.5% of affected patients), such as depression, mania, psychosis, and hallucinations [25-27]. Although it is uncommon in adult HE patients, children who present with coma and generalized tonic-clonic seizures have been reported to have status epilepticus (SE). Anti-epileptic medications do not work well for these patients [29]. The primary complication of HE in children has also been documented to be recurrent status epilepticus, with frontal brain involvement being linked to these symptoms [30]. Adult HE patients have also been linked to multiple anti-epileptic drug (AED) hypersensitivity and temporal epilepsy [31].
In older HE patients, subacute dementia with a subtle onset and schizophrenia-like symptoms has been reported [32]. There is a case study of a 60-year-old woman who had a history of HT for more than 40 years and presented with symptoms of schizophrenia-like illness. It took 40 years for this patient's diagnosis to be made following the onset of her schizophrenia-like symptoms [28]. In certain HE patients, the onset of psychosis has also been seen during corticosteroid therapy [33]. Opsoclonus, or erratic saccadic eye movements, is linked to ataxia before encephalopathy develops and can potentially appear as an early HE symptom [34]. There have been proposed to be two clinical subtypes of HE [35]. The first subtype is episodic, characterized by stroke-like symptoms that have a relapsing-remitting history and are associated with vasculitis [32]. The second subtype exhibits a more advanced course with an inflammatory beginning, a notable reduction in cognitive function, and memory loss [36,37].
Diagnosis/Testing/Imaging/Evaluation
Antibodies that define HT and HE
The existence of antithyroid antibodies that specifically target distinct thyroid gland epitopes is one of the main laboratory characteristics of HT and HE. There is a lot of disagreement regarding the importance of their existence and role in the etiology of HE. David Sinclair wrote a great assessment on the drawbacks of antibody testing in HT [38]. Graves' disease is caused by antithyrotropin antibody, also known as anti-thyroid stimulating hormone (anti-TSH), which is aimed at the thyrotropin receptor [39]. The literature on HE only has one case report in which the patient exhibited considerably higher levels of thyroid peroxidase (anti-TPO) and thyroglobulin (anti-TG) but only marginally raised levels of anti-TSH [1]. Antibodies directed against microsomes, which are produced from injured thyroid cells, are known as anti-TPO or originally antimicrosomal antibodies. These are the antibodies in the majority of HE cases and are most commonly linked to hyperthyroidism and hypothyroidism [18,40,41]. Nevertheless, they have also been detected in a small number of euthyroid individuals (14.4% of men and 25.8% of women), rheumatoid arthritis [42], insulin-dependent diabetic mellitus, and rheumatoid arthritis [43]. There is a lot of variation in the sensitivity of available laboratory techniques and kits, as well as in what is regarded as the "normal" reference range, which makes utilizing this antibody as a diagnostic criterion for HE and HT problematic [38]. The target of anti-TG antibodies is thyroid cell-resident thyroglobulin, also referred to as "colloid" [44]. These antibodies do not significantly outperform anti-TPO antibodies because they are not as prevalent in HE cases as anti-TPO antibodies [45]. About 10% of the 13,344 participants in the Third National Health and Nutrition Examination Study (NHANES III) who were free of illness, pregnant, not using steroids, or lacking biochemical hyperthyroidism or hypothyroidism showed anti-TG antibodies [18]. Recently, proteomic investigations have revealed anti-α-enolase antibodies in the blood of patients with HE as a possible antibody more specific for HE than HT [46]. A further investigation revealed that patients with HE were more likely than HT or control subjects to recognize the amino-terminal region of α-enolase [47]. The high expression of α-enolase in the endothelium provides support to the vasculitic explanation of HE, as demonstrated by these investigations [12,48]. Nevertheless, anti-α-enolase has also been detected in other autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease [49,50].
CSF findings
The most frequent observation in the CSF of patients with HE that has been reported is an increased protein content without pleocytosis [3,51,52]. Typically, the immunoglobulin G index falls within the reference range [51] and oligoclonal bands are occasionally, however not always, observed [53]. In one study, the CSF of HE patients included circulating immune complexes, anti-TG antibodies, and anti-TPO antibodies, but not the CSF of control patients [54]. There was no control group consisting of HT patients who did not have encephalopathy. According to the authors, their existence suggests intrathecal production.
Neuroimaging
In cases of HE, results from brain magnetic resonance imaging and computed tomography imaging have ranged from perfectly normal to different levels of nonspecific abnormalities. Cerebral atrophy [55], focal and confluent white matter abnormalities [3,56] cortical irregularities [57] and vasculitic alterations are among the findings [58]. Furthermore, results from magnetic resonance imaging can change over time in the same patient, decline with steroid use, and have a correlation with antibody levels. In patients with thyroid problems, single-photon emission computed tomography (SPECT) scanning has also been employed. Research utilizing SPECT on hypothyroidism-affected HT patients has revealed a notable change in the local cerebral blood flow [59,60]. These changes are observed in both euthyroid hypothyroid patients and hypothyroid individuals without neurologic symptoms [61]. The frontal lobes appeared to be most impacted in one study, which could account for the behavioral and psychiatric symptoms of HE that are frequently described. The findings of the HE patient case reports vary from normal to focal hypoperfusion to global [3].
EEG findings
The original 1966 paper by Lord Brain outlining the encephalopathic characteristics of his case included reports of EEG results. Between 1961 and 1966, the patient underwent serial EEGs. Their condition deteriorated over time, beginning with bitemporal abnormalities and continuing to bilateral loss of α activity and θ discharges. After that, they took a varying path that eventually normalized by 1966 [1]. These results were comparable to the EEG studies on myxoedema patients that Jellinek, a collaborator on Brain's study, had published four years prior [13]. According to a review by Chong et al., abnormal EEG results (most frequently diffuse slowing) were present in 98% of HE patients between 1966 and 2002 [3].
Neuropathology
Regretfully, there aren't many neuropathological reports for HE. Based on existing literature, the argument primarily divides into two categories: HE classified as a vasculitic or encephalitic process. The patient of Lord Brain passed away about ten years after he was first seen, and the postmortem report simply mentioned that the "central nervous system reported free from infarction, cerebral vessels congested, with a few atheromatous patches". There was hypertrophy and dilation of the left ventricle [62]. In 1992, there was a subsequent pathologic report that offered proof of a vasculopathic genesis for the illness. The walls of arterioles and venules displayed a localized region of lymphocytic infiltration in a stereotactic biopsy sample taken from a patient with HE [63]. A cerebral angiography in this instance was normal. A further example involving a patient with a lengthy history of HT revealed leptomeningeal venules invaded by T lymphocytes and a localized brain stem vasculitis [64]. Following the publication of this report, there was debate on the precise meaning of the term "vasculitis". Nolte et al. concluded that lymphocytic vasculitis is a pathogenic subtype that is well recognized and is defined by the presence of lymphocytes in the vessel wall. That being said, it does not follow that lymphocytic vasculitis does not exist only because the diagnosis is more challenging than for necrotizing arteritis [47]. A subsequent autopsy case from 2003 revealed a little lymphocytic infiltration in the venules and arterioles throughout the leptomeninges, cortex, white matter, and brainstem [65]. The literature also contains reports of pathologic abnormalities unrelated to vasculitis. The autopsy of a 27-year-old lady who had neurological encephalopathy that was fast progressing was documented by Striano et al., showed no lymphocytic infiltration [6]. In 2004, Oide presented an additional report on a nonvascular etiology, describing antineuronal autoantibodies that immunohistochemically identified a 36-kDa antigenic protein present in the neurons of the human cerebral cortex [66]. It was absent from the control group or in an HT patient who is not experiencing encephalopathy. Vasculitis was not evident in the brain pathology; nevertheless, an autopsy was performed following the steroid therapy. Two sequential biopsies on a young woman with sensory complaints, no encephalopathy, and a steroid-responsive white matter lesion were reported in one final pathologic report. The results of the biopsy revealed "relative axonal preservation and discrete microscopic foci of demyelination with rare perivascular lymphocytes" [67]. The patient did not exhibit clinical signs of encephalopathy, according to their own criteria of "cognitive impairment with or without neuropsychiatric symptoms", therefore it is still unclear if multiple sclerosis and ADEM (acute disseminated encephalomyelitis) are the correct diagnoses in this particular instance. These collections of neuropathological case reports only serve to highlight the illness we named HE's confusion and possible heterogeneity.
Differential Diagnosis
Systemic lupus erythematosus (SLE)
Seizures, acute confused states, affective and psychotic disorders, as well as cognitive difficulties, are examples of neuropsychiatric symptoms of SLE [68]. Thus, this could be a phenotype of the encephalopathy caused by Hashimoto's. Serum antibody profiles and a prior diagnosis of SLE may be used to distinguish it. Low titers of anti-TPO antibodies as well as anti-neuronal, antiphospholipid, and anti-DNA antibodies may be observed [69,70]. Since thrombotic disease is frequently associated with CNS signs of SLE (especially when antiphospholipid antibodies are present), neuroimaging evidence of venous thrombosis or infarction may help to explain the neurological characteristics of SLE and help to distinguish it from Hashimoto's encephalopathy [69,71,72]. Nonfocal symptoms, however, can be produced by more diffuse processes, and a diagnosis cannot be made based solely on the pathophysiology and antibody correlations of cognitive dysfunction or psychiatric symptoms [69].
Sporadic Cruetzfeldt Jacob disease (sCJD)
The symptoms of sCJD include a marked myoclonus, psychotic characteristics, and a dementia that progresses quickly. With this disease, ataxia, abnormal gait, personality changes, and seizures are also possible outcomes. Regular investigations are usually not very noteworthy. Periodic, triphasic sharp-wave complexes on the EEG and the finding of 14-3-3 protein in the CSF is used to confirm the diagnosis [73]. These results set sCJD apart from HE, as does the unremittingly fast decreasing course and absence of corticosteroid reactivity.
Vasculitis
As a differential diagnosis, isolated or primary CNS vasculitis should be taken into account. This is an uncommon kind of large-vessel vasculitis that manifests as encephalopathy, headaches, and, less frequently, ischemic stroke during a subacute phase. In as many as 50% of instances, angiography may be normal, MRI may be normal, and inflammatory markers may not be raised [74-76]. HE cannot occur if antithyroid antibodies are not present. Corticosteroids and cyclophosphamide can also be effective in treating this illness; nevertheless, a brain biopsy is frequently necessary to provide a final diagnosis [77].
Autoimmune hypophysitis
Pituitary hypofunction, hyperprolactinemia, diabetes insipidus, and sellar compression—which causes headaches and abnormalities in the visual field—are the hallmarks of autoimmune hypophysitis (AH) [78]. When there are metabolic disturbances brought on by endocrine dysfunction, encephalopathy may develop (such as hyponatraemia). Given that AH is often linked to Hashimoto's thyroiditis, anti-TPO antibodies may also be raised [79]. In these cases, a diagnosis of HE may be made. The diagnosis of AH can be supported by electrolyte problems, MRI findings of an intrasellar mass lesion, endocrine evidence of adrecorticotropic hormone (ACTH) deficiency, and, less precisely, antipituitary antibodies [80].
Paraneoplastic limbic encephalitis (PLE)
While seizures and focal neurological abnormalities are less common compared to HE, significant cognitive and behavioral changes can be observed in patients with paraneoplastic limbic encephalitis (PLE). It is believed that PLE is an autoimmune sub-acute encephalopathy associated with an underlying neoplasm, most frequently a breast, lung, or testicular tumor. Both the condition and the underlying cancer are associated with specific serum antineuronal antibodies. For example, antibodies against Hu, Ma1, Ma2, and CRMP/CV2 are linked to PLE caused by small cell carcinoma of the lung. For this disease, the underlying neoplasm and related antibodies must be found. There are no antithyroid antibodies found. More successful than corticosteroids or other types of immunomodulation is the treatment of the neoplasm [81].
Non PLE
Another diagnostic factor is non-PLE. Although complex partial seizures and sleep disturbances are more common than variations in conscious state and psychosis, the clinical symptoms of this condition are comparable to those of PLE [82]. Serum anti-volt-gated potassium channel antibodies are linked to this type of limbic encephalitis [83], but not antithyroid antibodies. MRI observations of unilateral or unilateral enlarged temporomesial structures that are hyperintense on FLAIR and T2-weighted sequences may aid in diagnosis, in contrast to HE [84,85]. Furthermore, bitemporomesial hypermetabolism can also be seen using fluorodeoxyglucose-PET [86]. Similar to HE, corticosteroid therapy is remarkably successful.
Rapidly progressing dementias
Fast-moving dementia represents a significant category of differential diagnosis. Alzheimer's disease is characterized by a nonfluctuating conscious state unless there is concomitant delirium, and it rarely manifests with myoclonus [87]. However, in elderly individuals suspected of having HE, delirium atop a longer-standing dementia is a crucial factor to take into account. Correspondence from family members or caregivers in detail can often shed light on these issues. DLB can cause parkinsonism, variable cognitive impairments, sleep disorders, and visual hallucinations in addition to altered conscious states [88,89]. Also documented is myoclonus [62,90], and the presentation of DLB can resemble that of sCJD [91]. Hashimoto's encephalopathy can be distinguished from DLB by the presence of antithyroid antibodies, Parkinsonian characteristics, and the lack of seizures or stroke-like episodes. Corticobasal ganglionic degeneration also occasionally presents psychotic symptoms, myoclonus, and dementia [92]. HE frequently results in stroke-like events, which can be mimicked by unilateral cortical symptoms. Unilateral cortical hypoperfusion or hypofunction may be seen on functional imaging; however, other characteristics that distinguish this disorder from HE includes progressive, asymmetric rigidity and apraxia, nonfluent aphasia, alien limb syndrome, and frontal lobe pattern of dementia [93].
Treatment and Monitoring
The first line therapy–Corticosteroids
It is advised to use prednisone (50–150 mg daily, or 1-2 mg/kg/d). It has also been used to administer high-dose IV methylprednisolone (500–1000 mg/d) [94,95]. About half of the cases had comprehensive response to the use of corticosteroids [96]. Following the initial course of corticosteroid medication, up to 40% of patients achieve total remission [97]. A tiny percentage of patients relapse in their mental symptoms and show resistance to steroid medication [98]. The length of corticosteroid treatment and the rate of taper should be adjusted in accordance with the clinical response [67,95,99]. Improvements in MRI and clinical outcomes show that brain lesions resolve well with early treatments [100].
HE resistant to corticosteroids may be treated with immunosuppressive medications
Combination therapy with immunosuppressive drugs such as methotrexate, cyclophosphamide, and azathioprine is advised for patients who are resistant to corticosteroids [97,101]. Early interventions with these immunosuppressive medications should be initiated if HE recurs in any patient. Adjunct therapy with immunosuppressive drugs, such as rituximab and an anti-CD20 monoclonal antibody, has also shown promise in treating HE patients who exhibit paraneoplastic opsoclonus syndrome [102]. An ideal treatment for HE would be natalizumab, a monoclonal antibody developed against an adhesion molecule (integrin). Natalizumab prevents inflammatory breakdown in the blood brain barrier and appears to be the most effective treatment currently available for EAE, the animal model for ADEM [13].
Patients who are unable to tolerate or take corticosteroids or immunosuppressant may be treated with plasma exchange and IVIG. Significant clinical improvements have been documented in both adults and children receiving IV immunoglobulin therapy. It has been demonstrated that plasma exchange can eliminate antithyroid peroxidase antibodies (anti-TPO) [96,103,104]. However, despite notable drops in anti-TPO antibodies in HE patients, no change in neurophysiologic or clinical parameters has been noted [99].
Seizures prevention
The anti-epileptic drug called levetiracetam is used to treat specific kinds of seizures [105]. Studies conducted in vivo have demonstrated the anti-inflammatory properties of this medication [106]. When used with other medications, like diabetes, levetiracetam can effectively treat people with HE who cannot tolerate steroids. It also has anti-inflammatory and antiseizure properties. In two diabetic HE instances, levetiracetam was reported to be a successful treatment [107]. More research is needed to confirm its targeted benefit in HE patients.
Prognosis
The majority of patients show full remission and a good response to steroid treatment. Some people get better even without steroid therapy [108]. Twelve percent of patients experience relapses, twelve percent show no improvement, and sixty percent have relapsing-remitting courses [3]. Cognitive decline is one of the aftereffects, and youngsters are more likely to experience recurring refractory seizures [5]. Higher serum TPO-Ab titers at the beginning were linked to better results [109]. It is thought that autoimmune encephalitis, including anti-NMDAR encephalitis, is a paraneoplastic condition. It is unknown if HE is a paraneoplastic condition as well. Because HE is a rare disease, there are no published data on the cancer prevalence in HE patients to our knowledge. Research on the incidence of cancer in HE patients is required.
Conclusion
HE is thus a relatively uncommon condition that manifests with myriad neurological symptoms like cognitive dysfunction, psychiatric symptoms, myoclonus and seizures. It is presumed to be an autoimmune condition despite lack of clear causality from a definite source. The treatment is relatively straightforward in most cases due to the use of steroids with great responsiveness seen. Collaborative management between internists, neurologists and psychiatrists is often necessary. It is necessary to consider this condition in patients presenting with unspecified causes of encephalopathy, especially with the presence of other signs of neurological dysfunction. The presence of other autoimmune disorders may also be a useful diagnostic clue. Testing modalities are often limited in utility, other than the exception of lab tests which are strongly supportive and EEG which is often abnormal without any pathognomic findings. Prompt neurological consultation is often imperative to enable timely diagnosis and minimize morbidity from this condition. Greater awareness of this condition among medical professionals of different fields would enable faster diagnosis and limit delays in evaluation and morbidity to patients. The future direction of our understanding of this disease should be aimed at finding the exact cause of HE and the underlying mechanism. A universally accepted diagnostic criteria for HE can prevent underdiagnosis and misdiagnosis. We must also look into the different treatment modalities that can be used in patients who don’t respond to corticosteroids and those who show remission.
|
Aspect |
Current Status |
|
Definition |
Cerebral dysfunction syndrome with elevated antithyroid peroxidase antibody titers that is thought to have an autoimmune cause. |
|
Etiology |
- Autoimmune reaction to antigens shared by the thyroid gland and CNS - Autoimmune vasculitis - Toxic effects of thyrotropin releasing hormone - Antithyroid antibodies may indicate genuine etiopathogenic variables that cause such encephalopathies by functional or cytotoxic effects, or they may simply be an autoimmune epiphenomenon in the context of encephalopathic processes of various etiologies. |
|
Symptoms |
- Most frequent symptoms –
- Other symptoms –
|
|
Diagnosis |
-Antibodies- anti TPO antibody, anti TG antibody, anti alpha enolase antibody -CSF findings –
-Neuroimaging –
-EEG- Bitemporal abnormalities continuing to bilateral loss of alpha and theta discharges. - Neuropathology-
|
|
Treatment |
- 1st line therapy – IV corticosteroids - Steroid unresponsive cases- Immunosuppressive medications like methotrexate, cyclophosphamide, azathioprine, rituximab and natalizumab can be used. - If both corticosteroids and immunosuppressants can’t be used- plasma exchange and IVIG can be used. - Levetiracetam- used in case of seizure episodes. |
|
Prognosis |
- Majority show full remission and good response to steroid therapy. - Some show remission even without steroid therapy. - 12% patients relapse, 12% patients don’t show improvement and 60% patients show relapsing-remitting course. |
|
Research |
Ongoing to better understand the pathogenesis and improve treatments. |
Author Contributions
Both authors were involved in research, writing, and final collation of the manuscript. Both of them have read and approved the final version of the manuscript.
Financial Statement
There are no financial disclosures regarding this review paper.
Disclosures
Both authors confirm that there are no relevant disclosures or conflicts of interest.
Ethical Statement
Both authors confirm that the information contained in this manuscript has been obtained ethically and is consistent with correct and ethical standards of research and scientific publishing.
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