Of the three cases cited above, two presented with rapidly progressive dementing syndromes with the possibility of an ongoing encephalopathy. The second patient had many features suggestive of a MSA-like syndrome with combined extrapyramidal, cerebellar and autonomic features. Onset of cognitive decline in this case had been a subtle but significant pointer towards consideration of an ongoing encephalopathic process. Such encephalopathic features led to appropriate investigations leading to the correct diagnosis. The typical features of HE (cognitive and psychiatric involvement, altered sensorium and seizures) were not present in the second patient [6•, 7••, 8]. However, HE encompasses a wide spectrum of neurological features. Cerebellar involvement [9, 10•] and extrapyramidal features [4, 11] in the form of tremors and myoclonus have been reported, as also autonomic features [12]. HE has been known to present with a pure, progressive, cerebellar syndrome with normal cognitive function and intellectual performance [13••]. Cognitive decline and psychosis/hallucinations would suggest a form of limbic encephalitis [14]. Stroke-like symptoms, myoclonus and tremors are also frequently seen, either alone or as part of a syndrome [15]. Sometimes, HE can present with an acute encephalopathy []. This diagnosis is usually considered in patients with the above neurological symptoms, accompanied by either a euthyroid state or mild hypothyroidism [16, 17] normal or non-specific MRI and CSF findings, increased serum levels of thyroid antibodies (anti-TPO and/or anti-TG) [18], a robust clinical response to steroids and exclusion of other possible causes. In the first two cases described herein, there had been rise in the anti-TPO antibody levels along with a rise in the anti-thyroglobulin levels in the second case. The third case, where presentation had been one of rapidly progressive dementia, had persistent high levels of anti-thyroglobulin antibodies but never any rise in the TPO antibodies. The exact cause for this discrepancy is not clear but the possibility of any correlation with clinical features needs to be looked into in large series of patients []. Also, this small case series highlights the need for checking both thyroglobulin and TPO antibodies for exclusion of HE in patients with suggestive clinical features.

HE was first described by Lord Brain and colleagues in 1966 in a case report of a 49-year-old man with Hashimoto’s disease and encephalopathy [19••]. The patient, previously diagnosed with Hashimoto thyroiditis, developed a neurologic illness consisting of altered mood and consciousness, along with stroke-like episodes causing transient aphasia, right or left hemiparesis, hemisensory symptoms, hemianopia and monocular blindness. These were followed by episodes of hallucinations, confusion, and involuntary movements (tremor and athetosis). CSF studies showed raised protein content with mild pleocytosis. Carotid angiography was normal, EEG showed generalized slowing. He was treated with prednisone and anticoagulant therapy with inconsistent response and ultimately resolved while taking only levothyroxine. Lord Brain et al. [••] summarized the case as one of a “stuttering brain disorder of an unusual kind with concurrent rise in the level of thyroid antibodies”, and concluded, showing remarkable foresight, “antibody studies in future cases of unexplained encephalopathy should show whether we have described a syndrome or a coincidence.”

Since 1966, many cases of HE have been reported with varied presentations —fulminant, acute, subacute or chronic patterns of altered mental status — occurring across all ages. The syndrome is relatively rare with an estimated prevalence of 2/100,000. Epidemiologically, HE is 4–5 times more common among females than males. The mean age at onset is 41–48 years [20, 21•]. However, it has been reported in pediatric populations as well [2, 22•]. Common clinical features include relapsing and remitting episodes of encephalopathy along with stroke-like symptoms, dementia, focal or generalized seizures, status epilepticus, myoclonus, tremor, and neuropsychiatric symptoms [23]. Two patterns of HE have been described, one showing predominantly stroke-like and focal symptoms, and another comprising progressive course of cognitive disorder with psychotic manifestations. Seizures, myoclonus, and tremor can occur in both types [24•]. Clinical features of HE are varied, but since the condition is treatable, the diagnosis has to be kept in mind in certain clinical situations.

Seizures are common occurring in about 2/3 of the patients. Diagnosis of HE should be considered in unexplained episodes of focal or generalized seizures, refractory to common antiepileptic drugs, with cognitive impairment and neuropsychiatric symptoms. New onset status epilepticus (SE), including epilepsia partialis continua (EPC), and non-convulsive SE (NCSE) have been reported [25••, 26,28,28]. A limbic encephalitis-like presentation with subacute onset memory deficits, decreased level of consciousness, seizures, and behavioral change can also occur [15]. Autoimmune encephalitis including Anti-IgLON5 disease [29••] needs to be excluded in such cases with appropriate tests for neuronal surface antibodies. Anti-IgLON5 disease is a complex neurological disease, the clinical features of which consist of a sleep disorder with non-rapid eye movement (REM) sleep parasomnia, REM behavior disorder, obstructive sleep apnea syndrome, stridor bulbar symptoms, gait abnormalities, extrapyramidal features, autonomic disturbances and cognitive dysfunction.

HE can cause progressive cognitive deterioration with dementia, neuropsychiatric symptoms, and impaired consciousness [30, 31]. This is seen more in older patients and HE should be considered in the differential diagnosis of rapidly progressive dementia, especially CJD. Even in patients with apparent degenerative dementias like Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, and cortico-basal degeneration, HE needs consideration if the course is too rapid or atypical.

Elevated thyroid antibodies, including anti-TPO (thyroid peroxidase) or antithyroglobulin are present in majority of cases, and are required for diagnosis. In a review of 105 patients with HE, anti-TPO antibodies were elevated in 100%, and antithyroglobulin antibodies in 48% [32•, 33•]. Thyroid-stimulating hormone antibodies may also be present. However, the titer of antibodies does not correlate with disease activity. Moreover, the presence of thyroid antibodies is not specific, as about 10% of general population has raised serum anti-TPO [34•, 35]. There are some reports of raised thyroid antibodies in the CSF, but the sensitivity and specificity are unclear. Antibodies against amino terminal domain of alpha enolase (NAE) have been proposed as a more reliable marker of HE [36•]. However, these antibodies have been described in a few reports, and have been found in a patient with CJD as well, casting doubt on its specificity [37].

Thyroid status varies from overt hypothyroidism to overt hyperthyroidism. But most patients with HE are either euthyroid or have subclinical hypothyroidism.

The majority of patients with HE have normal or non-specific MRI findings. Abnormal MRI findings include ischemic lesions, demyelination, edema, atrophy, and abnormal signals in the hippocampus or temporal lobe [38,40,41,42,42].

CSF studies show abnormalities, usually mild, in 80% of patients. Most common abnormality is raised protein content in around 75% of patients. Protein levels more than 100 mg/dl are uncommon, occurring in 20%. A mild lymphocytic pleocytosis is present in 10 to 25% [43].

Non-specific EEG abnormalities are observed in over 90% of patients, usually showing background slowing. Focal spikes or sharp waves, triphasic waves, and frontal intermittent rhythmic delta activity (FIRDA) have also been described. EEG may have some role in monitoring treatment response and there are reports of EEG abnormalities improving rapidly with steroid treatment [44•, 45]. The EEG also helps to exclude other conditions, such as CJD, in patients with rapidly progressive encephalopathy and myoclonus. Diagnostic criteria for HE are shown below in Table 1.

HE is treated with corticosteroids along with treatment of dysthyroid condition, if any. Since HE is rare, there are no guidelines regarding corticosteroid dose and/or duration. Oral prednisone 50–150 mg daily has been used. High dose intravenous methylprednisolone has been given in some patients. Most patients respond to steroid therapy with improvement occurring over weeks to months. Duration of therapy and tapering of steroids are adjusted according to the clinical response. Some patients require treatment to be continued for up to 2 years. Immunosuppressive medications, including azathioprine and cyclophosphamide, have been used in patients who do not tolerate corticosteroids, do not respond, or relapse during steroid tapering. There are some reports of good and prolonged response with rituximab. Intravenous immunoglobulin treatment produces significant improvement in both adults and children, but the efficacy of plasma exchange is doubtful, despite removal of antithyroid antibodies [48•, 49, 50, 51•].

The prognosis of HE is usually good. Patients can improve even if treatment is delayed for months or years after onset of symptoms. Residual cognitive improvement occurs in around 25% of patients with long-standing untreated disease. Patients usually remain disease-free after steroid tapering, but some relapse and require further courses of steroids and sometimes immunosuppressive therapy. There are some reports of spontaneous recovery as well [52, 53•].

The pathogenesis of HE is uncertain [1••]. Overt hypothyroidism can cause cerebral dysfunction, but there is no evidence that thyroid hormone dysregulation has any role in the pathogenesis of HE, as majority of the patients are euthyroid at presentation [54••]. The available evidences point towards an autoimmune etiology, causing encephalopathy due to vasculitis or other inflammatory process. As in most autoimmune conditions, the disease is more common in women. In more than 1/3 of patients, there is comorbidity with other systemic or organ-specific autoimmune diseases like SLE, Sjögren’s syndrome, pernicious anemia, sarcoidosis, and myasthenia gravis [5]. Most patients with HE respond to steroids or other immunosuppressive therapies. Elevated thyroid antibodies are consistent with an autoimmune process, though it is unlikely that these antibodies have a direct pathogenic role. The thyroid antibodies are diagnostic markers rather than etiologic agents. Pathologic examination at autopsy or brain biopsy in a few patients has shown lymphocytic infiltration around small arterioles or venules [24•]. Because of the uncertainty regarding its etiopathogenesis, HE has remained a controversial entity. A review by Chong et al. [53••] (2003) was titled “Hashimoto Encephalopathy – syndrome or myth?” The review concluded that “the combination of encephalopathy, high serum antithyroid antibody concentrations, and responsiveness to glucocorticoid therapy seems unlikely to be due to chance. However, there is no evidence of a pathogenic role for the antibodies, which are probably markers of some other autoimmune disorder affecting the brain.” Since there is no direct pathophysiologic link between antithyroid antibodies, Hashimoto thyroiditis and the cerebral syndrome, the nomenclature Hashimoto’s Encephalopathy could be misleading. The response to steroids led to a renaming to steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), though some cases do not respond to steroids including Lord Brain’s original patient. Another nomenclature is non-vasculitic autoimmune inflammatory meningoencephalitis (NAIM), but it probably does not reflect the neuropathology with accuracy [55•].

Most reports of HE appeared before the spectrum of autoimmune encephalitis was recognized and so tests for other autoantibodies were not done or done in a limited way. It is possible that some of the cases thus reported were actually autoimmune encephalitis patients, who are also responsive to steroids and immunosuppressive therapy, and the raised TPO antibody titer was just an incidental finding. In a recent review, Mattozzi et al. [14••] looked at 24 patients meeting the accepted diagnostic criteria for HE and lacking coexisting serum or CSF anti-glial or anti-neuronal antibodies. The patients had four clinical subtypes including rapidly progressive psychiatric syndrome in 29%, encephalopathy/cognitive impairment in 29%, new-onset refractory status epilepticus in 25%, and limbic encephalitis in 17%. There were no patients with stroke-like episodes. Surprisingly, only 32% responded to steroids. These patients were otherwise similar to those who did not respond, and it was not possible to distinguish them before treatment. TPO antibody levels were studied in two other groups, 74 with possible autoimmune encephalitis without neuronal antibodies, and 205 with different neuro-immunologic diseases. The frequency was around 8% in both groups, suggesting it is a non-specific finding, and of limited use in picking up possible HE cases in a group of patients with encephalopathy of unknown origin with negative neuronal antibodies.

Laboratory studies done so far have not yet confirmed any direct pathogenic effect of these antibodies (especially TPOAb) on the CNS. Autopsy and histopathological examinations have not shown the presence of antibodies in the structures of the nervous system, but only in the tissues of the thyroid gland [48•], even if these antibodies could be detected in high concentrations in the serum and sometimes in the CSF. Thyroid gland fibrosis evidenced by ultrasonography is more common in patients with anti-TPO antibody than with the anti-TG antibody [•]. This prompted some workers to question the value of anti-TG antibodies in the diagnosis of HE. Furthermore, no significant decrease in the levels of such antibodies could be detected in some patients after treatment with corticosteroids [56]. This is in contrast to our observations in two of the cases cited above.

Is it a relatively benign variety of immune-mediated encephalopathy of unknown pathogenesis? Does testing for TPO antibody have any value? Till we have answers to the above questions, it seems reasonable to continue testing for TPO and TG antibodies and consider a diagnosis of HE in the clinical situations discussed — patients presenting with SE, NCSE, neuropsychiatric problems with altered consciousness and fluctuating course, and rapidly progressive dementia, with inconclusive brain imaging, CSF, blood biochemistry, and infective profile. Such patients are now routinely worked up for autoimmune encephalitis with antibody panel in blood and CSF, and treated appropriately if positive, and sometimes even if the results are negative if the clinical suspicion is high. Just as the antibody panel tests are expensive, so are the treatments, usually consisting of IVIG along with steroids. Considering the diagnosis of HE in patients with suggestive clinical presentations along with raised TPO and or TG antibodies, may suggest an inexpensive line of treatment with oral steroids, and at least some patients will benefit. This is particularly important in resource-poor settings.

Currently, an aggressive form of Hashimoto’s thyroiditis accompanied by elevated serum IgG4 levels has been described. Features include a higher incidence in men (5:1) than in women, onset at a younger age, more intense thyroid inflammation and higher antithyroid antibody titers [57••, 58••]. Such subjects have excessive production of IgG4 + plasmocytes, which infiltrate various organs leading to fibrosis and sclerosis, and even inflammatory tumors [60]. Such cases are now classified with the IgG4-related disorders. Other members of the family include autoimmune pancreatitis, sclerosing cholangitis, interstitial nephritis, Sjögren syndrome, Reidel’s goiter and hypertrophic pachymeningitis. In relation to HE, it is possible that the IgG4 fraction may be responsible for the CNS involvement causing encephalopathy [59,60,61].