Is Hashimotos rare?

Hashimoto’s Encephalopathy Presenting with Unusual Behavioural Disturbances in an Adolescent Girl

Hashimoto’s encephalopathy (HE) is a rare autoimmune disorder with neurological and neuropsychiatric manifestations and elevated titres of anti-thyroid antibodies. Here we are reporting a case of HE in a 19-year-old girl who presented with seizure-like episodes, confusion, and behavioural disturbances with catatonic symptoms such as posturing, echopraxia, echolalia, and ambivalence. Patient did not respond to antipsychotics and anticonvulsants. On further investigation, patient was found to have high serum anti-TPO antibodies of about 1261 U/mL with euthyroid status, which supported a suspicion of HE. Our consultant neurologist confirmed the diagnosis and she was started on injection of methylprednisolone 750 mg OD. Since patient started showing clinical improvement, her antipsychotic medications were tapered off. On follow-up, patient has recovered and is functioning well. Since HE is a diagnosis of exclusion, very high anti-TPO antibodies and good response to steroids supported the diagnosis of HE in this patient after excluding other etiological possibilities. This case has been reported because the clinical presentation was predominantly neurobehavioural manifestations which is uncommon with HE.

1. Introduction

Hashimoto’s encephalopathy (HE) is a rare neuroendocrine disorder that may be often misdiagnosed and mistreated for a considerable time. The common neurobehavioural manifestations include seizure-like episodes which are often resistant to anticonvulsive treatment, myoclonus, confusion, headaches, hallucinations, stroke-like episodes, coma, impairment of cognitive function, mood swings, focal neurological deficits, disturbance of consciousness, presenile dementia, psychosis, and ataxia [1, 2]. However, such manifestations are not common clinical presentation of HE.

HE is more common in women than in men and occurs in all age groups. The estimated prevalence of HE was 2.1/100,000 [3]. An Asian study summarized the findings of 105 cases of HE and reported that, in most cases, the diagnosis was based on altered consciousness, negative finding for infective aetiology in cerebrospinal fluid (CSF), and high level of thyroid antibodies, with the latter found in 100% of the cases. Moreover, a high protein level in the CSF appeared in 78% of cases and abnormal electroencephalography (EEG) in 98% of cases [4]. In another review, the magnetic resonance imaging (MRI) of brain revealed ischemic areas, multiple tumours, granulomas, or various degenerative processes in 60% of the cases and single-photon emission computed tomography (SPECT) examination showed decreased perfusion in the cortical areas or basal ganglia [5].

2. Case Report

A 19-year-old girl presented with complaints of three episodes which mimic seizures during sleep over the past 3 months, first episode was characterized by loss of consciousness, tonic-clonic movements of both upper and lower limb, upward rolling of eyeballs, and tongue bite with postictal confusion lasting for 10 minutes, and the subsequent episodes were characterized by tonic-clonic movements of both upper and lower limbs and chanting “om namashivaya,” followed by unresponsiveness lasting for 10 to 15 minutes. Patient would sleep after these episodes and did not have any memories of those episodes. Then, one morning while sleeping she developed myoclonic jerks and screamed out of her bed with acute confusion, psychomotor agitation, and irrelevant talk which lasted for three days and was then brought to psychiatry OPD. There was no history suggestive of fever, headache, vomiting, and focal neurological deficits during this period. Physical examination was unremarkable. On examination, patient was restless, disoriented, producing abnormal clicking sound, and not obeying verbal commands. Patient was admitted to psychiatric ward for diagnostic clarification and further management. Patient was started on oral benzodiazepines and her behaviour was closely monitored. Her sleep and communication remained poor and she required assistance for maintaining her personal hygiene. Routine lab examinations were within normal limits. Her EEG recording showed normal study, and ultrasound abdomen and MRI brain plain and contrast were reported to be normal. Over the next couple of days, she was noticed to be pacing around aimlessly and started exhibiting abnormal behaviours such as dancing and crawling like snake. These behaviours varied over the days and she developed posturing, echopraxia, echolalia, and ambivalence subsequently. For these symptoms patient was started on injectable lorazepam 6 mg per day in three divided doses. Since patient’s status remained the same after few days, she was started with oral olanzapine 5 mg/day which was gradually increased to 15 mg/day. Meanwhile, patient was evaluated for the possibility of infective etiology, which was ruled out by neurophysician. The CSF analysis showed normal cell count, protein, and glucose levels. Thereafter patient was evaluated for autoimmune encephalopathies. On investigation, patient had high serum anti-TPO antibodies of 1261.4 U/mL (normal < 60) with euthyroid status and negative for other autoimmune encephalopathies including antibodies for voltage gated potassium channel, which supported a suspicion of Hashimoto’s encephalopathy. Therefore, again neurophysician consultation was sought and started on methyl prednisolone 750 mg/day intravenously for 5 days, followed by oral prednisolone 45 mg/day. Thereafter, patient started showing significant improvement clinically. Corticosteroids were gradually tapered over a period of 4 months and her antipsychotic medications were tapered off. On follow-up, patient recovered symptomatically and started functioning well.

3. Discussion

In this case, patient was reported with acute onset of neurobehavioural symptoms. All possible infective aetiologies were ruled out by neuroimaging and CSF Analysis and with appropriate serological investigations. Therefore, patient was symptomatically managed with psychotropic medications, which did not produce any significant improvement in her clinical status and was further complicated by the development of catatonic symptoms. Patient was further investigated for other possible etiologies such as autoimmune encephalopathies, of which anti-TPO antibodies were found to be elevated in spite of euthyroid status. Several case reports and research evidence suggest that the presence of elevated serum levels of antithyroid antibodies remains an essential characteristic of HE diagnosis, despite normal thyroid hormone levels [6, 7]. However, the titre of anti-thyroid antibodies does not correlate with severity or improvement [8]. The mechanism of HE does not appear to be related to the thyroid status, which can vary greatly in patients with HE. Several studies in the past reported varying thyroid status in HE patients, about 23% to 35% of patients had subclinical hypothyroidism, 17 to 20% had hypothyroidism, 7% had hyperthyroidism, and 18% to 45% of patients were euthyroid [4, 7]. The closely related autoimmune disorder, limbic encephalitis, was ruled out with negative voltage gated potassium channel antibodies. However, another close differential diagnosis, which shows similar manifestations as HE, is anti-NMDAR encephalitis. In our opinion, patient with anti-NMDAR encephalitis might represent more protracted courses and poor outcomes. HE, in general, responds successfully to corticosteroid treatment, whereas about 50% of patients with anti-NMDAR encephalitis do not improve with first-line treatment such as corticosteroid, IVIG, and plasma exchange; thus, they should continue to have second-line immunotherapy using rituximab, cyclophosphamide, or both [9, 10]. Majority of patients with anti-NMDAR encephalitis have underlying neoplasms such as ovarian teratoma. Though few patients do not have an underlying neoplasm, in all those patients with neoplasm, removal of the underlying cancers with initiation of first-line therapy is the most important step in accelerating improvement and decreasing relapse [9]. Nevertheless, all patients should undergo extensive tumour screening, at presentation and at yearly intervals. Our patient underwent routine imaging examinations and found no tumours. Another unique finding indicating anti-NMDAR encephalitis is EEG record showing extreme delta brush (slow waves with overriding fast beta activity) in 30% of patients [11] which was in contrast to the normal EEG recording in our patient. Furthermore, we excluded anti-NMDAR encephalitis based on the clinical grounds. However, we were not able to correlate with laboratory findings due to logistic reasons which would have been more appropriate. Our case report demonstrates that high index of suspicion over HE is needed in the evaluation of patients with acute onset neurobehavioural clinical presentations.

4. Conclusion

Hashimoto’s encephalopathy is a rare but very serious illness. The incidence is probably underestimated because of low overall awareness about the disease. HE may be found in cases of unexplained encephalopathy as well as in patients presenting with acute onset neurobehavioural manifestations, particularly together with the presence of high thyroid antibody levels, especially against thyroperoxidase. Likewise, even though steroid-resistant HE has been reported, other cause of encephalopathy should be considered when the response to steroid is not complete in cases with possible HE, especially in cases with any concomitant thyroid related diseases. Because of the autoimmune origin of the disease, corticosteroid treatment is usually proven to be effective. Therefore, HE needs to be added to the long list of differential diagnosis in cases presenting with atypical psychiatric presentation.

Additional Points

Limitation of the Study. However, the major limitation of our case report is the lack of full antibody testing for NMDAR, LGi1, CASPR2, and other antibodies associated with autoimmune forms of encephalitis. Since HE is more of a diagnosis of exclusion, doctors should have a clinical suspicion and good knowledge of all other autoimmune encephalopathies and exclude them with appropriate serum markers before making a diagnosis of HE.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

References

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Copyright

Copyright © 2017 Murugan Selvaraj Karthik et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hashimoto’s encephalopathy presenting with neurocognitive symptoms: a case report

Hashimoto’s encephalopathy is a neurological disorder of unknown cause associated with thyroid autoimmunity. The disease occurs primarily in the fifth decade of life and may present in two types — a sudden vasculitic type or a progressive subacute type associated to cognitive dysfunction, confusion and memory loss.

Case presentation

We report the case of a 62-year-old Hispanic woman, previously healthy, who developed a subacute onset of declining upper brain function. Serologic studies demonstrated high levels of antithyroid antibodies. Electroencephalographic and magnetic resonance image findings were consistent with Hashimoto’s encephalopathy.

Conclusion

Hashimoto’s encephalopathy is a diagnosis of exclusion. This unusual disorder is often under-recognized because of the multiple and protracted neurocognitive manifestations; therefore, it is important to be aware of the clinical manifestations to make a correct diagnosis.

Introduction

Hashimoto’s encephalopathy (HE) is an uncommon neurologic syndrome associated with Hashimoto’s thyroiditis. It was initially described in 1966 [1], and it remains a controversial disorder. The cause of HE has been proposed to be autoimmune because of its association with other immunologic disorders (myasthenia gravis, glomerulonephritis, primary biliary cirrhosis, pernicious anemia and rheumatoid arthritis), female predominance, inflammatory findings in cerebrospinal fluid (CSF) and response to treatment with steroids [1, 2]. Other authors suggest that HE may represent an autoimmune cerebral vasculitis resulting from either endothelial inflammation or immune complex deposition [1–3].

Clinical findings are variable and nonspecific. In this case report, we present the case of a patient with subacute onset of declining upper brain functions associated with Hashimoto’s thyroiditis.

Case presentation

Over a five-month period, a 62-year-old Hispanic woman who was previously healthy developed tremor in the right arm, enuresis, slowness in performing her daily activities, walking difficulties and trouble with getting dressed. Additionally, her relatives observed transient episodes of disorientation and inappropriate irritability.

Initially, the patient was admitted to another hospital, where she was found to have apraxia, dysphasia, attention deficit and amnesic episodes. She had no sensory or motor deficits.

Laboratory studies at that time revealed the presence of antithyroid antibodies as well as slightly high serum thyrotropin (TSH) concentration (Table 1). Examination of the CSF was normal. Magnetic resonance images (MRI) showed nodular focal subcortical lesions suggestive of demyelination (Figure 1). A diagnosis of encephalitis and hypothyroidism was made, and the patient received levothyroxine.

Fifteen days later, the patient had two episodes of inappropriate behavior and transient anterograde amnesia. With these symptoms, she was admitted to our hospital.

The laboratory examination showed no significant change compared with the patient’s previous laboratory results except normalization of hemogram values. Additionally, antinuclear antibody titer, anti-double-stranded DNA, anti-hepatitis B core antigen, hepatitis B surface antigen, anti-hepatitis C virus, lupic anticoagulant and Venereal Disease Research Laboratory test results were negative. Also, the anticardiolipin antibody IgG level was 10.8 U/GPL (reference range,

Considering the clinical and laboratory findings, a diagnosis of encephalopathy of undetermined origin was made. The electroencephalogram (EEG) showed a slow background activity with theta waves and paroxysmal activity at the hyperventilation maneuver (Figure 2). The thyroid biopsy showed lymphocytic chronic thyroiditis, and a diagnosis of HE was considered.

At discharge, the patient was treated with prednisone at doses of 1 mg/kg body weight. Thirty days later, she was experiencing a mild improvement in her symptoms. However, she never returned for her scheduled follow-up medical appointments.

Discussion

HE is an unusual neurologic disorder whose etiology, pathogenesis and histologic characteristics are unclear. A systematic review published in 2003 [1] reported only 85 well-documented cases in the literature; however, this syndrome may be underrecognized. A hospital-based epidemiologic study of neurologic symptoms consistent with HE estimated its prevalence to be about 2.1 per 100,000 [4]. The disorder occurs more frequently between age 44 to 46 years, with a female-to-male ratio of four to one [1, 5].

The clinical manifestations usually include acute to subacute onset of confusion with alteration of consciousness. Two major patterns of presentation were described: (1) 25% of patients follow a stroke-like pattern of multiple recurrent episodes of focal neurologic deficits with a variable degree of cognitive dysfunction and consciousness impairment [1, 2], and (2) the remaining 75% present with a diffuse progressive pattern of slow cognitive decline with dementia, confusion and hallucinations [1, 2]. These two clinical patterns may overlap over the course of the disease. In this case report, our patient’s clinical manifestations are more consistent with the second form of presentation, which is more common.

Two-thirds of patients may experience focal or generalized tonic-clonic seizures, and 12% may present with status epilepticus. Also, myoclonus or tremor is seen in up to 38% of patients; hyperreflexia and other pyramidal tract signs in 85% of patients; and psychosis, visual hallucinations and paranoid delusions have been reported in 25% to 36% of patients [1, 2, 5].

The mechanism of HE does not appear to be related to the thyroid status, which can vary greatly in patients with HE. In two recent reviews, 23% to 35% of patients had subclinical hypothyroidism, 17% to 20% had hypothyroidism, 7% had hyperthyroidism and 18% to 45% were euthyroid [1, 5]. The development of neurologic symptoms may occur up to three years before the onset of autoimmune thyroiditis [6].

The presence of elevated serums levels of antithyroid antibodies remains an essential characteristic of HE diagnosis, and suggest the presence of thyroid autoimmunity [1, 5]. Although in some cases, the diagnosis is supported by the association with Hashimoto’s thyroiditis, it is possible that some patients develop HE without a concomitant clinical thyroid disease because asymptomatic thyroid autoimmunity is frequent in these patients [1, 5].

The pathogenic role of thyroid antibodies remains unknown, there is no evidence that any antithyroid antibody reacts with brain tissue or affects nerve function, and there is no clear correlation between the severity of the neurologic symptoms and the concentration of these antibodies [1, 4].

Antithyroid antibodies have also been related to other autoimmune conditions such as myopathy, depression, bipolar disease and dementia, but the prevalence of these antibodies in the general population (ranging from 2%-20%) make it difficult to establish whether a real association exists [7].

Infrequently, the titers of antithyroid antibodies (TPOAb and TgAb) are measured in the CSF. In one case series, nine of 12 patients with encephalopathy and elevated serum antithyroid antibodies had elevated CSF autoantibody titers [4]. A systematic review found that 13% of published cases of HE reported antithyroid antibodies in the CSF [5]. However, the titers of antithyroid antibodies in the CSF do not correlate with the clinical stage of the disease, and the sensitivity and specificity of this finding remain unclear [4, 5].

An autoantibody against the amino terminal end of the enzyme α-enolase, an antigen of the thyroid and the brain, has been identified as a potential biomarker of HE [5, 8]. A study found serum autoantibody reactivity in five of six patients with HE compared with two of 17 patients with Hashimoto’s thyroiditis but no HE and in none of 25 healthy control subjects [8]. This antigen is also found in endothelial cells, suggesting an autoimmune vasculitic mechanism; however, this has not been confirmed by neuroimaging techniques [5].

In some patients, C-reactive protein and the erythrocyte sedimentation rate are elevated [9], and in one series, mild elevation of liver enzymes was found in 12 of 20 patients [9)], which is concordant with the mild elevation observed in our patient.

Although the CSF analysis results were normal in our patient, a lymphocytic pleocytosis has been found in 14% of reported patients; in 4% of patients, it may contain more than 100 cells/mm 3 . An elevated protein concentration occurs in 78% of patients, and in 20% of patients, it may be greater than 100 mg/dL. The blood glucose concentration is usually normal [1, 2].

Nonspecific EEG abnormalities are seen in 90% to 98% of patients, which is usually a nonspecific slow background activity. The same pattern was observed in our patient. Focal spikes or sharp waves and transient epileptic activity are less common [2, 10].

In a review of 82 patients with HE, brain computed tomography or MRI showed abnormalities in 49% such as cerebral atrophy, focal cortical abnormality, diffuse subcortical abnormality and nonspecific subcortical focal white matter abnormality. The latter was observed in our patient as subcortical foci of demyelination [1].

The differential diagnosis of HE must consider any condition associated with delirium, rapidly progressive dementia, seizures or focal neurologic deficits [5]. Thus, the list of diseases that can be confused with HE is vast, including stroke or transient ischemic attack, cerebral vasculitis, carcinomatous meningitis, toxic metabolic encephalopathies, paraneoplastic syndromes, Creutzfeldt-Jakob disease, degenerative dementia and psychiatric diseases [1, 5].

The long-term prognosis is variable, although a high percentage of patients respond to treatment; others could have a progressive or a relapsing course [1, 5]. The symptoms usually improve with glucocorticoid therapy; however, it is not necessary because of treatment. A systematic review of 85 cases published of HE found clinical response in 98% of patients treated with glucocorticoids, 92% of patients treated with glucocorticoids and levothyroxine and 67% of patients treated with levothyroxine only [1].

Although our patient had a mild improvement of her symptoms, the long-term effect of the therapy could not be assessed because the patient did not return for her follow-up medical appointments.

Conclusion

HE frequently presents with a myriad of neurocognitive symptoms and normal findings in several different examinations. This syndrome may go unrecognized for a long time; therefore, it should be kept in mind when evaluating a patient with cognitive dysfunction and high titers of antithyroid antibodies.

Consent

Written consent was obtained from the patient for publication of the case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of the journal.

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Author information

Authors and Affiliations

1. Department of Medicine, Arzobispo Loayza Hospital, Lima, Peru Carlos Canelo-Aybar, David Loja-Oropeza, Jose Cuadra-Urteaga & Franco Romani-Romani

1. Carlos Canelo-Aybar