Curr Neurol Neurosci Rep (2014) 14:476 DOI 10.1007/s11910-014-0476-2

BEHAVIOR (H KIRSHNER, SECTION EDITOR)

Hashimoto’s Encephalopathy: A Brief Review Howard S. Kirshner

# Springer Science+Business Media New York 2014

Abstract Hashimoto’s encephalopathy (HE) is a syndrome of altered mental status, hallucinations, delusional thinking, and often, epileptic seizures. It is diagnosed by the clinical syndrome, the presence of elevated titers of antithyroid antibodies, the lack of another diagnosis based on clinical evaluation, and the response to corticosteroid and other immunosuppressant treatment. This review discusses the symptoms, pathophysiology, and treatment of HE. The disorder is important to recognize because aggressive treatment may bring about a favorable clinical outcome. The disorder has a relatively benign prognosis, compared with many of the entities for which it can be mistaken. Keywords Hashimoto’s . Encephalopathy . Dementia . Steroid responsive encephalopathy associated with antithyroid antibodies . Nonvasculitic autoimmune meningoencephalitis

Introduction Hashimoto’s encephalopathy (HE) is defined as a syndrome of altered mental status, with confusion, hallucinations, delusional thinking, and sometimes seizures, in the presence of elevated titers of antithyroid antibodies [1, 2]. It is a relatively recently recognized disorder; the syndrome was first described by Brain and colleagues in 1966 [3], in a case report of a 49year-old man who developed hallucinations, agitation, and tremor, in the setting of treated hypothyroidism. The syndrome remains relatively rare, with an estimated prevalence of 2/100,000 [4]. The importance of recognition of the This article is part of the Topical Collection on Behavior H. S. Kirshner (*) A-0118 Vanderbilt Medical Center North, Nashville, TN 37232, USA e-mail: [email protected]

syndrome is that it is treatable, with corticosteroids or other immunosuppressive agents, and many patients have recovered well after treatment. For this reason, HE should be considered in all patients presenting with encephalopathies. Since 1966, many cases of Hashimoto’s encephalopathy have been reported, with many, varied presentations. The syndrome can be chronic, as in dementia [5], or more acute, resembling a delirium or rapidly progressive dementia [6]. In the more acute form, there are often fulminant symptoms of confusion, hallucinations, epileptic seizures, tremor, myoclonus, and focal neurologic abnormalities such as ataxia. Seizures, even status epilepticus [7], myoclonus [8, 9], and tremor [9] have been described. Focal ataxia has been reported, in associated with mental status changes [10–12]. In terms of psychiatric manifestations, patients can be depressed [13, 14], or can have a hyperactive, manic state [15], or even an acute psychosis [14, 16, 17]. Two recently reported cases [18, 19] have had a selective deficit in short-term memory, without confusion or dementia, 1 purely verbal amnesia, associated with EEG slowing [19]. The patient improved to normal, and the EEG also normalized, following corticosteroid treatment. We recently reported 13 patients with Hashimoto’s encephalopathy, of whom the median age was 49 [20••]. The 2 most common clinical presentations were a subacute, progressive deterioration of cognitive function (62 %) and seizures (46 %), but most patients had both cognitive dysfunction and seizures. In terms of thyroid status, 3 patients were euthyroid, 2 had subclinical hypothyroidism, and the other 8 were hypothyroid. Three patients had other autoimmune disorders, 1 each with Sjogren’s syndrome, rheumatoid arthritis, and multiple sclerosis (MS). One patient also tested positive for anti-GAD antibodies, and 1 had antiphospholipid antibodies. Antithyroid antibodies were elevated in all 13 patients. Spinal fluid analysis was done on 10 patients; 4 (40 %) had elevated protein levels, 1 patient with multiple sclerosis had oligoclonal bands. EEG abnormalities were identified in 8 of 12 patients,

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but most of the findings reflected encephalopathy, only 3 with epileptiform activity. MRI of the brain in 12 patients was only nonspecifically abnormal; most had nonspecific white matter changes, with the 1 patient with MS showing abnormalities consistent with demyelinating plaques. In terms of treatment, all patients received high dose corticosteroids, 5 with intravenous methylprednisolone. In all 12 patients, the symptoms improved rapidly. One patient could not tolerate steroids but responded to intravenous immunoglobulin (IVIg). Most patients also received chemotherapy or immunosuppressive agents in addition, including IVIg, mycophenolate, azathioprine, and methotrexate, but the best response appeared to result from intravenous rituximab. Our case series supported the potentially benign course of the disease with appropriate treatment, and it also provided experience with newer immunosuppressive treatment regimens.

Differential Diagnosis of HE Hashimoto’s encephalopathy can mimic other diseases such as recurrent acute disseminated encephalomyelitis (ADEM), progressive ataxia, and Creutzfeldt–Jakob disease [4, 8, 11, 12, 20••]. HE can also be considered in the differential diagnosis of rapidly progressive dementias. Patterson, Takada, and Geschwind [21••] developed a mnemonic called “VITAMINS” to aid in the differential diagnosis of rapidly progressive dementias. This includes Vascular (multi-infarct dementia, strategic infarct dementia, inflammatory cerebral amyloid angiopathy, primary CNS angiitis, and cerebral venous sinus thrombosis); Infectious (neurosyphilis, Whipple’s disease, Lyme disease, HIV dementia, Herpes simplex encephalitis); toxic-metabolic (Wernicke’s encephalopathy, extrapontine myelinolysis, vitamin B12 deficiency, acquired hepatocerebral degeneration, acute intermittent porphyria); autoimmune (Hashimoto’s Encephalopathy, NMDA or n-methyl-d-aspartate-Receptor encephalopathy, encephalopathy with voltage-gated potassium channel antibodies, Limbic encephalitis, and acute demyelinating encephalomyelitis); metastasis/neoplasia (primary CNS lymphoma, gliomatosis cerebri); iatrogenic/inborn errors of metabolism (most commonly medication-related syndromes); neurodegenerative (Creutzfeldt-Jakob disease, Alzheimer’s disease, Lewy body dementia, behavior variant frontotemporal dementia, and corticobasal degeneration); and systemic/seizures (hypertensive encephalopathy, seizures, or nonconvulsive status epilepticus). In their series from UCSF, prion diseases were the most common, at 62 %, but this likely reflects their referral bias as a center for the study and treatment of prion diseases. Other causes included 15 % other neurodegenerative diseases, 8 % autoimmune disorders, 4 % infectious diseases, and 2 % each for psychiatric, toxic-metabolic, neoplastic, and vascular causes; 4 % were of undetermined etiology, often

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leukoencephalopathies. The authors emphasized that 17 % of the rapidly progressive dementia cases referred to their center had potentially treatable causes (50 % autoimmune, 13 % each infectious, psychiatric, and cancer, and 10 % toxic-metabolic). A dementia center in Greece [22] reported a somewhat different distribution of rapidly progressive dementing illnesses: the most common causes (27 %) were related to reversible causes, including toxic/metabolic, infectious, autoimmune, vasculitis, and hydrocephalus, followed by Alzheimer’s disease (18 %), frontotemporal dementia (16 %), Creutzfeldt-Jakob disease (CJD) (13 %), and various other neurodegenerative diseases (13 %). Despite its relatively uncommon occurrence, HE is important to recognize as a treatable cause of encephalopathy or rapidly progressive dementia, compared with the classic rapidly progressive dementia, Creutzfeldt-Jakob disease. Another autoimmune illness, which has received recent attention as a cause of acute confusion and seizures, is encephalitis or encephalopathy related to antibodies against the n-methyl-d-aspartate subtype of glutamate receptor, or “antiNMDAR encephalitis” [23]. This disorder was discovered only in 2007. Patients can present with psychotic symptoms, acute delirium, memory loss, language disorders, and seizures, and over time, the course can degenerate into a catatonic state or dementia. Like HE, the disorder can present in childhood or adulthood. It has an association with ovarian teratomas, but these are not found in many cases. The syndrome responds to immunosuppressive treatments such as corticosteroids, intravenous immunoglobulin, plasma exchange, rituximab, or chemotherapy agents such as cyclophosphamide [23]. The syndrome, like HE, is likely underrecognized. A gripping, self-told book about a young reporter who developed this syndrome was published by Susannah Cahalan [24].

Pathogenesis of HE A key component of the diagnosis of HE depends on the finding of elevated antithyroid antibodies, which can be either anti-thyroid peroxidase or antithyroglobulin in type. For this reason, an autoimmune basis has been assumed for HE, though the precise etiology remains unclear. It was originally postulated that antibodies against thyroid tissue might cross the blood brain barrier and cross-react with antigens in the brain and thereby produce an encephalopathy [25]. Antithyroid antibodies from patients with HE have been reported to bind to cerebellar astrocytes [26], and antithyroid antibodies have been found in cerebrospinal fluid taken from patients with HE [25]. Following immunosuppressive therapy, there was a reduction in antibody titers in parallel with clinical improvement, suggesting that the antibodies are a good marker for the disease process. This correlation between falling antibody titers and clinical response to treatment was also seen

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with antibodies in the blood in our series [20]. The direct antibody theory of the pathogenesis of HE, however, appears to be overly simplistic, for several reasons. Antithyroid antibodies can be found in other disorders, especially Graves’ disease, without symptoms of encephalopathy. In fact, antithyroid antibodies are commonly found in the general population, at a rate likely hundreds of times more commonly than in patients with HE, making it unlikely that the antibodies are the direct mediators of HE [27•, 28, 29]. Second, the serum concentration of anti-thyroid antibodies does not correlate well with the severity of HE [20••]. Third, many patients with autoimmune diseases such as SLE develop antibodies against antigens associated with other organs and tissues, apparently unrelated to the symptoms of the disease. Elevated antithyroid antibodies in patients with HE could simply represent a byproduct of a general autoimmune process. Given this uncertainty about the autoimmune basis of Hashimoto’s encephalopathy, it has been proposed to rename the syndrome “Steroid Responsive Encephalopathy Associated with Antithyroid Antibodies” (SREAT, [30]). Another proposal is the name “Nonvasculitic Autoimmune Meningoencephalitis” (NAIM, [31]). These alternative names for the condition, however, raise their own problems. Some cases of HE do not clearly respond to corticosteroid treatment, so calling them “SREAT” would be misleading. The term “NAIM” includes several other disorders, such as encephalopathy due to Sjogren’s syndrome or systemic lupus erythematosis. Hashimoto’s encephalopathy, though perhaps not an ideal term, preserves the central concepts of a syndrome of encephalopathy, seen in association with the presence of anti-thyroid antibodies. It remains the widely used term for this syndrome.

Treatment of HE High dose corticosteroids are the first line treatment for HE [2, 30]. However, steroids are usually tapered to avoid side effects. Once the corticosteroids are weaned, the patient may relapse, necessitating the use of other, steroid-sparing therapies to avoid long-term adverse effects [2, 32]. Several alternative treatments, including IVIg, methotrexate, mycophenolate, and azathioprine have been used in such situations with variable efficacies [2, 20••, 32]. Most recently, rituximab has appeared to be effective in the treatment of HE. In our recent review [20••], we reported the use of rituximab in 7 of 13 patients. There was complete or nearly complete resolution of symptoms in all 7 patients, including those who had experienced an incomplete response to other therapies. Rituximab is well tolerated and usually resulted in durable remissions, without need for long-term steroids. In addition, we used mycophenolate mofetil in 3 and azathioprine in 4 patients, with good responses. These agents appear to be effective

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alternatives to rituximab. On the other hand, maintenance IVIg did not produce long-term remissions in our patients.

Conclusions Hashimoto’s encephalopathy is an autoimmune encephalopathy associated with antithyroid antibodies, characterized by acute or chronic mental status changes, psychiatric symptoms, epileptic seizures, and sometimes other neurologic deficits, such as ataxia and myoclonus. HE resembles rapidly progressive dementias, such as Creutzfeldt Jakob disease, which have much worse prognosis. Its pathogenesis is presumably autoimmune, though the exact relationship between the disorder and the anti-thyroid antibodies remains uncertain. Treatment with immunosuppressive agents appears to improve symptoms, and many treated patients have a benign course. For this reason, recognition of the syndrome is clinically important.

Compliance with Ethics Guidelines Conflict of Interest Howard S. Kirshner declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Hashimoto's encephalopathy: a brief review.

Hashimoto's encephalopathy (HE) is a syndrome of altered mental status, hallucinations, delusional thinking, and often, epileptic seizures. It is diag...
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