ADVERTISEMENT
Steroid-Responsive Encephalopathy with Associated Thyroiditis (SREAT) in a Patient Misdiagnosed with Alzheimer’s Disease
Steroid-responsive encephalopathy with associated thyroiditis (SREAT), also known as Hashimoto’s encephalopathy, is an autoimmune disorder characterized by cognitive dysfunction, high titers of thyroid auto-antibodies, and prompt response to corticosteroids, in the absence of any other identifiable cause of encephalopathy. Though rare, SREAT can present with sub-acute cognitive decline that mimics the progression of dementia in the elderly. The authors present the case of a 71-year-old male with a 1-year history of progressive cognitive dysfunction that was initially believed to be due to Alzheimer’s disease. It was subsequently determined that the patient had SREAT. The literature on the pathogenesis, epidemiology, clinical presentation, treatment, and prognosis of the disease is also presented.
Key words: dementia, autoimmune disease, hypothyroidism, Hashimoto’s encephalopathy
Steroid-responsive encephalopathy with associated thyroiditis (SREAT), also referred to as Hashimoto’s encephalopathy, is an autoimmune condition characterized by encephalopathy, cognitive dysfunction, elevated thyroglobulin and/or thyroperoxidase antibodies, and therapeutic response to corticosteroids, in the absence of any other identifiable cause of encephalopathy, such as infection or structural brain disease.1 SREAT is a poorly understood disease. Although SREAT was first described in 1966 as a syndrome of severe hypothyroidism coincident with encephalopathy, it is now recognized that only 20% of patients with SREAT have overt thyroid disease, despite having high titers of thyroid autoantibodies.2
Overall, SREAT is rare; its prevalence is estimated to be less than 2 per 100,000 individuals.3 Because of its variable clinical presentation, and because diagnosis requires the measurement of antibody titers that are not routinely ordered, it is likely that the prevalence is actually much higher.1 To date, more than 250 cases of SREAT have been reported in patients whose ages vary considerably and include those in the geriatric age group.1 However, many of these cases likely include T3 toxicosis, or hypothyroidism in the sub-acute and chronic phases. Multiple case series also suggest that females are disproportionately affected, an observation in line with its classification as an autoimmune disorder.1,2
SREAT appears to present into distinct subtypes: (1) an episodic, stroke-like, vasculitic condition with a relapsing-remitting course, and (2) a progressive cognitive decline resembling rapidly progressive dementia.4 Our patient presented with the latter subtype, but, according to family, may have had elements of the former as well. Central to the clinical presentation is altered mental status, but the severity may range from a slowly progressive decline to fulminant encephalopathy. In 66% of patients, this is accompanied by seizures, which may be partial or generalized and rarely may result in status epilepticus. Myoclonus, ataxia, hallucinations, paranoid delusions, depression, and mania as well as visual, motor, and sensory deficits have also been described.2,5
Because SREAT may be characterized in older adults by symptoms similar to those of Alzheimer’s disease and other dementias or epilepsy, and because it is such a rare disease, it is likely to be missed by clinicians who encounter it. We present the case of a 71-year-old man with progressively worsening mental status associated with visual hallucinations and hypersomnia who was ultimately diagnosed with SREAT. We further highlight features that should raise clinical suspicion for SREAT and review the literature on this important but likely under-recognized condition.
Case Presentation
A 71-year old man with coronary artery disease presented after a 6-month history of worsening confusion associated with hypersomnia, difficulty speaking, and decreased short-term recall, diagnosed by his primary care provider as Alzheimer’s disease. Over the past week, he had become progressively more agitated and began to have visual hallucinations, leading his wife to seek medical assistance. One year prior, he had been a highly functioning English high school teacher without any apparent cognitive dysfunction. His family reported that the patient did not recently experience any fevers or chills but that he did have night sweats. They also reported that he exhibited weight loss of approximately 30 lbs over a 2-month period. Additionally, he apparently had two similar episodes of altered mental status over the past decade, both of which resolved within 2 weeks and were not investigated further.
On presentation, vital signs were within normal limits (temperature, 99.1 °C; heart rate, 97 beats per minute; respiratory rate, 18 breaths per minute; blood pressure, 114/72; oxygen saturation, 94% on room air). The patient appeared cachectic with prominent temporal wasting. He was somnolent, and replied only with indistinct mumbling. Pupils were equal, round, and reactive to light bilaterally. Patellar and bicipital deep tendon reflexes were 2+ bilaterally with sustained ankle clonus. The rest of the physical examination was unremarkable.
Complete metabolic panel was ordered, demonstrating mildly elevated aspartate aminotransferase levels (88 U/L; normal range, 17–59 U/L) and alkaline phosphatase levels (189 U/L; normal range, 38–126 U/L) but normal alanine transaminase levels (45 U/L; normal range, 21–72 U/L). Erythrocyte sedimentation rate and C-reactive protein levels were both elevated, at 55 mL per hour and 219 mg/dL, respectively. Free thyroxine and thyroid-stimulating hormone were normal. Other analyses (diagnostic panel for human immunodeficiency virus, herpes simplex virus and rapid plasma reagin; cerebrospinal fluid protein and glucose levels; urinalysis; and thiamine, cobalamin, and folate levels) were unrevealing. EEG revealed nonspecific slow, continuous triphasic wave activity without epileptiform discharges, and MRI revealed mild global atrophy with microangiopathic changes.
Given the sub-acute course, absence of any apparent infectious source, and inflammatory nature of the encephalopathy, autoantibody titers were measured. Titers revealed elevated perinuclear anti-neutrophil cytoplasmic antibodies (1:160; normal levels, <1:20) and myeloperoxidase concentration 25.3 U/mL (normal, 0.0–9.0 U/mL) and were positive for rheumatoid factor (>320 IU/mL). In the absence of infection, malignancy, or structural brain disease, the patient was tentatively diagnosed with autoimmune nonvasculitic encephalopathy, and empiric intravenous methylprednisolone was started. Within 4 hours, the patient became more alert, was conversant, and was oriented to time, location, and situation.
Blood samples were sent for evaluation of thyroperoxidase antibody (anti-TG) and thyroglobulin antibody (anti-TPO), both of which were found to be highly elevated (673.1 IU/mL and 74.5 IU/mL, respectively; normal concentration for both, <5 IU/mL), consistent with SREAT. The patient was discharged alert, oriented, and attentive, on a 2-month prednisone taper. One year after discharge, he has had no further episodes of altered mental status.
Discussion
Due to its rarity, very little is known about the pathophysiology of SREAT. Despite being initially described as Hashimoto’s encephalopathy, it is unclear whether anti-TG and anti-TPO are directly involved in its pathogenesis. Some experimental evidence does suggest that antithyroid antibodies may bind to cerebellar astrocytes and mediate CNS function, and that, in particular, anti-TG localizes to vascular smooth muscles in the brain.6,7 However, the clinical significance of these findings remains contested. Conversely, multiple lines of evidence suggest that the elaboration of anti-TG and anti-TPO are epiphenomena of a larger immunologic disturbance and that these antibodies do not directly contribute to the pathogenesis of the disease. Indeed, while thyroid antibody titers are almost always elevated in SREAT, these levels do not appear to be correlated to the severity of disease.2
Similarly, the presence of thyroid antibodies in serum is poorly predictive of the disease, as over 11% of the general American population has elevated titers, particularly middle-aged American females.8 Additionally, thyroid antibodies are not the only antibodies found in SREAT: as in this case, patients frequently test positive for other autoantibodies, suggesting the polyclonal activation of B-cells, and possible elaboration of an as-of-yet unknown autoantibody that results in neurologic damage. Although this antibody has not been definitively identified, attention has focused on antibodies against alpha-enolase, an enzyme expressed on the surface of neurons.9
There are no established guidelines on the diagnostic evaluation of SREAT. However, since the diagnosis of SREAT demands exclusion of any alternative cause of encephalopathy, physicians ought to be methodical in their approach. As with any other case, a thorough history and physical examination should be performed in order to determine the extent, chronicity, and course of disease, including any antecedent episodes. Other causes of apparent rapidly progressive dementia—including depression, HIV, syphilis, CNS vasculitis, and Creutzfeld-Jacob Disease—should be thoroughly excluded through laboratory, radiographic, and electroencephalographic testing.1,5,10
In this case, there were some features that helped to clarify the diagnosis relatively early in the presentation. The patient’s sub-acute deterioration, cachectic condition, and elevated levels of inflammatory markers in the absence of any obvious infectious source suggested an autoimmune etiology, which prompted the ordering of serologies and the institution of an empiric trial of corticosteroids. The lack of any focal MRI findings or EEG findings reduced the likelihood of Creutzfeld-Jakob disease, primary CNS vasculitis, and paraneoplastic limbic encephalitis, other diseases whose clinical courses often mimic SREAT.1 And because the patient responded so dramatically to methylprednisolone, and because he had high titers of rheumatoid factor, perinuclear anti-neutrophil cytoplasmic antibodies, and myeloperoxidase in the absence of clinically evident vasculitis, an autoimmune nonvasculitic process seemed likely. At this point, anti-TPO and anti-TG were drawn, which were elevated, thus confirming the diagnosis of SREAT.
As the nomenclature of SREAT suggests, steroids are the mainstay of treatment. Intravenous methylprednisolone and prednisone are considered first line agents in the acute management of the disease, often in conjunction with levothyroxine. Ninety-eight percent of patients with SREAT respond promptly to corticosteroids, often over the course of hours or days, with full recovery in 4–6 weeks.2 Following this initial clinical improvement, a slow prednisone taper is often administered. While many patients do not require further treatment, others may require more prolonged courses of immunosuppression, such as with azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil. In the minority of cases in which steroids are not effective, intravenous immunoglobulin administration and plasmapharesis have been attempted, but the results have been mixed. Individual case reports also describe levothyroxine and neuroleptics as adjunct therapy.1
SREAT bears a favorable prognosis, with many patients returning to their baseline or close to their baseline within weeks. In a case review by Kothbauer-Margreiter and associates, 40% had no further relapses, while the remaining required additional short courses of immunosuppression.4
Conclusion
SREAT is a rare but likely under-recognized and under-diagnosed autoimmune condition that presents with cognitive dysfunction, often with prominent neuropsychiatric manifestations suggesting rapidly progressive dementia. Because most cases respond to immunosuppression, physicians should maintain a high index of clinical suspicion, especially for cases in which the cause of encephalopathy remains unknown despite exhaustive evaluation. At the same time, because measurements of antibody titers are expensive and widespread screening will likely lead to false positive results, physicians should be judicious in their decision to pursue testing. In highly suspicious cases, a closely monitored empiric trial of methylprednisolone may be considered while awaiting results of thyroperoxidase and thyroglobulin antibody tests. When diagnosed early, the prognosis of SREAT is excellent, further underscoring the need for clinicians to recognize this condition.
1. Lee SW, Donlon S, Caplan JP. Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) or Hashimoto’s encephalopathy: a case and review. Psychosomatics. 2011;52(2):99–108.
2. Chong JY, Rowland LP, Utiger RD. Hashimoto encephalopathy: syndrome or myth? Arch Neurol. 2003;60(2):164–171.
3. Ferracci F, Moretto G, Candeago RM, Cimini N, Conte F, Gentile M, Papa N, Carnevale A. Antithyroid antibodies in the CSF: their role in the pathogenesis of Hashimoto’s encephalopathy. Neurology. 2003;60(4):712–714.
4. Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW. Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment. J Neurol. 1996;243(8):585–593.
5. Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. 2006;63(2):197–202.
6. 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.
7. Moodley K, Botha J, Raidoo DM, Naidoo S. Immuno-localisation of anti-thyroid antibodies in adult human cerebral cortex. J Neurol Sci. 2011;302(1-2):114–117.
8. 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):489-499.
9. Ochi H, Horiuchi I, Araki N, et al. Proteomic analysis of human brain identifies alpha-enolase as a novel autoantigen in Hashimoto’s encephalopathy. FEBS Lett. 2002;528(1-3):197–202.
10. Castillo P, Boeve B, Schäuble B, et al. Steroid-responsive encephalopathy associated with thyroid autoimmunity: Clinical and laboratory findings [Abstract]. Neurology. 2002;58(Suppl 3):A248.
