Clinical Endocrinology (2014) 81, 936–942
LETTERS TO THE EDITOR
Autoimmune encephalopathy in the context of Graves’ disease with ophthalmopathy Dear Editor, More than 40 years after its initial description by Brain et al.,1 ‘Hashimoto’s encephalopathy’ (HE) remains an enigmatic clinical entity. Although no universally accepted definition exists, commonly employed diagnostic criteria include an acute or subacute presentation with neuropsychiatric symptoms consistent with encephalopathy, presence of serum antithyroid antibodies and exclusion of alternative infective or metabolic causes.2The vast majority of HE cases described in the literature relate to patients demonstrating either hypothyroidism or euthyroidism.2–5 Here, we describe an atypical presentation of autoimmune encephalopathy in the context of autoimmune hyperthyroidism (Graves’ disease). A 67-year-old female patient had a 3-year history of Graves’ hyperthyroidism, well controlled on long-term carbimazole. She had a 5-year history of moderate Graves’ ophthalmopathy, only requiring squint surgery. Her past medical history included coeliac disease and hypertension; she smoked but did not drink alcohol regularly. Other medications included aspirin, sertraline and bendroflumethiazide. On clinic review, she appeared confused, unkempt and had evidently lost weight. Her family reported a subacute history of cognitive decline over the preceding month (including disorientation, falls and inability to perform daily routine tasks such as doing the laundry or using her mobile phone), with dramatic deterioration during the preceding 5 days. They also reported an acute hospital admission with confusion, which resolved spontaneously within 24 h, 4 weeks earlier. On examination, she demonstrated a coarse tremor of her upper and lower limbs but was clinically and biochemically euthyroid. She had normal vital signs and was afebrile. Neurological assessment revealed tremor and ankle clonus, with bilateral hyperreflexia, but normal plantar responses. Full blood count, basic biochemistry and septic screen (blood cultures, chest X-ray, urine microscopy and cultures) were normal. Her thyroid function tests were consistent with good control with carbimazole, with a FT4 of 193 pM, (normal range 10–22 pM) and a TSH of 014 miu/l (normal range 03–45 miu/l). A CT scan of her brain showed no abnormalities. She was commenced on empirical treatment for viral encephalitis with intravenous aciclovir. The only cerebrospinal fluid (CSF) abnormality detected was high protein (094 g/dl), with negative oligoclonal bands and CSF microbiology, including negative viral PCR (herpes simplex types 1 and 2, varicella zoster, cytomegalovirus, Epstein–Barr virus, adenovirus, enterovirus, polyoma virus). She manifested a fluctuating mental state for the next 3 days, with frequent episodes of agitation. On the fourth day of her admission, she suffered three brief tonic–clonic seizures. Anti-epileptic drug treatment was commenced. Neurology 936
review raised the possibility of autoimmune encephalopathy, and high-dose intravenous dexamethasone (4 mg three times per day) was introduced. An autoimmune screen revealed high antithyroid peroxidase (1009 U/ml) and antinuclear antibody (1:1600) titres; at this point, a modest elevation of her inflammatory markers was noted (Neutrophils 91/ll, CRP 53 mg/l). Her electroencephalogram (EEG) revealed diffuse slow-wave activity, while an MRI of the brain with contrast was unremarkable. HIV and syphilis serology, anti-N-methyl D-aspartate (NMDA) receptor antibodies, voltage-gated potassium channel antibodies, GAD antibodies and paraneoplastic antibody screen were all negative. A putative diagnosis of autoimmune encephalitis (likely ‘Hashimoto’s encephalitis’) was made. She responded well to immunosuppression with glucocorticoids, with the tremor and hyper-reflexia disappearing and her cognitive state returning to near normal within 6 days. Intravenous ceftriaxone and aciclovir were stopped after 7 days once the viral PCR was known to be negative. A repeat lumbar puncture, 10 days after the first, revealed a normal protein content (052 g/l), and she was discharged on prednisolone 40 mg daily (tapering regimen). On follow-up a month later, she showed complete neurocognitive recovery, corroborated by a normal EEG, and reported no further convulsive episodes. There are more than 100 published cases of HE; however, to our knowledge, only nine occurred in the context of clinical hyperthyroidism.2,5 The neuropsychiatric manifestations of HE are remarkably diverse, and may include cognitive and behavioural changes ranging from confusion to overt psychosis, seizures, extrapyramidal symptoms (tremor, chorea, myoclonus) and cerebellar symptoms (ataxia, central nystagmus). Some cases are characterized by vascular symptoms emulating stroke.2,3 In the absence of a definitive diagnostic test, HE remains a diagnosis of exclusion which requires comprehensive investigation to exclude important differential diagnoses. This should include thyroid function tests to exclude poorly controlled hyperthyroidism or profound hypothyroidism, serum electrolytes, renal and liver function tests, blood gases and toxicology to exclude metabolic or toxic causes, septic screen, CT head and MRI head to exclude structural intracranial pathology (including ischaemic and inflammatory lesions) and a lumbar puncture to exclude central nervous system infection. EEG is used to exclude nonconvulsive status epilepticus and may show changes of encephalopathy.2,3 The mainstay of treatment is immunosuppression. The vast majority of reported cases of HE responded well to glucocorticoids (although there may be selection bias, as many authors would only endorse the diagnosis of HE on condition of a successful clinical outcome with immunosuppression). Chong et al.,2 in their review of 85 published cases of HE, reported a 96% response rate to glucocorticoids. Many experts consider the term ‘Hashimoto’s encephalopathy’ a misnomer, as there is no evidence that the antithyroid © 2014 John Wiley & Sons Ltd
Letters to the Editor 937 antibodies are directly involved in the pathophysiology of the neuropsychiatric syndrome.2–4 We concur with this view and believe that antithyroid antibodies act as a marker of enhanced autoimmunity predisposing to the development of other organspecific autoimmune pathologies; thus, alternative descriptive terms such as ‘encephalopathy associated with autoimmune thyroid disease’ may be more appropriate. Our case indeed demonstrated three features of enhanced autoimmunity, namely autoimmune thyroiditis, Graves’ ophthalmopathy and coeliac disease. It is important to remember that there is no evidence, nor indeed any theoretical rationale, to suggest that a putative diagnosis of HE should alter the antithyroid therapy of the patient, which should always be based on an accurate clinical and biochemical assessment of the present thyroid status. A lower threshold to treat subclinical hypothyroidism has been proposed by some authors, but there is currently no evidence to support such a strategy.3 In conclusion, although the pathophysiology of HE and its relation to the autoimmune pathways underpinning thyroid disease has yet to be elucidated, the condition should always be included in the differential diagnosis of the acutely confused patient with thyroid disease, including Grave’s disease, especially given the presence of a readily available treatment with excellent response rates.
Competing interests/financial disclosure Nothing to declare. Vasileios Chortis*, Matthew R. Edmunds†, Edward T. Littleton‡ and Kristien Boelaert* *School of Clinical and Experimental Medicine, University of Birmingham, †Academic Unit of Ophthalmology, University of Birmingham, Birmingham and Midland Eye Centre, and ‡Department of Neurology, University Hospital Birmingham NHS Trust, Birmingham, UK E-mail: [email protected] doi: 10.1111/cen.12448
References 1 Brain, L., Jellinek, E.H. & Ball, K. (1966) Hashimoto’s disease and encephalopathy. Lancet, 2, 512–514. 2 Chong, J.Y., Rowland, L.P. & Utiger, R.D. (2003) Hashimoto encephalopathy: syndrome or myth? Archives of Neurology, 60, 164–171. 3 Fatourechi, V. (2005) Hashimoto’s encephalopathy: myth or reality? An endocrinologist’s perspective. Best Practice & Research Clinical Endocrinology & Metabolism, 19, 53–66. 4 Sawka, A.M., Fatourechi, V., Boeve, B.F. et al. (2002) Rarity of encephalopathy associated with autoimmune thyroiditis: a case series from Mayo Clinic from 1950 to 1996. Thyroid, 12, 393–398. 5 Payer, J., Petrovic, T., Lisy, L. et al. (2012) Hashimoto encephalopathy: a rare intricate syndrome. International Journal of Endocrinology and Metabolism, 10, 506–514. © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 936–942
Saving lives of in-patients with adrenal insufficiency: implementation of an alert scheme within the Newcastle-upon-Tyne Hospitals e-Prescribing platform Dear Sir, For individuals who are steroid-dependent, acute adrenal crisis is a significant cause of morbidity and mortality. Through clinical experience and involvement with support groups, we have observed that fear of an adrenal crisis can have a significant impact upon patients’ quality of life and psychosocial function. The introduction of a universal European steroiddependence emergency card, as detailed by Quinkler et al.,1 is a welcome step forward in attempts to improve safety for this vulnerable group of patients. However, as the authors point out, improving care for individuals with an acute adrenal crisis, both in the prehospital setting and in hospital, requires a multifaceted approach, and the addition of a new alert device is unlikely, by itself, to be enough to improve outcomes in this group. It is now widely accepted that individuals who are steroiddependent should receive structured education, which should focus on adaptation of steroid regimens for sickness and travel, the need to carry a warning card or wear a piece of alert jewellery at all times, and practical advice on initial crisis management with IM steroids before seeking prompt medical attention. Another key approach to improving patient safety for steroiddependent patients is to target education strategies at care providers regarding recognition of adrenal crisis and appropriate management of this life-threatening condition. Nevertheless, patients frequently report that for reasons that are frustratingly elusive, medical and paramedical staff can be surprisingly resistant to patient-supplied information in the emergency care and in-patient contexts. Indeed, iatrogenic adrenal crises in the hospital setting, due to omitted glucocorticoid prescriptions in patients admitted for other reasons, remain all too common ‘never events’.2 In the Newcastle-upon-Tyne Hospitals, an electronic patient record and prescribing platform (eRecord) was rolled out in 2009–2010, allowing registered users to access patient laboratory results, radiology imaging/reports and inpatient prescription data. It is the sole platform for ordering laboratory and radiologic/sonographic investigations, and for prescribing and dispensing in-patient medication (including the emergency room and medical assessment suite). eRecord alerts prescribers to significant drug interactions and patient allergies, but also has an underutilised functionality to ‘flag-up’ patients with defined medical conditions. After a recent local audit revealed that less than half of steroiddependent patients admitted carried a steroid alert card, and that steroid doses were not being appropriately escalated in acutely unwell patients being admitted, we decided to create an eRecord alert. We first designed an on-screen ‘pop-up’ alert (Fig. 1) for patients logged as having adrenal insufficiency, which appears whenever a new user logs into any such patient’s record for the
Copyright of Clinical Endocrinology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTERS TO THE EDITOR
Autoimmune encephalopathy in the context of Graves’ disease with ophthalmopathy Dear Editor, More than 40 years after its initial description by Brain et al.,1 ‘Hashimoto’s encephalopathy’ (HE) remains an enigmatic clinical entity. Although no universally accepted definition exists, commonly employed diagnostic criteria include an acute or subacute presentation with neuropsychiatric symptoms consistent with encephalopathy, presence of serum antithyroid antibodies and exclusion of alternative infective or metabolic causes.2The vast majority of HE cases described in the literature relate to patients demonstrating either hypothyroidism or euthyroidism.2–5 Here, we describe an atypical presentation of autoimmune encephalopathy in the context of autoimmune hyperthyroidism (Graves’ disease). A 67-year-old female patient had a 3-year history of Graves’ hyperthyroidism, well controlled on long-term carbimazole. She had a 5-year history of moderate Graves’ ophthalmopathy, only requiring squint surgery. Her past medical history included coeliac disease and hypertension; she smoked but did not drink alcohol regularly. Other medications included aspirin, sertraline and bendroflumethiazide. On clinic review, she appeared confused, unkempt and had evidently lost weight. Her family reported a subacute history of cognitive decline over the preceding month (including disorientation, falls and inability to perform daily routine tasks such as doing the laundry or using her mobile phone), with dramatic deterioration during the preceding 5 days. They also reported an acute hospital admission with confusion, which resolved spontaneously within 24 h, 4 weeks earlier. On examination, she demonstrated a coarse tremor of her upper and lower limbs but was clinically and biochemically euthyroid. She had normal vital signs and was afebrile. Neurological assessment revealed tremor and ankle clonus, with bilateral hyperreflexia, but normal plantar responses. Full blood count, basic biochemistry and septic screen (blood cultures, chest X-ray, urine microscopy and cultures) were normal. Her thyroid function tests were consistent with good control with carbimazole, with a FT4 of 193 pM, (normal range 10–22 pM) and a TSH of 014 miu/l (normal range 03–45 miu/l). A CT scan of her brain showed no abnormalities. She was commenced on empirical treatment for viral encephalitis with intravenous aciclovir. The only cerebrospinal fluid (CSF) abnormality detected was high protein (094 g/dl), with negative oligoclonal bands and CSF microbiology, including negative viral PCR (herpes simplex types 1 and 2, varicella zoster, cytomegalovirus, Epstein–Barr virus, adenovirus, enterovirus, polyoma virus). She manifested a fluctuating mental state for the next 3 days, with frequent episodes of agitation. On the fourth day of her admission, she suffered three brief tonic–clonic seizures. Anti-epileptic drug treatment was commenced. Neurology 936
review raised the possibility of autoimmune encephalopathy, and high-dose intravenous dexamethasone (4 mg three times per day) was introduced. An autoimmune screen revealed high antithyroid peroxidase (1009 U/ml) and antinuclear antibody (1:1600) titres; at this point, a modest elevation of her inflammatory markers was noted (Neutrophils 91/ll, CRP 53 mg/l). Her electroencephalogram (EEG) revealed diffuse slow-wave activity, while an MRI of the brain with contrast was unremarkable. HIV and syphilis serology, anti-N-methyl D-aspartate (NMDA) receptor antibodies, voltage-gated potassium channel antibodies, GAD antibodies and paraneoplastic antibody screen were all negative. A putative diagnosis of autoimmune encephalitis (likely ‘Hashimoto’s encephalitis’) was made. She responded well to immunosuppression with glucocorticoids, with the tremor and hyper-reflexia disappearing and her cognitive state returning to near normal within 6 days. Intravenous ceftriaxone and aciclovir were stopped after 7 days once the viral PCR was known to be negative. A repeat lumbar puncture, 10 days after the first, revealed a normal protein content (052 g/l), and she was discharged on prednisolone 40 mg daily (tapering regimen). On follow-up a month later, she showed complete neurocognitive recovery, corroborated by a normal EEG, and reported no further convulsive episodes. There are more than 100 published cases of HE; however, to our knowledge, only nine occurred in the context of clinical hyperthyroidism.2,5 The neuropsychiatric manifestations of HE are remarkably diverse, and may include cognitive and behavioural changes ranging from confusion to overt psychosis, seizures, extrapyramidal symptoms (tremor, chorea, myoclonus) and cerebellar symptoms (ataxia, central nystagmus). Some cases are characterized by vascular symptoms emulating stroke.2,3 In the absence of a definitive diagnostic test, HE remains a diagnosis of exclusion which requires comprehensive investigation to exclude important differential diagnoses. This should include thyroid function tests to exclude poorly controlled hyperthyroidism or profound hypothyroidism, serum electrolytes, renal and liver function tests, blood gases and toxicology to exclude metabolic or toxic causes, septic screen, CT head and MRI head to exclude structural intracranial pathology (including ischaemic and inflammatory lesions) and a lumbar puncture to exclude central nervous system infection. EEG is used to exclude nonconvulsive status epilepticus and may show changes of encephalopathy.2,3 The mainstay of treatment is immunosuppression. The vast majority of reported cases of HE responded well to glucocorticoids (although there may be selection bias, as many authors would only endorse the diagnosis of HE on condition of a successful clinical outcome with immunosuppression). Chong et al.,2 in their review of 85 published cases of HE, reported a 96% response rate to glucocorticoids. Many experts consider the term ‘Hashimoto’s encephalopathy’ a misnomer, as there is no evidence that the antithyroid © 2014 John Wiley & Sons Ltd
Letters to the Editor 937 antibodies are directly involved in the pathophysiology of the neuropsychiatric syndrome.2–4 We concur with this view and believe that antithyroid antibodies act as a marker of enhanced autoimmunity predisposing to the development of other organspecific autoimmune pathologies; thus, alternative descriptive terms such as ‘encephalopathy associated with autoimmune thyroid disease’ may be more appropriate. Our case indeed demonstrated three features of enhanced autoimmunity, namely autoimmune thyroiditis, Graves’ ophthalmopathy and coeliac disease. It is important to remember that there is no evidence, nor indeed any theoretical rationale, to suggest that a putative diagnosis of HE should alter the antithyroid therapy of the patient, which should always be based on an accurate clinical and biochemical assessment of the present thyroid status. A lower threshold to treat subclinical hypothyroidism has been proposed by some authors, but there is currently no evidence to support such a strategy.3 In conclusion, although the pathophysiology of HE and its relation to the autoimmune pathways underpinning thyroid disease has yet to be elucidated, the condition should always be included in the differential diagnosis of the acutely confused patient with thyroid disease, including Grave’s disease, especially given the presence of a readily available treatment with excellent response rates.
Competing interests/financial disclosure Nothing to declare. Vasileios Chortis*, Matthew R. Edmunds†, Edward T. Littleton‡ and Kristien Boelaert* *School of Clinical and Experimental Medicine, University of Birmingham, †Academic Unit of Ophthalmology, University of Birmingham, Birmingham and Midland Eye Centre, and ‡Department of Neurology, University Hospital Birmingham NHS Trust, Birmingham, UK E-mail: [email protected] doi: 10.1111/cen.12448
References 1 Brain, L., Jellinek, E.H. & Ball, K. (1966) Hashimoto’s disease and encephalopathy. Lancet, 2, 512–514. 2 Chong, J.Y., Rowland, L.P. & Utiger, R.D. (2003) Hashimoto encephalopathy: syndrome or myth? Archives of Neurology, 60, 164–171. 3 Fatourechi, V. (2005) Hashimoto’s encephalopathy: myth or reality? An endocrinologist’s perspective. Best Practice & Research Clinical Endocrinology & Metabolism, 19, 53–66. 4 Sawka, A.M., Fatourechi, V., Boeve, B.F. et al. (2002) Rarity of encephalopathy associated with autoimmune thyroiditis: a case series from Mayo Clinic from 1950 to 1996. Thyroid, 12, 393–398. 5 Payer, J., Petrovic, T., Lisy, L. et al. (2012) Hashimoto encephalopathy: a rare intricate syndrome. International Journal of Endocrinology and Metabolism, 10, 506–514. © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 936–942
Saving lives of in-patients with adrenal insufficiency: implementation of an alert scheme within the Newcastle-upon-Tyne Hospitals e-Prescribing platform Dear Sir, For individuals who are steroid-dependent, acute adrenal crisis is a significant cause of morbidity and mortality. Through clinical experience and involvement with support groups, we have observed that fear of an adrenal crisis can have a significant impact upon patients’ quality of life and psychosocial function. The introduction of a universal European steroiddependence emergency card, as detailed by Quinkler et al.,1 is a welcome step forward in attempts to improve safety for this vulnerable group of patients. However, as the authors point out, improving care for individuals with an acute adrenal crisis, both in the prehospital setting and in hospital, requires a multifaceted approach, and the addition of a new alert device is unlikely, by itself, to be enough to improve outcomes in this group. It is now widely accepted that individuals who are steroiddependent should receive structured education, which should focus on adaptation of steroid regimens for sickness and travel, the need to carry a warning card or wear a piece of alert jewellery at all times, and practical advice on initial crisis management with IM steroids before seeking prompt medical attention. Another key approach to improving patient safety for steroiddependent patients is to target education strategies at care providers regarding recognition of adrenal crisis and appropriate management of this life-threatening condition. Nevertheless, patients frequently report that for reasons that are frustratingly elusive, medical and paramedical staff can be surprisingly resistant to patient-supplied information in the emergency care and in-patient contexts. Indeed, iatrogenic adrenal crises in the hospital setting, due to omitted glucocorticoid prescriptions in patients admitted for other reasons, remain all too common ‘never events’.2 In the Newcastle-upon-Tyne Hospitals, an electronic patient record and prescribing platform (eRecord) was rolled out in 2009–2010, allowing registered users to access patient laboratory results, radiology imaging/reports and inpatient prescription data. It is the sole platform for ordering laboratory and radiologic/sonographic investigations, and for prescribing and dispensing in-patient medication (including the emergency room and medical assessment suite). eRecord alerts prescribers to significant drug interactions and patient allergies, but also has an underutilised functionality to ‘flag-up’ patients with defined medical conditions. After a recent local audit revealed that less than half of steroiddependent patients admitted carried a steroid alert card, and that steroid doses were not being appropriately escalated in acutely unwell patients being admitted, we decided to create an eRecord alert. We first designed an on-screen ‘pop-up’ alert (Fig. 1) for patients logged as having adrenal insufficiency, which appears whenever a new user logs into any such patient’s record for the
Copyright of Clinical Endocrinology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
