DOI 10.1515/jpem-2013-0435 J Pediatr Endocr Met 2014; 27(7-8): 737–744
Saroj Kumar Patnaik*, Vimal Upreti and Pawan Dhull
Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) in childhood Abstract Aim: Steroid responsive encephalopathy with autoimmune thyroiditis (SREAT) is a clinically and electrographically heterogeneous steroid-responsive encephalopathy associated with thyroid autoantibodies. We report an adolescent with SREAT and review PubMed literature relating to childhood. Methods: A 14-year-old boy, without any preceding history of trauma, meningoencephalitis or seizures, was admitted in a comatose state. A similar episode of loss of consciousness 2 months prior with normal neuroimaging and electroencephalogram (EEG) had been followed by behavioral alterations. A year previously, during evaluation for increased appetite and poor weight gain, he was noted to have small goitre with thyroid-stimulating hormone (TSH) 7.26 mIU/L, T3 1.232 nmol/L, and T4 117.63 nmol/L. Routine hemogram, blood biochemistry, thyroid function tests including free hormone levels, ultrasonography thyroid and magnetic resonance imaging were normal. EEG showed diffuse slowing of all waves. Cerebrospinal fluid showed no pleocytosis and electrophoresis showed oligoclonal band. Viral studies and serum N-methyl-Daspartate receptor antibody levels were negative. Antithyroid peroxidase (Anti-TPO) antibodies were raised. Intervention was with intravenous dexamethasone 4 mg every 6 h for 1 week followed by tapering schedule of oral prednisolone over 6 months. Results: He regained consciousness after the second dose of dexamethasone and was discharged on day 7 in a fully conscious and ambulant state on a tapering course of low dose prednisolone for 6 months. He remains euthyroid with normal sensorium and behavior at 18 months follow-up. Only 50 cases below 18 years age were identified amongst 300 PubMed articles up to 31 July 2013. Conclusion: Prompt steroid therapy following early recognition by high clinical suspicion and measurement of antithyroid antibody titers can lead to a favorable prognosis in SREAT. Keywords: autoimmune thyroiditis; childhood; encephalopathy; Hashimotos; SREAT; steroid responsive.
*Corresponding author: Saroj Kumar Patnaik, Department of Pediatrics, Command Hospital Air Force, Bangalore, PO AGRAM, Bangalore 560007, India, Phone: +91-80-25582232, +91-7676883233, E-mail: [email protected]; [email protected] Vimal Upreti: Department of Endocrinology, Command Hospital Air Force, Bangalore, India Pawan Dhull: Department of Neurology, Command Hospital Air Force, Bangalore, India
Introduction Unexplained encephalopathy often merits exclusion of an endocrinopathy. Autoimmune etiology involving both neural and hormonal pathways in cases of encephalopathy have been studied extensively in recent years (1, 2). Observations of frequent occurrence of autoimmune antibodies in ‘investigation negative encephalopathy’ have led to conceptualization of distinct group of nonvasculitic autoimmune meningoencephalitis (NAIM) or neuronal surface antibody associated syndromes (1, 2). The hallmark of these disorders is a cognitive impairment with varying grades of pyramidal/extrapyramidal involvement, neuropsychiatric symptoms and seizure-like activity with diffuse slowing on electroencephalogram (EEG), essentially, normal neuroimaging and cerebrospinal fluid (CSF) picture, demonstrable autoimmune antibodies in CSF and blood with dramatic symptomatic response to steroids and possible tendency to recur off-steroids (1, 2). Paraneoplastic syndromes and non-oncological disorders with neural nonspecific serologic evidence of autoimmunity are the two broad groups of such disorders (2). Amongst the latter, antibodies directed towards (i) neurotransmitter receptors, such as N-methyl-Daspartate (NMDA) or voltage gated potassium channels, and (ii) autoimmune thyroid antibodies, are the two major subgroups. The former usually presents similar to limbic encephalitis. The latter was labeled as Hashimoto’s encephalopathy from its first description in 1966 and autoimmune origin is presumed owing to high titres of anti-thyroid peroxidase (TPO) antibodies (3). Anti-TPO antibodies occur in the normal population as well as in many neurologic conditions responsive to steroids. This coupled with occurrence of encephalopathy in Graves’
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738 Patnaik et al.: SREAT in childhood disease has led to the renaming of Hashimoto’s encephalopathy as steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) (1, 4–8). An alternative acronym EAATD (encephalopathy associated with autoimmune thyroid disease) also has been proposed. We report an illustrative case and review the published pediatric literature regarding this eminently treatable entity of concern to pediatricians, intensivists, endocrinologists, psychiatrists and neurologists.
Materials and methods Case report A 14-year-old male adolescent was admitted in February 2012 with a single episode of sudden onset loss of consciousness lasting 10 min. Clinical examination, EEG and magnetic resonance imaging (MRI) were normal and he was discharged without any medication to follow-up in neurology outpatient department. A fortnight later, he became restless at home with decreased sleep and a neuropsychiatric consult led to a label of dissociative disorder. Over the subsequent 4 weeks, he gradually deteriorated with persistent temper tantrums and defiant behavior in spite of behavior therapy and family counselling prescribed by a psychiatrist. In April 2012, over 3 days his parents noted excessive sweating, an unsteady gait and mild slurring of speech. His behavior further deteriorated in the form of abusive language and he lapsed into coma after going to sleep following dinner with other family members at home. There was no preceding trauma, drug intake, substance abuse, fever, headache, convulsion, audiovisual disturbances or bladder-bowel incontinence. He had perinatal asphyxia during forceps extraction and his parents were not related. His elder sister, aged 18 years, had grand mal epilepsy. At
admission, the patient weighed 39 kg, was afebrile (36.9 C) with heart rate 112/min, respiratory rate 22/min, blood pressures 114/70 mm Hg, Glasgow Coma Scale 3/15 with 3 mm sluggish pupils, normal fundoscopy, areflexia with bilateral extensor plantars without any meningismus or features of raised intracranial tension. He was put on a ventilator and treated with empirical antibiotics and acyclovir, pending investigation reports. Lumbar puncture revealed clear, normal pressure, acellular CSF with normal protein (0.11 g/L); globulins not increased) and sugar (4.44 mmol/L) and lactate dehydrogenase (LDH) 81 U/l. Acid fast bacillus (AFB)/Gram/fungal stains were negative and cultures were sterile. Serological tests for syphilis, HIV, toxoplasmosis, cytomegalovirus, herpes simplex virus, hepatitis B and Ebstein-Barr virus were negative. CSF serology and polymerase chain reaction (PCR) for enterovirus, measles, mumps, varicella, and arboviruses were negative. CSF electrophoresis revealed a positive oligoclonal band. The Mantoux test was negative. EEG showed generalized slowing with frequency around 2–3 Hz (Figure 1). With persistent coma and negative routine investigations including CSF and neuroimaging (see Table 1), his past medical documents were reviewed. He had been treated earlier for a fracture ulna (right) in 2008 and scabies in 2009. From 2011, he remained under follow-up with otorhinolaryngologist for a deviated left nasal septum and recurrent rhinosinusitis. The most recent episode was treated with amoxicillin in January 2012. He had previously been referred in March 2011 for poor weight gain in spite of an increased appetite for 6 months and a mild goitre with subclinical hypothyroidism was noted. USS thyroid was normal; thyroid scan revealed normal uptake with right lobe uptake greater than left. With persistent coma without evident infective/metabolic derangement after 5 days of admission, a possibility of autoimmune encephalopathy was entertained and he was exhibited to intravenous dexamethasone 4 mg every 6 h. He dramatically regained consciousness after two doses of dexamethasone by injection and was discharged home on day 7 in a fully conscious and ambulant state on a tapering course of low dose prednisolone for 6 months. At 18 months follow-up, he remains euthyroid without any recurrence of altered sensorium and has a normal behavior and school performance.
Figure 1 Electroencephalogram at admission showing generalized slowing with frequency around 2–3 Hz.
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Patnaik et al.: SREAT in childhood 739 Table 1 Temporal profile of investigations. Date
22/03/11
Clinical presentation
Wt loss Episode of Mild goiter URTI
ESR (mm/h) Hb (g/L) TLC (×103/L) DLC (number fraction)
15 142
Platelet count ( × 105/mm3) Urine RE/ME
CXR T3 [nmol/L (N: 1.078–3.234)] T4 [nmol/L (N: 51.48–154.44)] TSH [mIU/L (N: 0.5–6.0)] Anti-TPO antibody levels [IU/mL (N: left lobe Negative Negative Negative
Discharge after recovery from coma
01/08/13
WNL Normal awake record Normal
Right lobe 11.0 × 14.0 mm Left lobe 9.6 × 12.1 mm Isthmus 2.0 mm no focal defect normal vascularity normal lymph nodes Normal
EEG, electroencephalogram; NMDA, N-methyl-D-aspartate; ESR, Erythrocyte Sedimentation Rate; Hb, Hemoglobin; TLC, White Blood cell Count; DLC, White Blood cell Differential count; P, polymorphonuclear cell; L, lymphocyte; E, eosinophil; M, monocyte; B, basophil; Urine RE/ ME, Urine routine examination/microscopic examination; CXR, Chest X Ray; USS, Ultrasonography; T3, Triiodothyronine Total; T4, Thyroxine Total; TSH, Thyroid-stimulating hormone; Anti-TPO, Anti-thyroid peroxidase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; Ca, Serum Calcium; Na, Serum sodium; K, Serum potassium; BUN, Blood urea nitrogen; ECG, Electrocardiogram; HIV, Human Immunodeficiency virus; HBsAg, Hepatitis B surface Antigen; VDRL, Venereal Diseases Reference Laboratory test.
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740 Patnaik et al.: SREAT in childhood
Literature search PubMed was searched using the following strategy: “Hashimoto’s encephalitis” OR “Hashimoto’s encephalopathy” OR “steroid responsive encephalopathy with autoimmune thyroiditis” up to 31 July 2013. Articles pertaining to pediatric age group were narrowed down and reviewed using a filter of age 18 years and less.
Results Our PubMed search revealed 300 articles of Hashimoto’s encephalopathy; 50 pertained to children 18 years or less. Less than five reports are from the Indian subcontinent (5, 6). The relevant literature review is presented in the discussion section.
Discussion Hashimoto’s encephalopathy or SREAT is a rare disorder with prevalence estimate of 2.1 per 100,000. Unawareness and lack of consensus diagnostic criteria for SREAT result in under diagnosis and mislabeling as viral encephalitis (6, 8). A viral etiology remains difficult to disprove in the absence of appropriate diagnostic facilities. Amongst various diagnostic criteria, those proposed by Castillo et al. are the most comprehensive (9) (Table 2). Mean age of presentation in adults is 44 years; most children are above 9 years. Females are more frequently afflicted. Chronic cognitive impairment is a rare presentation (8–10). Recurrent acute/subacute episodes of focal neurological deficit with confusion or seizures akin to our case are more likely. Natural history ranges from a monophasic illness to a remitting-relapsing illness. While spontaneous remissions do occur, dramatic response to cortico steroids as seen in the current report is characteristic (1, 2, 4, 5). Improvement occurs within days. Exceptional cases require prolonged therapy over months. Two clinical subtypes have been proposed by some authors, vasculitic and diffuse progressive (9, 10) (Table 2). These may overlap and may be impossible to differentiate clinically in children. Our case displayed many clinical features described in the literature. Epileptic seizures including status epilepticus at onset is the commonest association with childhood SREAT. Behavioral manifestations range from rumination syndrome to breath holding spells. Neurocognitive impairment leads to a subtle decline in school performance or presents as coma, stupor and confusion. Neuropsychiatric features such as acute personality changes, hallucinations and
psychosis also occur. Extrapyramidal symptoms such as ataxia, asymmetric chorea, cerebellar dysfunction and myoclonus are also observed. Rare reports of optic neuritis and alternating hemiplegia also exist (8–17). Etiopathogenetic mechanism remains unknown. Higher prevalence in females, fluctuating course, specific steroid responsiveness, raised antithyroid antibodies and reported association with other autoimmune disorders do suggest an autoimmune basis for SREAT (4, 6, 17, 18). Although autoimmunity directed against common brainthyroid antigens is an attractive hypothesis, no shared antigen has been identified between the thyroid gland and brain (6, 18). Thyroid hormones increase the cortical serotonergic neurotransmission, and plays an important role in regulating central noradrenergic and gammaaminobutyric acid function (6, 17, 19). It is tempting to speculate that antithyroid antibodies may interfere with the neurotransmitter pathways and result in the clinical picture of SREAT. Apart from anti-TPO and anti-thyroglobulin antibodies present in serum and CSF, other autoantibodies, such as anti-parietal cell antibody or anti-intrinsic factor antibody, as well as antibodies against alpha-enolase and dimethylargininase-1 have also been identified in SREAT (1–3, 17, 20). However, in the absence of a strong correlation between disease severity and antithyroid antibody titres, SREAT might be a mere endpoint manifestation of non-structural abnormalities of CNS function resulting in a coincidence of endocrinopathies, epilepsy and psychoneurologic disorders (1, 6, 7). Thyroiditis and encephalopathy may represent two concurrent autoimmune diseases (18). While the trigger of the autoimmune process is not known, it could be an as yet unidentified viral infection, which is known to induce neurotransmitter receptor activation. For example, H1N1 induced NMDA receptor activation is well documented (21). Our child had rhinosinusitis prior to onset of his symptoms but in the absence of specific viral studies, we cannot pinpoint a causal relationship. The time lag between evidence of autoimmunity and typical presentation of SREAT is well documented in the literature (19). Although considered as a nonvasculitic disorder, lymphocytic vasculitis of cerebral venules and arterioles, lymphocytic perivascular cuffs and microglial activation have been documented in a few rare recurrent cases undergoing brain biopsy prior to steroid therapy (12). Biopsy proven primary CNS demyelination has also been reported (18–23). Although nonspecific, cerebral edema has also been described in many cases and other poorly characterized factors may also contribute. For example, significantly low levels of vitamin D were documented in patients with autoimmune thyroid diseases that were
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Patnaik et al.: SREAT in childhood 741 Table 2 Modified diagnostic criteria for SREAT [adapted from Castillo et al. (see Ref (9))]. A diagnosis of SREAT must fulfil all the following positive and should not fulfil any negative criteria
Positive criteria
Encephalopathy
Steroid responsiveness
Cognitive impairment and one or more of the followinga: (i) Neuropsychiatric features (e.g., hallucinations, delusions, or paranoia) (ii) Myoclonus (iii) Seizures – generalized tonic-clonic or partial (iv) Focal neurologic deficits Complete or near complete return to the patient’s neurologic baseline status following corticosteroid treatment Relapses may occur TSH: 0.3–20 mIU/L Euthyroid: TSH 0.3–5.0 mIU/L Mildly hypothryoid:5.1–20.0 mIU/L
Near normal thyroid function – derangement of thyroid function alone should be insufficient to explain occurrence of encephalopathy Immunological evidence of autoimmunity in form of presence in serum/CSF autoantibodies
Neurophysiology
Neuroimaging
Laboratory
Negative criteria
Lack of improvement to an adequate trial of steroids at 2 mg/kg of prednisolone or equivalent for at least 2 weeks
Significant hypothyroidism: TSH > 20 mIU/L Myxedema coma Symptomatic thyrotoxicosis
Mandatory: Antithyroid autoantibodiesb: Anti-TPO+/ anti-TG Corroborative: Anti anti-parietal cell antibody/anti-intrinsic factor antibody/antialpha-enolase/anti dimethylargininase-1 Normal EEG OR, Steroid responsive EEG abnormalities (diffuse/rhythmic generalized or bifrontotemporal slow wave abnormalities or rarely focal changes) OR, EEG Nonresponsiveness to antiepileptics OR EEG Worsening with antiepilectics Normal OR mild isolated cerebral edema or demyelination insufficient to explain encephalopathy
Serologic evidence of the neuronal surface antibody syndromes (such as voltage-gated calcium channel, voltage-gated potassium channel, anti-NMDA or anti-AMDA receptor or other currently recognized paraneoplastic autoantibodies to indicate another diagnosis) EEG specific patterns of epileptiform disorder consistent with other specific epilepsy EEG nonresponsiveness to immunomodulation
Findings on neuroimaging studies indicating vascular, neoplastic, or other structural lesions to explain the encephalopathy Other evidence in blood, urine, or CSF analyses of an infectious, toxic, metabolic, or neoplastic process to explain the encephalopathy
a Two clinical patterns of presentation have been described: (i) vasculitic presentation, which is stroke-like episodes and mild cognitive impairment; and (ii) diffuse progressive presentation. Seizures have been reported to be the commonest presentation, followed by confusion, myoclonus, cognitive impairment and altered consciousness. Pyramidal, extrapyramidal, myelopathic or cerebellar involvements have also been described. Neuropsychiatric features, such as psychosis, depression and dementia are well recognized and, in rare cases, may be the initial presentation. Differential diagnosis: main subgroups include (i) other autoimmune-encephalopathies without cancer but with neural nonspecific serologic evidence of autoimmunity such as NMDA/AMDA encephalitis; (ii) paraneoplastic encephalopathies, which present as limbic encephalitis; (iii) central nervous system (CNS) vasculitis (primary or secondary); (iv) chronic CNS infections, prion diseases, especially Creutzfeldt-Jakob disease, HIV and neurosyphilis; and (v) mitochondrial cytopathies, especially MELAS. bThere may be a time lag in appearance of autoantibodies and EEG abnormalities as well as disappearance of same after therapy. Abbreviations: EEG, electroencephalogram; TG, thyroglubulin; TSH, Thyroid stimulating hormone; Anti-TPO, anti- thyroid peroxidase; NMDA, N-methyl D- aspartate; AMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor); MELAS, mitochondrial encpahlopathy with lactic acidosis; CSF, cerebrospinal fluid; HIV, human immunodeficiency virus.
related to the presence of anti-thyroid antibodies and abnormal thyroid function tests (24). Routine blood tests are nonspecific. Most frequent laboratory abnormalities are transaminasitis and elevated
erythrocyte sedimentation rate (ESR) (8, 23). Elevated serum ammonia level may occur in presence of hypothyroidism (8, 23). Intrathecal inflammation in CSF is seen in 2 0% cases in children during a follow-up up to 48 months (15). As long-term cognitive sequelae are important, especially in children, a formal neuropsychological assessment after recovery would be vital. This can detect subtle abnormalities early on and helps in guiding long-term steroid therapy (31). Our child continued to be lethargic with poor academic performance
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Patnaik et al.: SREAT in childhood 743
and had subtle mood changes. We chose to use a combination of IV dexamethasone followed by long-term low dose prednisolone. The antithyroid antibody titter may be a marker of treatment response but the long-term significance of the same is not clear (17). In our case, the anti-TPO levels normalized over 18 months. One must keep a lookout for other autoimmune endocrinopathies, apart from thyroiditis in these cases. Although most cases are euthyroid at presentation, periodic monitoring of thyroid function in cases of recovered SREAT must be maintained for an early identification of clinical hypothyroidism/hyperthyroidism and specific therapy. In conclusion, SREAT remains a fascinating but poorly understood clinically and electrographically heterogeneous steroid-responsive encephalopathy associated with thyroid autoantibodies. Characterization of etiopathogenesis remains unsatisfactory. A high level of suspicion is necessary to establish the diagnosis in cases of ‘investigation negative’ acute or subacute encephalopathy presenting to the intensive care unit, as well as those presenting with progressive/relapsing behavioral and cognitive changes, unexplained myoclonus, seizures,
pyramidal tract/extrapyramidal/cerebellar dysfunction or movement disorder. Although the diagnosis is often overlooked at presentation, antithyroid antibody titers should be measured in these situations, even if standard thyroid function tests are normal. Diffusely abnormal EEG, high CSF protein level without pleocytosis and normal neuroimaging provide corroborative clues. A teenage girl with antecedent thyroid disease merits specific attention. Awareness of this entity is crucial given that early recognition and prompt steroid treatment may lead to a favorable prognosis. Neuropsychological assessment is important in all cases. Disclaimer: The opinions reflected in the article are the personal opinions and viewpoints of individual authors and in no way reflect the official position of Directorate General of Armed Forces Medical Services of India. Conflict of interest statement: The authors have nothing to disclose. Received November 11, 2013; accepted January 14, 2014; previously published online March 6, 2014
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744 Patnaik et al.: SREAT in childhood 18. Mitchell RS, Yager JY, Marks SD. Childhood onset demyelination and Graves’ disease: shared antigen or autoimmune clustering? J Pediatr Endocrinol Metab 2007;20:1233–6. 19. Lopez-Giovaneli J, Moreaud O, Faure P, Debaty I, Chabre O, et al. Cortico-responsive encephalopathy associated with autoimmune thyroiditis (SREAT):about two case reports characterized by a gap between the diagnosis of autoimmune thyroiditis and neurological disorders. Ann Endocrinol (Paris) 2007;68:173–6. 20. Matsunaga A, Yoneda M. Anti-NAE autoantibodies and clinical spectrum in Hashimoto’s encephalopathy. Rinsho Byori 2009;57:271–8. 21. Takanashi J, Takahashi Y, Imamura A, Kodama K, Watanabe A, et al. Late delirious behavior with 2009 H1N1 influenza: mild autoimmune-mediated encephalitis? Pediatrics 2012;129:e1068–71. 22. Mahad DJ, Staugaitis S, Ruggieri P, Parisi J, KleinschmidtDemasters BK, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis and primary CNS demyelination. J Neurol Sci 2005;228:3–5. 23. Santra G, De D, Phaujdar S, Rudra A, Dutta PS. Hashimoto’s encephalopathy. J Assoc Physicians India 2012;60:48–50. 24. Kivity S, Agmon-Levin N, Zisappl M, Shapira Y, Nagy EV, et al. Vitamin D and autoimmune thyroid diseases. Cell Mol Immunol 2011;8:243–7.
25. Giovanella L, Pedrazzi P, Jandus P, Marone C. Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) with negative thyroperoxidase antibodies. Eur J Clin Invest 2008;38:693–4. 26. Rodriguez AJ, Jicha GA, Steeves TD, Benarroch EE, Westmoreland BF. EEG changes in a patient with steroid-responsive encephalopathy associated with antibodies to thyroperoxidase (SREAT, Hashimoto’s encephalopathy). J Clin Neurophysiol 2006;23:371–3. 27. Grommes C, Griffin C, Downes KA, Lerner AJ. Steroid-responsive encephalopathy associated with autoimmune thyroiditis presenting with diffusion MR imaging changes. AJNR Am J Neuroradiol 2008;29:1550–1. 28. Mancardi MM, Fazzini F, Rossi A, Gaggero R. Hashimoto’s encephalopathy with selective involvement of the nucleus accumbens: a case report. Neuropediatrics 2005;36:218–20. 29. Bektas Ö, Yılmaz A, Kendirli T, Sıklar Z, Deda G. Hashimoto encephalopathy causing drug-resistant status epilepticus treated with plasmapheresis. Pediatr Neurol 2012;46:132–5. 30. Olmez I, Moses H, Sriram S, Kirshner H, Lagrange AH, et al. Diagnostic and therapeutic aspects of Hashimoto’s encephalopathy. J Neurol Sci 2013;331:67–71. 31. Brooks BL, Barlow KM. A methodology for assessing treatment response in Hashimoto’s encephalopathy: a case study demonstrating repeated computerized neuropsychological testing. J Child Neurol 2011;26:786–91.
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Saroj Kumar Patnaik*, Vimal Upreti and Pawan Dhull
Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) in childhood Abstract Aim: Steroid responsive encephalopathy with autoimmune thyroiditis (SREAT) is a clinically and electrographically heterogeneous steroid-responsive encephalopathy associated with thyroid autoantibodies. We report an adolescent with SREAT and review PubMed literature relating to childhood. Methods: A 14-year-old boy, without any preceding history of trauma, meningoencephalitis or seizures, was admitted in a comatose state. A similar episode of loss of consciousness 2 months prior with normal neuroimaging and electroencephalogram (EEG) had been followed by behavioral alterations. A year previously, during evaluation for increased appetite and poor weight gain, he was noted to have small goitre with thyroid-stimulating hormone (TSH) 7.26 mIU/L, T3 1.232 nmol/L, and T4 117.63 nmol/L. Routine hemogram, blood biochemistry, thyroid function tests including free hormone levels, ultrasonography thyroid and magnetic resonance imaging were normal. EEG showed diffuse slowing of all waves. Cerebrospinal fluid showed no pleocytosis and electrophoresis showed oligoclonal band. Viral studies and serum N-methyl-Daspartate receptor antibody levels were negative. Antithyroid peroxidase (Anti-TPO) antibodies were raised. Intervention was with intravenous dexamethasone 4 mg every 6 h for 1 week followed by tapering schedule of oral prednisolone over 6 months. Results: He regained consciousness after the second dose of dexamethasone and was discharged on day 7 in a fully conscious and ambulant state on a tapering course of low dose prednisolone for 6 months. He remains euthyroid with normal sensorium and behavior at 18 months follow-up. Only 50 cases below 18 years age were identified amongst 300 PubMed articles up to 31 July 2013. Conclusion: Prompt steroid therapy following early recognition by high clinical suspicion and measurement of antithyroid antibody titers can lead to a favorable prognosis in SREAT. Keywords: autoimmune thyroiditis; childhood; encephalopathy; Hashimotos; SREAT; steroid responsive.
*Corresponding author: Saroj Kumar Patnaik, Department of Pediatrics, Command Hospital Air Force, Bangalore, PO AGRAM, Bangalore 560007, India, Phone: +91-80-25582232, +91-7676883233, E-mail: [email protected]; [email protected] Vimal Upreti: Department of Endocrinology, Command Hospital Air Force, Bangalore, India Pawan Dhull: Department of Neurology, Command Hospital Air Force, Bangalore, India
Introduction Unexplained encephalopathy often merits exclusion of an endocrinopathy. Autoimmune etiology involving both neural and hormonal pathways in cases of encephalopathy have been studied extensively in recent years (1, 2). Observations of frequent occurrence of autoimmune antibodies in ‘investigation negative encephalopathy’ have led to conceptualization of distinct group of nonvasculitic autoimmune meningoencephalitis (NAIM) or neuronal surface antibody associated syndromes (1, 2). The hallmark of these disorders is a cognitive impairment with varying grades of pyramidal/extrapyramidal involvement, neuropsychiatric symptoms and seizure-like activity with diffuse slowing on electroencephalogram (EEG), essentially, normal neuroimaging and cerebrospinal fluid (CSF) picture, demonstrable autoimmune antibodies in CSF and blood with dramatic symptomatic response to steroids and possible tendency to recur off-steroids (1, 2). Paraneoplastic syndromes and non-oncological disorders with neural nonspecific serologic evidence of autoimmunity are the two broad groups of such disorders (2). Amongst the latter, antibodies directed towards (i) neurotransmitter receptors, such as N-methyl-Daspartate (NMDA) or voltage gated potassium channels, and (ii) autoimmune thyroid antibodies, are the two major subgroups. The former usually presents similar to limbic encephalitis. The latter was labeled as Hashimoto’s encephalopathy from its first description in 1966 and autoimmune origin is presumed owing to high titres of anti-thyroid peroxidase (TPO) antibodies (3). Anti-TPO antibodies occur in the normal population as well as in many neurologic conditions responsive to steroids. This coupled with occurrence of encephalopathy in Graves’
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738 Patnaik et al.: SREAT in childhood disease has led to the renaming of Hashimoto’s encephalopathy as steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) (1, 4–8). An alternative acronym EAATD (encephalopathy associated with autoimmune thyroid disease) also has been proposed. We report an illustrative case and review the published pediatric literature regarding this eminently treatable entity of concern to pediatricians, intensivists, endocrinologists, psychiatrists and neurologists.
Materials and methods Case report A 14-year-old male adolescent was admitted in February 2012 with a single episode of sudden onset loss of consciousness lasting 10 min. Clinical examination, EEG and magnetic resonance imaging (MRI) were normal and he was discharged without any medication to follow-up in neurology outpatient department. A fortnight later, he became restless at home with decreased sleep and a neuropsychiatric consult led to a label of dissociative disorder. Over the subsequent 4 weeks, he gradually deteriorated with persistent temper tantrums and defiant behavior in spite of behavior therapy and family counselling prescribed by a psychiatrist. In April 2012, over 3 days his parents noted excessive sweating, an unsteady gait and mild slurring of speech. His behavior further deteriorated in the form of abusive language and he lapsed into coma after going to sleep following dinner with other family members at home. There was no preceding trauma, drug intake, substance abuse, fever, headache, convulsion, audiovisual disturbances or bladder-bowel incontinence. He had perinatal asphyxia during forceps extraction and his parents were not related. His elder sister, aged 18 years, had grand mal epilepsy. At
admission, the patient weighed 39 kg, was afebrile (36.9 C) with heart rate 112/min, respiratory rate 22/min, blood pressures 114/70 mm Hg, Glasgow Coma Scale 3/15 with 3 mm sluggish pupils, normal fundoscopy, areflexia with bilateral extensor plantars without any meningismus or features of raised intracranial tension. He was put on a ventilator and treated with empirical antibiotics and acyclovir, pending investigation reports. Lumbar puncture revealed clear, normal pressure, acellular CSF with normal protein (0.11 g/L); globulins not increased) and sugar (4.44 mmol/L) and lactate dehydrogenase (LDH) 81 U/l. Acid fast bacillus (AFB)/Gram/fungal stains were negative and cultures were sterile. Serological tests for syphilis, HIV, toxoplasmosis, cytomegalovirus, herpes simplex virus, hepatitis B and Ebstein-Barr virus were negative. CSF serology and polymerase chain reaction (PCR) for enterovirus, measles, mumps, varicella, and arboviruses were negative. CSF electrophoresis revealed a positive oligoclonal band. The Mantoux test was negative. EEG showed generalized slowing with frequency around 2–3 Hz (Figure 1). With persistent coma and negative routine investigations including CSF and neuroimaging (see Table 1), his past medical documents were reviewed. He had been treated earlier for a fracture ulna (right) in 2008 and scabies in 2009. From 2011, he remained under follow-up with otorhinolaryngologist for a deviated left nasal septum and recurrent rhinosinusitis. The most recent episode was treated with amoxicillin in January 2012. He had previously been referred in March 2011 for poor weight gain in spite of an increased appetite for 6 months and a mild goitre with subclinical hypothyroidism was noted. USS thyroid was normal; thyroid scan revealed normal uptake with right lobe uptake greater than left. With persistent coma without evident infective/metabolic derangement after 5 days of admission, a possibility of autoimmune encephalopathy was entertained and he was exhibited to intravenous dexamethasone 4 mg every 6 h. He dramatically regained consciousness after two doses of dexamethasone by injection and was discharged home on day 7 in a fully conscious and ambulant state on a tapering course of low dose prednisolone for 6 months. At 18 months follow-up, he remains euthyroid without any recurrence of altered sensorium and has a normal behavior and school performance.
Figure 1 Electroencephalogram at admission showing generalized slowing with frequency around 2–3 Hz.
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Patnaik et al.: SREAT in childhood 739 Table 1 Temporal profile of investigations. Date
22/03/11
Clinical presentation
Wt loss Episode of Mild goiter URTI
ESR (mm/h) Hb (g/L) TLC (×103/L) DLC (number fraction)
15 142
Platelet count ( × 105/mm3) Urine RE/ME
CXR T3 [nmol/L (N: 1.078–3.234)] T4 [nmol/L (N: 51.48–154.44)] TSH [mIU/L (N: 0.5–6.0)] Anti-TPO antibody levels [IU/mL (N: left lobe Negative Negative Negative
Discharge after recovery from coma
01/08/13
WNL Normal awake record Normal
Right lobe 11.0 × 14.0 mm Left lobe 9.6 × 12.1 mm Isthmus 2.0 mm no focal defect normal vascularity normal lymph nodes Normal
EEG, electroencephalogram; NMDA, N-methyl-D-aspartate; ESR, Erythrocyte Sedimentation Rate; Hb, Hemoglobin; TLC, White Blood cell Count; DLC, White Blood cell Differential count; P, polymorphonuclear cell; L, lymphocyte; E, eosinophil; M, monocyte; B, basophil; Urine RE/ ME, Urine routine examination/microscopic examination; CXR, Chest X Ray; USS, Ultrasonography; T3, Triiodothyronine Total; T4, Thyroxine Total; TSH, Thyroid-stimulating hormone; Anti-TPO, Anti-thyroid peroxidase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; Ca, Serum Calcium; Na, Serum sodium; K, Serum potassium; BUN, Blood urea nitrogen; ECG, Electrocardiogram; HIV, Human Immunodeficiency virus; HBsAg, Hepatitis B surface Antigen; VDRL, Venereal Diseases Reference Laboratory test.
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740 Patnaik et al.: SREAT in childhood
Literature search PubMed was searched using the following strategy: “Hashimoto’s encephalitis” OR “Hashimoto’s encephalopathy” OR “steroid responsive encephalopathy with autoimmune thyroiditis” up to 31 July 2013. Articles pertaining to pediatric age group were narrowed down and reviewed using a filter of age 18 years and less.
Results Our PubMed search revealed 300 articles of Hashimoto’s encephalopathy; 50 pertained to children 18 years or less. Less than five reports are from the Indian subcontinent (5, 6). The relevant literature review is presented in the discussion section.
Discussion Hashimoto’s encephalopathy or SREAT is a rare disorder with prevalence estimate of 2.1 per 100,000. Unawareness and lack of consensus diagnostic criteria for SREAT result in under diagnosis and mislabeling as viral encephalitis (6, 8). A viral etiology remains difficult to disprove in the absence of appropriate diagnostic facilities. Amongst various diagnostic criteria, those proposed by Castillo et al. are the most comprehensive (9) (Table 2). Mean age of presentation in adults is 44 years; most children are above 9 years. Females are more frequently afflicted. Chronic cognitive impairment is a rare presentation (8–10). Recurrent acute/subacute episodes of focal neurological deficit with confusion or seizures akin to our case are more likely. Natural history ranges from a monophasic illness to a remitting-relapsing illness. While spontaneous remissions do occur, dramatic response to cortico steroids as seen in the current report is characteristic (1, 2, 4, 5). Improvement occurs within days. Exceptional cases require prolonged therapy over months. Two clinical subtypes have been proposed by some authors, vasculitic and diffuse progressive (9, 10) (Table 2). These may overlap and may be impossible to differentiate clinically in children. Our case displayed many clinical features described in the literature. Epileptic seizures including status epilepticus at onset is the commonest association with childhood SREAT. Behavioral manifestations range from rumination syndrome to breath holding spells. Neurocognitive impairment leads to a subtle decline in school performance or presents as coma, stupor and confusion. Neuropsychiatric features such as acute personality changes, hallucinations and
psychosis also occur. Extrapyramidal symptoms such as ataxia, asymmetric chorea, cerebellar dysfunction and myoclonus are also observed. Rare reports of optic neuritis and alternating hemiplegia also exist (8–17). Etiopathogenetic mechanism remains unknown. Higher prevalence in females, fluctuating course, specific steroid responsiveness, raised antithyroid antibodies and reported association with other autoimmune disorders do suggest an autoimmune basis for SREAT (4, 6, 17, 18). Although autoimmunity directed against common brainthyroid antigens is an attractive hypothesis, no shared antigen has been identified between the thyroid gland and brain (6, 18). Thyroid hormones increase the cortical serotonergic neurotransmission, and plays an important role in regulating central noradrenergic and gammaaminobutyric acid function (6, 17, 19). It is tempting to speculate that antithyroid antibodies may interfere with the neurotransmitter pathways and result in the clinical picture of SREAT. Apart from anti-TPO and anti-thyroglobulin antibodies present in serum and CSF, other autoantibodies, such as anti-parietal cell antibody or anti-intrinsic factor antibody, as well as antibodies against alpha-enolase and dimethylargininase-1 have also been identified in SREAT (1–3, 17, 20). However, in the absence of a strong correlation between disease severity and antithyroid antibody titres, SREAT might be a mere endpoint manifestation of non-structural abnormalities of CNS function resulting in a coincidence of endocrinopathies, epilepsy and psychoneurologic disorders (1, 6, 7). Thyroiditis and encephalopathy may represent two concurrent autoimmune diseases (18). While the trigger of the autoimmune process is not known, it could be an as yet unidentified viral infection, which is known to induce neurotransmitter receptor activation. For example, H1N1 induced NMDA receptor activation is well documented (21). Our child had rhinosinusitis prior to onset of his symptoms but in the absence of specific viral studies, we cannot pinpoint a causal relationship. The time lag between evidence of autoimmunity and typical presentation of SREAT is well documented in the literature (19). Although considered as a nonvasculitic disorder, lymphocytic vasculitis of cerebral venules and arterioles, lymphocytic perivascular cuffs and microglial activation have been documented in a few rare recurrent cases undergoing brain biopsy prior to steroid therapy (12). Biopsy proven primary CNS demyelination has also been reported (18–23). Although nonspecific, cerebral edema has also been described in many cases and other poorly characterized factors may also contribute. For example, significantly low levels of vitamin D were documented in patients with autoimmune thyroid diseases that were
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Patnaik et al.: SREAT in childhood 741 Table 2 Modified diagnostic criteria for SREAT [adapted from Castillo et al. (see Ref (9))]. A diagnosis of SREAT must fulfil all the following positive and should not fulfil any negative criteria
Positive criteria
Encephalopathy
Steroid responsiveness
Cognitive impairment and one or more of the followinga: (i) Neuropsychiatric features (e.g., hallucinations, delusions, or paranoia) (ii) Myoclonus (iii) Seizures – generalized tonic-clonic or partial (iv) Focal neurologic deficits Complete or near complete return to the patient’s neurologic baseline status following corticosteroid treatment Relapses may occur TSH: 0.3–20 mIU/L Euthyroid: TSH 0.3–5.0 mIU/L Mildly hypothryoid:5.1–20.0 mIU/L
Near normal thyroid function – derangement of thyroid function alone should be insufficient to explain occurrence of encephalopathy Immunological evidence of autoimmunity in form of presence in serum/CSF autoantibodies
Neurophysiology
Neuroimaging
Laboratory
Negative criteria
Lack of improvement to an adequate trial of steroids at 2 mg/kg of prednisolone or equivalent for at least 2 weeks
Significant hypothyroidism: TSH > 20 mIU/L Myxedema coma Symptomatic thyrotoxicosis
Mandatory: Antithyroid autoantibodiesb: Anti-TPO+/ anti-TG Corroborative: Anti anti-parietal cell antibody/anti-intrinsic factor antibody/antialpha-enolase/anti dimethylargininase-1 Normal EEG OR, Steroid responsive EEG abnormalities (diffuse/rhythmic generalized or bifrontotemporal slow wave abnormalities or rarely focal changes) OR, EEG Nonresponsiveness to antiepileptics OR EEG Worsening with antiepilectics Normal OR mild isolated cerebral edema or demyelination insufficient to explain encephalopathy
Serologic evidence of the neuronal surface antibody syndromes (such as voltage-gated calcium channel, voltage-gated potassium channel, anti-NMDA or anti-AMDA receptor or other currently recognized paraneoplastic autoantibodies to indicate another diagnosis) EEG specific patterns of epileptiform disorder consistent with other specific epilepsy EEG nonresponsiveness to immunomodulation
Findings on neuroimaging studies indicating vascular, neoplastic, or other structural lesions to explain the encephalopathy Other evidence in blood, urine, or CSF analyses of an infectious, toxic, metabolic, or neoplastic process to explain the encephalopathy
a Two clinical patterns of presentation have been described: (i) vasculitic presentation, which is stroke-like episodes and mild cognitive impairment; and (ii) diffuse progressive presentation. Seizures have been reported to be the commonest presentation, followed by confusion, myoclonus, cognitive impairment and altered consciousness. Pyramidal, extrapyramidal, myelopathic or cerebellar involvements have also been described. Neuropsychiatric features, such as psychosis, depression and dementia are well recognized and, in rare cases, may be the initial presentation. Differential diagnosis: main subgroups include (i) other autoimmune-encephalopathies without cancer but with neural nonspecific serologic evidence of autoimmunity such as NMDA/AMDA encephalitis; (ii) paraneoplastic encephalopathies, which present as limbic encephalitis; (iii) central nervous system (CNS) vasculitis (primary or secondary); (iv) chronic CNS infections, prion diseases, especially Creutzfeldt-Jakob disease, HIV and neurosyphilis; and (v) mitochondrial cytopathies, especially MELAS. bThere may be a time lag in appearance of autoantibodies and EEG abnormalities as well as disappearance of same after therapy. Abbreviations: EEG, electroencephalogram; TG, thyroglubulin; TSH, Thyroid stimulating hormone; Anti-TPO, anti- thyroid peroxidase; NMDA, N-methyl D- aspartate; AMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor); MELAS, mitochondrial encpahlopathy with lactic acidosis; CSF, cerebrospinal fluid; HIV, human immunodeficiency virus.
related to the presence of anti-thyroid antibodies and abnormal thyroid function tests (24). Routine blood tests are nonspecific. Most frequent laboratory abnormalities are transaminasitis and elevated
erythrocyte sedimentation rate (ESR) (8, 23). Elevated serum ammonia level may occur in presence of hypothyroidism (8, 23). Intrathecal inflammation in CSF is seen in 2 0% cases in children during a follow-up up to 48 months (15). As long-term cognitive sequelae are important, especially in children, a formal neuropsychological assessment after recovery would be vital. This can detect subtle abnormalities early on and helps in guiding long-term steroid therapy (31). Our child continued to be lethargic with poor academic performance
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Patnaik et al.: SREAT in childhood 743
and had subtle mood changes. We chose to use a combination of IV dexamethasone followed by long-term low dose prednisolone. The antithyroid antibody titter may be a marker of treatment response but the long-term significance of the same is not clear (17). In our case, the anti-TPO levels normalized over 18 months. One must keep a lookout for other autoimmune endocrinopathies, apart from thyroiditis in these cases. Although most cases are euthyroid at presentation, periodic monitoring of thyroid function in cases of recovered SREAT must be maintained for an early identification of clinical hypothyroidism/hyperthyroidism and specific therapy. In conclusion, SREAT remains a fascinating but poorly understood clinically and electrographically heterogeneous steroid-responsive encephalopathy associated with thyroid autoantibodies. Characterization of etiopathogenesis remains unsatisfactory. A high level of suspicion is necessary to establish the diagnosis in cases of ‘investigation negative’ acute or subacute encephalopathy presenting to the intensive care unit, as well as those presenting with progressive/relapsing behavioral and cognitive changes, unexplained myoclonus, seizures,
pyramidal tract/extrapyramidal/cerebellar dysfunction or movement disorder. Although the diagnosis is often overlooked at presentation, antithyroid antibody titers should be measured in these situations, even if standard thyroid function tests are normal. Diffusely abnormal EEG, high CSF protein level without pleocytosis and normal neuroimaging provide corroborative clues. A teenage girl with antecedent thyroid disease merits specific attention. Awareness of this entity is crucial given that early recognition and prompt steroid treatment may lead to a favorable prognosis. Neuropsychological assessment is important in all cases. Disclaimer: The opinions reflected in the article are the personal opinions and viewpoints of individual authors and in no way reflect the official position of Directorate General of Armed Forces Medical Services of India. Conflict of interest statement: The authors have nothing to disclose. Received November 11, 2013; accepted January 14, 2014; previously published online March 6, 2014
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