Accepted ManuscriptTitle: Pediatric acute-onset neuropsychiatric syndrome (PANS) misdiagnosed as autism spectrum disorderAuthors: Marcus Vinicius M. Goncalves, Rodrigo Harger, Vera Braatz, Laura F. Parolin, Audred C. Biondo Eboni
PII:DOI: Reference:To appear in:Author: Maria Aparecida N. Fontana
PII:DOI: Reference:To appear in: Received date:
S0165-2478(18)30319-5 https://doi.org/10.1016/j.imlet.2018.09.009 IMLET 6243
Immunology Letters
PII:DOI: Reference:To appear in:Authors: Andrea Anacleto, Yara Dadalti Fragoso
S0165-2478(18)30319-5 https://doi.org/10.1016/j.imlet.2018.09.009 IMLET 6243S0165-2478(18)30319-5 https://doi.org/10.1016/j.imlet.2018.09.009 IMLET 6243Immunology Letters9-7-2018
Immunology Letters
Please cite this article as: Goncalves MVM, Harger R, Braatz V, Parolin LF, Biondo Eboni AC, Fontana MAN, Anacleto A, Fragoso YD, Pediatric acute- onset neuropsychiatric syndrome (PANS) misdiagnosed as autism spectrum disorder, Immunology Letters (2018), https://doi.org/10.1016/j.imlet.2018.09.009This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pediatric acute-onset neuropsychiatric syndrome (PANS) misdiagnosed as autism spectrum disorderMarcus Vinicius M. Goncalves1, Rodrigo Harger1, Vera Braatz1, Laura F. Parolin1, Audred C. Biondo Eboni1, Maria Aparecida N. Fontana2, Andrea Anacleto3, Yara Dadalti Fragoso3.
- 1- DepartmentofNeurology,UniversidadedaRegiaodeJoinville,UNIVILLE, Joinville, SC, Brazil
- 2- DepartmentofPsychiatry,UniversidadedaRegiaodeJoinville,UNIVILLE, Joinville SC, Brazil
- 3- Department of Neurology, Universidade Metropolitana de Santos, UNIMES, Santos, SP, Brazil
Highlights
- Neuroimmune diseases in childhood are difficult to identify and theirincorrect diagnoses may lead to dramatic consequences
- After a viral infection, a boy was diagnosed as a severe case of autismspectrum disorder
- Five years later, the case was correctly diagnosed and treated as aneurimmune disease
- This is a case of pediatric acute-onset neuropsychiatric syndrome(PANS), triggered by a variety of childhood infections.
Correspondence
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Dear EditorUnfortunately, misdiagnoses of immunological diseases are not rare events in clinical practice. Neuroimmune diseases in childhood are particularly difficult to identify and the incorrect diagnoses may lead to dramatic consequences in the life of a child. In addition, manifestations of autism spectrum disorders are often considered as having neuroimmune etiology, further complicating matters [1,2]. We would like to bring to discussion the case of a six-year old boy who remained severely disabled for five years of his life due to misdiagnoses of immune-related neuropsychiatric symptoms.A six-year-old boy was referred to our group for investigation of a severe neuropsychiatric disorder. At the age of 14 months, he had presented a viral infection, diagnosed as a common cold. At the time, the child presented flu-like symptoms, myalgia, fever, conjunctivitis and middle ear infection. Three weeks later, he developed subacute behavioral changes, becoming agitated, irritable and sleepless. Motor and language skills, which had been adequate for his age, showed marked regression. He started to present excessive blinking and shoulder contractions (described by the family and doctors as “motor tics”) and progressively lost social interaction. Twenty months later, he was diagnosed as a severe case of autism spectrum disorder (ASD), of severity level 4, scoring 52 points on the Childhood Autism Rating Scale (CARS). Despite multidisciplinary care, his clinical condition worsened over the next few years, with frequent tics and notable social isolation. At the age of six years, he was referred for more detailed investigation, which showed positivity for anti-CaM kinase II autoantibodies of 140% (normal range 53 to 130). Autoantibodies against CaM
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kinase II are the hallmark of pediatric acute-onset neuropsychiatric syndrome (PANS), a relatively rare autoimmune disease that can be triggered by a variety of childhood infections [3]. The child was treated with intravenous immunoglobulin (IVIG) 2g/kg, with dramatic improvement immediately after the first of five days of infusions. The symptoms reappeared a few weeks after the last infusion, and magnetic resonance imaging at the time was unremarkable, while the electroencephalogram (figure 1) showed bursts of diffuse slow waves lasting up to 9 seconds.Insert figure 1IVIG therapy was restarted, leading to complete remission of the agitation, tics, irritability and behavioral disorder. At present, the child undergoes treatment with pulses of rituximab 375mg/m2 scheduled to occur every six months.CaM kinase II contains a calcium/calmodulin-dependent protein kinase type II alpha chain and is an important kinase in the central nervous system with a function that may relate to long-term potentiation of neurotransmitter release. CaM kinase II becomes autophosphorylated at Thr-286, allowing the kinase to switch from a calmodulin-dependent to a calmodulin-independent state [4]. CaM kinase II is composed of four different chains: alpha, beta, gamma and delta, and the different isoforms assemble into homo- or heteromultimeric holoenzymes composed of 8 to 12 subunits. Despite the pronounced level of distress and disability often associated with PANS, children are often misdiagnosed and remain without proper treatment. The videos accompanying this report clearly show the bedridden child with the incorrect diagnoses (video 1) and an active child, recovering well after the correct diagnoses and treatment (videos 2 and 3).
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Conflicts of interest and funding: none.
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References
[1]- C. Gottfried, V. Bambini-Junior, F. Francis, R. Riesgo, W. Savino. The impact of neuroimmune alterations in autism spectrum disorder. Front Psychiatry. (2015) 6:121.doi: 10.3389/fpsyt.2015.00121.
[2]- C.J McDougle, S.M. Landino, A. Vahabzadeh, J. O'Rourke, N.R. Zurcher, B.C. Finger, M.L. Palumbo, J. Helt, J.E. Mullett, J.M. Hooker, W.A. Carlezon-Jr. Toward an immune-mediated subtype of autism spectrum disorder. Brain Res. (2015) 1617:72-92.doi: 10.1016/j.brainres.2014.09.048.[3]- T.K. Murphy, D.M. Gerardi, J.F. Leckman. Pediatric acute-onset neuropsychiatric syndrome. Psychiatr Clin North Am. (2014) 37:353-374.doi: 10.1016/j.psc.2014.06.001.[4]- A.M. Jama, J. Fenton, S.D. Robertson, K. Török. Time-dependent auto- inactivation of phospho-Thr286-alphaCa2+/calmodulin-dependent protein kinase II. J Biol Chem. (2009) 284:28146-28155.doi: 10.1074/jbc.M109.005900.
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Figure 1 - Electroencephalogram showing bursts of diffuse slow waves lasting up to 9 seconds.