View source for PANDAS

{{short description|Hypothesis in pediatric medicine}}
{{About||the animal|Giant panda|other uses|Pandas (disambiguation)}}
{{Use mdy dates|date=November 2021}}
{{Infobox medical condition (new)
| name            = PANDAS
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| image           = Streptococcus pyogenes 01.jpg
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| caption         = ''Streptococcus pyogenes'' (stained red), a common group A streptococcal bacterium. PANDAS is speculated to be an [[Autoimmune disease|autoimmune condition]] in which the body's own antibodies to streptococci attack the basal ganglion cells of the brain, by a concept known as molecular mimicry.
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| field           = [[Neurology]], [[Psychiatry]]
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'''Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections''' ('''PANDAS''') is a controversial<ref name=Leonardi2024>{{cite journal |vauthors=Leonardi L, Perna C, Bernabei I, Fiore M, Ma M, Frankovich J, Tarani L, Spalice A |title=Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Immunological Features Underpinning Controversial Entities |journal=Children |volume=11 |issue=9  |date=August 2024 |page=1043 |pmid=39334578 |pmc=11430956 |doi=10.3390/children11091043|doi-access=free }}</ref><ref name= Hsu2021>{{cite journal |vauthors=Hsu CJ, Wong LC, Lee WT |title=Immunological dysfunction in Tourette syndrome and related disorders |journal=Int J Mol Sci |volume=22 |issue=2 |date=January 2021 |page=853 |pmid=33467014 |pmc=7839977 |doi=10.3390/ijms22020853 |type= Review|doi-access=free }}</ref><ref>{{cite book |vauthors=Marazziti D, Palermo S, Arone A, et al.|title=Neuroinflammation, Gut-Brain Axis and Immunity in Neuropsychiatric Disorders |chapter=Obsessive-Compulsive Disorder, PANDAS, and Tourette Syndrome: Immuno-inflammatory Disorders |series=Advances in Experimental Medicine and Biology |volume=1411 |pages=275–300 |date=2023 |pmid=36949315 |doi=10.1007/978-981-19-7376-5_13 |isbn=978-981-19-7375-8 |chapter-url=}}</ref><ref name=LaBella2023>{{cite journal |vauthors=La Bella S, Scorrano G, Rinaldi M, Di Ludovico A, Mainieri F, Attanasi M, Spalice A, Chiarelli F, Breda L |title=Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease |journal=Microorganisms |volume=11 |issue=10 |date=October 2023 |page=2549 |pmid=37894207 |pmc=10609001 |doi=10.3390/microorganisms11102549 |doi-access=free |quote=Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is one of the most controversial diseases in pediatric rheumatology.}}</ref> [[Working hypothesis|hypothetical diagnosis]] for a subset of children with rapid onset of [[obsessive-compulsive disorder]] (OCD) or [[tic disorder]]s.<ref name= Sigra2018/> Symptoms are proposed to be caused by [[Group A streptococcal infection|group A streptococcal]] (GAS), and more specifically, group A beta-hemolytic streptococcal (GABHS) infections.<ref name=Sigra2018/> OCD and tic disorders are hypothesized to arise in a subset of children as a result of a post-[[streptococcus|streptococcal]] autoimmune process.<ref name= Dale2017/><ref name= Marazziti2018/><ref name= Zibordi2018/> The proposed link between infection and these disorders is that an [[autoimmunity|autoimmune reaction]] to infection produces antibodies that interfere with [[basal ganglia]] function, causing symptom exacerbations, and this autoimmune response results in a broad range of neuropsychiatric symptoms.<ref name=Sigra2018/>

The PANDAS hypothesis, first described in 1998, was based on observations in clinical case studies by [[Susan Swedo]] ''et al'' at the US [[National Institute of Mental Health]] and in subsequent clinical trials where children appeared to have dramatic and sudden OCD exacerbations and tic disorders following infections.<ref name=BPNACon /> Whether PANDAS was a distinct entity differing from other cases of tic disorders or OCD is debated.<ref name= Hsu2021/><ref name= Chiarello2017/><ref name=Robertson2011>{{cite journal |author=Robertson MM |title=Gilles de la Tourette syndrome: the complexities of phenotype and treatment |journal=Br J Hosp Med (Lond) |volume=72 |issue=2 |pages=100–7 |date=February 2011 |pmid=21378617 |url=http://www.bjhm.co.uk/downloads/BJHM_100_107_Tourette_plus_extra.pdf |doi=10.12968/hmed.2011.72.2.100}}</ref> As the PANDAS hypothesis was unconfirmed and unsupported by data, a new definition was proposed by Swedo and colleagues in 2012.<ref name= Wilbur2019/>  In addition to the 2012 broader '''pediatric acute-onset neuropsychiatric syndrome''' (PANS), two other categories have been proposed: '''childhood acute neuropsychiatric symptoms''' (CANS) and '''pediatric infection-triggered autoimmune neuropsychiatric disorders''' (PITAND).<ref name= Sigra2018/> The CANS/PANS hypotheses include different possible mechanisms underlying acute-onset neuropsychiatric conditions, but do not exclude GAS infections as a cause in a subset of individuals.<ref name= Marazziti2018/><ref name= Zibordi2018/> PANDAS, PANS and CANS are the focus of clinical and laboratory research but remain unproven.<ref name= Wilbur2019>{{cite journal |vauthors=Wilbur C, Bitnun A, Kronenberg S, Laxer RM, Levy DM, Logan WJ, Shouldice M, Yeh EA |title=PANDAS/PANS in childhood: Controversies and evidence |journal=Paediatr Child Health |volume=24 |issue=2 |pages=85–91 |date=May 2019 |pmid=30996598 |pmc=6462125 |doi=10.1093/pch/pxy145}}</ref><ref name= Dale2017>{{cite journal |vauthors=Dale RC |title=Tics and Tourette: a clinical, pathophysiological and etiological review |journal=Curr Opin Pediatr |volume=29 |issue=6 |pages=665–673 |date=December 2017 |pmid=28915150 |doi=10.1097/MOP.0000000000000546 |s2cid=13654194 |type= Review}}</ref><ref name= Marazziti2018>{{cite journal |vauthors=Marazziti D, Mucci F, Fontenelle LF |title=Immune system and obsessive-compulsive disorder |journal=Psychoneuroendocrinology |volume=93 |pages=39–44 |date=July 2018 |pmid=29689421 |doi=10.1016/j.psyneuen.2018.04.013 |s2cid=13681480 |type= Review}}</ref><ref name= Zibordi2018>{{cite journal |vauthors=Zibordi F, Zorzi G, Carecchio M, Nardocci N |title=CANS: Childhood acute neuropsychiatric syndromes |journal=Eur J Paediatr Neurol |volume=22 |issue=2 |pages=316–320 |date=March 2018 |pmid=29398245 |doi=10.1016/j.ejpn.2018.01.011 |type= Review}}</ref>

There is no diagnostic test to accurately confirm PANDAS;<ref name= Ueda2021/> the diagnostic criteria are unevenly applied and the conditions may be overdiagnosed.<ref name= Wilbur2019/> Treatment for children suspected of PANDAS is generally the same as the standard treatments for Tourette syndrome (TS) and OCD.<ref name= Wilbur2019/>  There is insufficient evidence or consensus to support treatment, although experimental treatments are sometimes used,<ref name=Sigra2018/> and [[adverse effect]]s from unproven treatments are expected.<ref name=Johnson2021/> The media and the internet have contributed to an ongoing PANDAS controversy,<ref name=Murphy2010/><ref name=Swerdlow2005/> with reports of the difficulties of families who believe their children have PANDAS or PANS.<ref name= Wilbur2019/> Attempts to influence public policy have been advanced by advocacy networks.<ref name= Wilbur2019/>

== Characteristics ==
The children originally described by [[Susan Swedo]] et al. (1998)<ref name=Swedo1998>{{cite journal|vauthors=Swedo SE, Leonard HL, Garvey M, etal |title=Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases |journal=Am J Psychiatry |volume=155 |issue=2 |pages=264–71 |date=February 1998 |pmid=9464208 |url= http://ajp.psychiatryonline.org/article.aspx?volume=155&page=264 |doi=10.1176/ajp.155.2.264|s2cid=22081877 |url-access=subscription }}</ref> usually had an abrupt onset of symptoms, including motor or vocal [[tic]]s, obsessions, or compulsions.<ref name= Pichichero2009/><ref name=Moretti2008/> In addition to an [[obsessive–compulsive disorder|obsessive–compulsive]] or [[tic disorder]] diagnosis, children may have other symptoms associated with exacerbations such as [[emotional lability]], [[enuresis]], anxiety, and deterioration in handwriting.<ref name=Moretti2008/> There may be periods of remission.<ref name=Lombroso2008>{{Cite journal|journal=Brain Dev |year=2008 |volume=30 |issue=4 |pages=231–7 |title=Tourette syndrome and obsessive–compulsive disorder |vauthors=Lombroso PJ, Scahill L |doi=10.1016/j.braindev.2007.09.001 |pmid=17937978 |pmc=2291145 }}</ref> In the PANDAS model, this abrupt onset is thought to be preceded by a [[Group A streptococcal infection|strep]] throat infection. As the clinical spectrum of PANDAS appears to resemble that of [[Tourette syndrome]] (TS or TD, for Tourette's disorder), some researchers hypothesized that PANDAS and TS may be associated; this idea is challenged and a focus for research.<ref name=Chiarello2017/><ref name=Boileau2011/><ref name=Cortese2011/><ref name=Felling2011/>

Pediatric acute-onset neuropsychiatric syndrome (PANS)<ref name= Wilbur2019/><ref name= Sigra2018/> is a hypothesized disorder characterized by the sudden onset of OCD symptoms or eating restrictions, concomitant with acute behavioral deterioration or severe neuropsychiatric symptoms including sleep, emotional and behavioral disturbances, regression in school performance, or motor and sensory issues.<ref name=Wilbur2019/><!-- See Table 2--><ref name=Sigra2018/> PANS eliminated tic disorders as a primary criterion and placed more emphasis on acute-onset OCD, while allowing for causes other than streptococcal infection. Since PANS encompasses a broader group than PANDAS, children may be more likely to be labeled with PANS and receive testing and treatments promoted for PANDAS that lack scientific support.<ref name= Wilbur2019/>

==Classification==
[[File:Proposed PANDAS.svg|thumb|upright|alt=OCD and chronic tic disorders intersect but neither is a subset of the other. Tic-related OCD is their intersection. PANDAS is a small subset of the union of OCD and tic disorders, and is in all three subregions of their union.|A possible relationship between PANDAS and other early-onset conditions.<ref name=LeckmanBloch2009>{{cite journal |vauthors=Leckman JF, Bloch MH, King RA |title=Symptom dimensions and subtypes of obsessive-compulsive disorder: a developmental perspective |journal=Dialogues Clin Neurosci |volume=11 |issue=1 |pages=21–33 |date=2009 |doi=10.31887/DCNS.2009.11.1/jfleckman |pmid=19432385 |pmc=3181902 }}</ref>]]

PANDAS is hypothesized to be an [[autoimmune disorder]] that results in a variable combination of tics, obsessions, compulsions, and other symptoms with sudden or abrupt onset that may be severe enough to qualify for diagnoses such as chronic tic disorder, OCD, and TS.<ref name= Sigra2018/><ref name= Pichichero2009/> As of 2024, the autoimmune hypothesis of PANDAS is controversial and disputed.<ref name=Leonardi2024/><ref name=LaBella2023/><ref name= Wilbur2019/><ref name= BPNACon/><ref name=EuropeanPartI>{{cite journal |vauthors=Szejko N, Robinson S, Hartmann A, et al |title=European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part I: assessment |journal=Eur Child Adolesc Psychiatry |date=October 2021 |volume=31 |issue=3 |pages=383–402 |pmid=34661764 |pmc=8521086 |doi=10.1007/s00787-021-01842-2}}</ref><ref name=Nielsen2019>{{cite journal |vauthors=Nielsen MØ, Köhler-Forsberg O, Hjorthøj C, Benros ME, Nordentoft M, Orlovska-Waast S |title=Streptococcal Infections and Exacerbations in PANDAS: A Systematic Review and Meta-analysis |journal=Pediatr Infect Dis J |volume=38 |issue=2 |pages=189–194 |date=February 2019 |pmid=30325890 |doi=10.1097/INF.0000000000002218 |s2cid=53523695 }}</ref><ref>{{cite journal |vauthors=Thomas F, Nicolò L, Lucia S, Santi V, Giulia D, Spreafico E, Alessandro O, Alessandro F, Mara A, Giorgia T, Luigi MG, Salvatore S |title=IL-17 in serum and cerebrospinal fluid of pediatric patients with acute neuropsychiatric disorders: Implications for PANDAS and PANS |journal=Eur J Paediatr Neurol |volume=54 |pages=1–7 |date=November 2024 |pmid=39556906 |doi=10.1016/j.ejpn.2024.11.004|url=https://linkinghub.elsevier.com/retrieve/pii/S1090379824001703 |quote=The underlying mechanism of PANDAS and PANS is thought to be autoimmune, but the pathophysiology of the human disease is still controversial and the very existence of those disease entities has long been debated among physicians|doi-access=free |hdl=11573/1735823 |hdl-access=free }}</ref>

PANS, CANS and PITANDs are also hypothesized to be autoimmune disorders.<ref name= Sigra2018/>

===Cause===
The PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are disputed and unconfirmed.<ref name= Wilbur2019/><ref name= Johnson2021/><ref name= Boileau2011>{{cite journal |author=Boileau B |title=A review of obsessive-compulsive disorder in children and adolescents |journal=Dialogues Clin Neurosci |volume=13 |issue=4 |pages=401–11 |year=2011 |doi=10.31887/DCNS.2011.13.4/bboileau |pmid=22275846 |pmc=3263388}}</ref><ref name= Felling2011>{{cite journal |vauthors=Felling RJ, Singer HS |title=Neurobiology of Tourette syndrome: current status and need for further investigation |journal=J. Neurosci. |volume=31 |issue=35 |pages=12387–95 |date=August 2011 |pmid=21880899 |pmc=6703258 |doi=10.1523/JNEUROSCI.0150-11.2011 }}</ref> The cause is thought to be akin to that of [[Sydenham's chorea]] (SC), which is known to result from childhood [[Group A streptococcal infection|group A streptococcal (GAS) infection]] leading to the autoimmune disorder [[rheumatic fever]] of which SC is one manifestation. Like SC, PANDAS is thought to involve autoimmunity to the brain's [[basal ganglia]].<ref name=Pichichero2009>{{Cite book|author=Pichichero ME |chapter=The PANDAS Syndrome |title=Hot Topics in Infection and Immunity in Children V |volume=634 |pages=205–16 |year=2009 |pmid=19280860  |publisher=Springer |isbn=978-0-387-79837-0|doi=10.1007/978-0-387-79838-7_17|series=Advances in Experimental Medicine and Biology |quote= PANDAS is not yet a validated nosological construct.}} Courtesy link to [https://books.google.com/books?id=CxfTmEAqdAoC&q=pichichero&pg=PA205 partial pages].</ref>{{efn|Unlike SC, PANDAS is not associated with other manifestations of acute rheumatic fever, such as [[inflammation of the heart]].<ref name= Pichichero2009/>}}

To establish that a disorder is an autoimmune disorder, the [[Ernst Witebsky|Witebsky criteria]] require 
# that there be a self-reactive antibody, 
# that a particular target for the antibody is identified (autoantigen) 
# that the disorder can be caused in animals and 
# that transferring antibodies from one animal to another triggers the disorder (passive transfer).<ref name=Giavannoni2006>{{Cite book|author=Giavannoni G|title=PANDAS: overview of the hypothesis|series=Advances in Neurology |year=2006 |volume=99 |pages=159–65 |pmid=16536362 |publisher=Lippincott Williams & Wilkins| isbn=978-0-7817-9970-6}} Courtesy link to [https://books.google.com/books?id=hhE74A1fTQkC&pg=PA159 pp. 159–62].</ref>

Results of studies investigating an autoimmune cause that meet Witebsky's criteria are inconsistent, controversial, and subject to methodological limitations.<ref name= Chiarello2017/>

To show that a microorganism causes a disorder, the [[Koch's postulates|Koch postulates]] would require one show that the organism is present in all cases of the disorder, that the organism can be extracted from those with the disorder and be cultured, that transferring the organism into healthy subjects causes the disorder, and the organism can be re-isolated from the infected party.<ref name=Giavannoni2006 /> Giavanonni notes that the Koch postulates are not useful in substantiating PANDAS a post-infectious disorder because the organism may no longer be present when symptoms emerge, multiple organisms may cause the symptoms, and the symptoms may be a rare reaction to a common pathogen.<ref name=Giavannoni2006 />

Some studies support acute exacerbations associated with streptococcal infections among clinically defined PANDAS subjects; others studies have found no association between abrupt onset or exacerbation with infection.<ref name= Wilbur2019/><ref name=Moretti2008>{{Cite journal|vauthors=Moretti G, Pasquini M, Mandarelli G, Tarsitani L, Biondi M |title=What every psychiatrist should know about PANDAS: a review |journal=Clin Pract Epidemiol Ment Health |volume=4|issue=1 |pages=13 |year=2008 |pmid=18495013 |pmc=2413218 |doi=10.1186/1745-0179-4-13 |doi-access=free }}</ref> The PANS hypothesis, then, expands the causes beyond streptococcal infection and postulates that the cause can be genetic, metabolic, or infectious.<ref name= BPNACon/>

Among children with PANS or PANDAS, studies are inconsistent, and the hypothesis that antibodies trigger symptoms is unproven; some studies showed antibodies in children with PANS/PANDAS, but those results were not replicated in other studies.<ref name= Wilbur2019/> A large multicenter study (EMTICS—European Multicentre Tics in Children Studies) showed no evidence in children with chronic tic disorders of strep infections leading to tic exacerbation,<ref name= BPNACon/><ref name= Ueda2021/> or specific antibodies in children with tics, and a study of the [[cerebrospinal fluid]] of adults with TS similarly found no specific antibodies.<ref name= Ueda2021/> The antibodies that were found by one group were collectively named the "Cunningham Panel"; subsequent independent testing showed this panel of antibodies did not distinguish between children with and without PANS, and its reliability is unproven.<ref name= Wilbur2019/><ref name= Martino2020>{{cite journal |vauthors=Martino D, Johnson I, Leckman JF |title=What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders? |journal=Front Neurol |volume=11 |issue= |pages=567407 |date=2020 |pmid=33041996 |pmc=7525089 |doi=10.3389/fneur.2020.567407 |type= Review|doi-access=free }}</ref> A consensus statement from the British Paediatric Neurology Association (BPNA), states that a "causal infection (rather than coincidental infection) or an inflammatory or autoimmune pathogenesis" has not been confirmed, and that "no consistent biomarkers have been identified that accurately diagnose PANDAS or are reliably associated with brain inflammation".<ref name= BPNACon/><ref name= Dale2017/>

===Mechanism===
The mechanism is hypothesized to be similar to that of [[rheumatic fever]], an autoimmune disorder triggered by streptococcal infections, where antibodies attack the brain and cause neuropsychiatric conditions.<ref name=Sigra2018/><ref name=Moretti2008/> The [[molecular mimicry]] hypothesis is a proposed mechanism for PANDAS:<ref name=Ueda2021/> this hypothesis is that [[antigen]]s on the cell wall of the streptococcal bacteria are similar in some way to the [[protein]]s of the heart valve, joints, or brain. Because the antibodies set off an immune reaction which damages those [[biological tissue|tissue]]s, the child with rheumatic fever can develop Sydenham's.<ref name=Bonthius2003>{{Cite journal|vauthors=Bonthius D, Karacay B |title=Sydenham's chorea: not gone and not forgotten |journal=Semin Pediatr Neurol |volume=10 |issue=1 |pages=11–9 |year=2003 |pmid=12785743 |doi=10.1016/S1071-9091(02)00004-9}}</ref> In a typical [[bacteria]]l infection, the body produces [[antibody|antibodies]] against the invading bacteria, and the antibodies help eliminate the bacteria from the body. In some rheumatic fever patients, autoantibodies may attack heart tissue, leading to carditis, or cross-react with joints, leading to arthritis.<ref name=Lombroso2008/> In PANDAS, it is believed that tics and OCD are produced in a similar manner. One part of the brain that may be affected in PANDAS is the [[basal ganglia]], which is believed to be responsible for movement and behavior. It is thought that similar to Sydenham's, the antibodies cross-react with neuronal brain tissue in the basal ganglia to cause the tics and OCD that characterize PANDAS.<ref name= Ueda2021/><ref name=Moretti2008/><ref name = LeckmanBloch2009/>

Whether the group of patients diagnosed with PANDAS have developed tics and OCD through a different mechanism (pathophysiology) than seen in other people diagnosed with TS is unclear.<ref name=Robertson2011/><ref name=Singer2011>{{cite book|author=Singer HS |title=Hyperkinetic Movement Disorders |chapter=Tourette syndrome and other tic disorders |volume=100 |pages=641–57 |year=2011 |pmid=21496613 |doi=10.1016/B978-0-444-52014-2.00046-X |series=Handbook of Clinical Neurology |isbn=9780444520142}}</ref><ref name=LeckmanDSM5/><ref name=Kalra2009/>  Studies of this hypothesis are inconsistent: the strongest supportive evidence comes from a controlled study of 144 children (Mell et al., 2005), but prospective longitudinal studies have not produced conclusive results,<ref name=LeckmanDSM5/> and other studies do not support the hypothesis.<ref name= Ueda2021/>

==Diagnosis==
Neither PANDAS nor PANS are listed as a diagnosis in the 2013 fifth version of the ''[[Diagnostic and Statistical Manual of Mental Disorders]]'' ([[DSM 5]]){{efn|Swedo served as the chair of the Neurodevelopmental Disorders Work Group on the DSM-5 Task Force.<ref>{{cite web|url=http://www.psych.org/MainMenu/Research/DSMIV/DSMV/MeettheTaskForce/SusanSwedoMD.aspx |title= Susan Swedo, M.D.|publisher= American Psychiatric Association|archive-url= https://web.archive.org/web/20120223112644/http://www.psych.org/MainMenu/Research/DSMIV/DSMV/MeettheTaskForce/SusanSwedoMD.aspx |archive-date= February 23, 2012|access-date= November 24, 2021}}</ref>}} or confirmed as distinct disorders.<ref name=BPNACon/><ref name= Chiarello2017>{{cite journal |vauthors=Chiarello F, Spitoni S, Hollander E, Matucci Cerinic M, Pallanti S |title=An expert opinion on PANDAS/PANS: highlights and controversies |journal=Int J Psychiatry Clin Pract |volume=21 |issue=2 |pages=91–98 |date=June 2017 |pmid=28498087 |doi=10.1080/13651501.2017.1285941|s2cid=3457971 }}</ref><ref name= Nazeer2020>{{cite journal |vauthors=Nazeer A, Latif F, Mondal A, Azeem MW, Greydanus DE |title=Obsessive-compulsive disorder in children and adolescents: epidemiology, diagnosis and management |journal=Transl Pediatr |volume=9 |issue=Suppl 1 |pages=S76–S93 |date=February 2020 |pmid=32206586 |pmc=7082239 |doi=10.21037/tp.2019.10.02 |doi-access=free }}</ref><ref name= Gilbert2019>{{cite journal |vauthors=Gilbert DL |title=Inflammation in Tic Disorders and Obsessive-Compulsive Disorder: Are PANS and PANDAS a Path Forward? |journal=J Child Neurol |volume=34 |issue=10 |pages=598–611 |date=September 2019 |pmid=31111754 |pmc=8552228 |doi=10.1177/0883073819848635 }}</ref> PANDAS is mentioned in the [[World Health Organization]]'s [[ICD-11]], effective in 2022, under autoimmune [[Central nervous system disease|central nervous system disorders]], but diagnostic criteria are not defined and no specific code for PANS or PANDAS is given.<ref name= BPNACon>{{cite web|url= https://bpna.org.uk/_common/show_unpro_doc.php?doc=2021Consensusstatementonchildhoodneuropsychiatricpresentations_72d9cfce4e96a31e4f40cb3ba943cb43.pdf |publisher= British Paediatric Neurology Association |title= Consensus statement on childhood neuropsychiatric presentations, with a focus on PANDAS/PANS |date= April 2021 |access-date= November 24, 2021}} See [https://bpna.org.uk/?page=pans-pandas summary here].</ref><ref>{{cite web|title= 8E4A.0 Paraneoplastic or Autoimmune Disorders of the Central Nervous System, Brain or Spinal Cord |work= ICD-11 for Mortality and Morbidity Statistics |publisher= World Health Organization |url= https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/496011112 |date= May 2021 |access-date= November 24, 2021}}</ref> The 2021 European clinical guidelines developed by the [[European Society for the Study of Tourette syndrome]] (ESSTS) did not support the additions made to ICD-11.<ref name=EuropeanGuidelines>{{cite journal |vauthors=Müller-Vahl KR, Szejko N, Verdellen C, et al |title=European clinical guidelines for Tourette syndrome and other tic disorders: summary statement |journal=Eur Child Adolesc Psychiatry  |date=July 2021 |volume=31 |issue=3 |pages=377–382 |pmid=34244849 |doi=10.1007/s00787-021-01832-4 |pmc=8940881 |s2cid=235781456 }}</ref>

Swedo ''et al'' in their 1998 paper proposed five diagnostic criteria for PANDAS:<ref name=Lombroso2008 /> "(1) the presence of a tic disorder and/or OCD consistent with DSM-IV; (2) prepubertal onset of neuropsychiatric symptoms; (3) a history of a sudden onset of symptoms and/or an episodic course with abrupt symptom exacerbation interspersed with periods of partial or complete remission; (4) evidence of a temporal association between onset or exacerbation of symptoms and a prior streptococcal infection; and (5) adventitious movements (e.g., motoric hyperactivity and choreiform movements) during symptom exacerbation".<ref name=Lombroso2008/>

The proposed PANS criteria call for abrupt onset of OCD (severe enough to warrant a DSM diagnosis) or restricted food intake, along with severe and acute neuropsychiatric symptoms from at least two of the following: anxiety, emotional lability or depression, irritability or oppositional behaviors, developmental regression, academic deterioration, sensory or motor difficulties, or sleep or urinary disturbances.  The symptoms should not be better explained by another disorder, such as Syndenham chorea or Tourette syndrome.<ref name= Wilbur2019/> The authors stated that all other causes must be excluded ([[diagnosis of exclusion]]) for PANS to be considered.<ref name= BPNACon/>

There is no diagnostic test to accurately confirm PANDAS.<ref name= Ueda2021/> The diagnostic criteria of all the proposed conditions (PANDAS, PITANDs, CANS and PANS) are based on symptoms and presentation, rather than on signs of autoimmunity.<ref name=Sigra2018/> A commercial test known as the Autoimmune Brain Panel (also known as the Cunningham Panel)—intended to diagnose PANDAS and PANS based on assays of antibodies—did not distinguish between children with and without PANS when independently tested.<ref name=Wilbur2019/><ref name=Ueda2021/>{{efn|See 2017 study of the Cunningham Panel<ref name= HesselmarkOriginal>{{cite journal |vauthors=Hesselmark E, Bejerot S |title=Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel |journal=J Neuroimmunol |volume=312 |issue= |pages=31–37 |date=November 2017 |pmid=28919236 |doi=10.1016/j.jneuroim.2017.09.002|s2cid=24495364 |url= https://www.jni-journal.com/article/S0165-5728(17)30071-1/fulltext|doi-access=free }}</ref> and erratum based on collection tubes.<ref name= HesselmarkCorrigendum>{{cite journal |vauthors=Hesselmark E, Bejerot S |title=Corrigendum to Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel [J. Neuroimmunol. 312. (2017) 31-37] |journal=J Neuroimmunol |volume=313 |pages=116–117 |date=December 2017 |pmid=29153602 |doi=10.1016/j.jneuroim.2017.11.001|s2cid=7958313 |quote=We have evaluated the clinical value of the Cunningham Panel as a diagnostic tool. Our results indicate that the panel does not contribute to correct diagnosis in a clinical setting.|doi-access=free }}</ref>}}

PANDAS may be overdiagnosed: the diagnostic criteria are unevenly applied and a presumed diagnosis may be conferred in "children in whom immune-mediated symptoms are unlikely",<ref name= Wilbur2019/> according to Wilbur ''et al'' (2019). Most patients diagnosed with PANDAS by community physicians did not meet the criteria when examined by specialists, suggesting the PANDAS diagnosis is conferred by community physicians without conclusive evidence.<ref name=Shulman2009>{{Cite journal|author=Shulman ST |title=Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update |journal=Curr. Opin. Pediatr. |volume=21 |issue=1 |pages=127–30 |date=February 2009 |pmid=19242249 |doi=10.1097/MOP.0b013e32831db2c4 |s2cid=37434919 |quote=Despite continued research in the field, the relationship between GAS and specific neuropsychiatric disorders (PANDAS) remains elusive. }} See lay summary [http://www.medscape.com/viewarticle/547096?rss PANDAS May Be Overdiagnosed, Contributing to Overuse of Antibiotics], Medscape, October 26, 2006.</ref><ref name=Ueda2021/><ref name=LeckmanDSM5>{{cite journal  |vauthors=Leckman JF, Denys D, Simpson HB, etal |title=Obsessive-compulsive disorder: a review of the diagnostic criteria and possible subtypes and dimensional specifiers for DSM-V |journal=Depress Anxiety |volume=27 |issue=6 |pages=507–27 |date=June 2010 |pmid=20217853 |doi=10.1002/da.20669 |pmc=3974619 }}</ref>

Because symptoms overlap with many other psychiatric conditions, [[differential diagnosis]] is challenging.<ref name= Sigra2018/> There are several difficulties in distinguishing PANDAS from TS. The two have a similar onset and waxing and waning course, and the sudden onset or exacerbation in tics hypothesized in PANDAS is not uncommon in TS. There is a higher rate of OCD and TS among relatives of children with PANDAS, and those children often have tics preceding a PANDAS diagnosis or may be predisposed to tic disorders; what appears to be a dramatic onset due to GAS infection "may be the natural course of tic disorders", according to Ueda and Black (2021).<ref name= Ueda2021/>

==Treatment==
Treatment for children suspected of PANDAS is generally the same as the standard treatments for TS and OCD.<ref name=Wilbur2019/><ref name=Murphy2010/><ref name= deOliveira2010>{{cite journal |vauthors=de Oliveira SK, Pelajo CF |title=Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS): a Controversial Diagnosis |journal=Curr Infect Dis Rep |volume=12 |issue=2 |pages=103–9 |date=March 2010 |pmid=21308506 |doi=10.1007/s11908-010-0082-7 |s2cid=30969859 |url= https://link.springer.com/article/10.1007%2Fs11908-010-0082-7 |url-access=subscription }}</ref> These include [[cognitive behavioral therapy]] and medications to treat OCD such as [[selective serotonin reuptake inhibitor]]s (SSRIs);<ref name= Wilbur2019/> and "conventional therapy for tics".<ref name= deOliveira2010/>

When individuals have "persistent or disabling symptoms", Wilbur (2019) ''et al'' recommend referral to specialists, treatment of identified acute streptococcal infections according to established guidelines, and immunotherapy only in clinical trials.<ref name= Wilbur2019/>

The use of [[psychotropic medication]]s for PANS/PANDAS is widespread, although controlled trials were lacking {{as of|2019|lc=y}}.<ref name=Wilbur2019/>

===Experimental===
Prophylactic antibiotic treatments for tics and OCD are experimental<ref name=Shulman2009 /> and their use is challenged;<ref name=LeckmanDSM5/> overdiagnosis of PANDAS may have led to overuse of antibiotics to treat tics or OCD in the absence of active infection.<ref name=LeckmanDSM5/> Evidence for antibiotic treatment is inconclusive for PANS, PANDAS, PITAND and CANS.<ref name= Sigra2018/> Murphy, Kurlan and [[James Leckman|Leckman]] (2010) said, "The use of prophylactic antibiotics to treat PANDAS has become widespread in the community, although the evidence supporting their use is equivocal."<ref name=Murphy2010/>

{{as of|2019}}, there is no evidence supporting the use [[rituximab]] or [[Mycophenolic acid|mycophenolate mofetil]] for treating PANDAS/PANS.<ref name= Wilbur2019/>

There is inconclusive evidence supporting immunomodulatory therapies ([[intravenous immunoglobulin]] (IVIG) or [[Plasmapheresis|therapeutic plasma exchange]] (TPE)<ref name=Moretti2008/>) for PANS and PANDAS; most studies have methodological issues.<ref name=Sigra2018/> IVIG was ''perceived'' as effective based on a self-reported survey.<ref name= Sigra2018/> Kalra and Swedo wrote in 2009, "Because IVIG and plasma exchange both carry a substantial risk of adverse effects, use of these modalities should be reserved for children with particularly severe symptoms and a clear-cut PANDAS presentation."<ref name=Kalra2009>{{cite journal |vauthors=Kalra SK, Swedo SE |title=Children with obsessive-compulsive disorder: are they just "little adults"? |journal=J. Clin. Invest. |volume=119 |issue=4 |pages=737–46 |date=April 2009 |pmid=19339765 |pmc=2662563 |doi=10.1172/JCI37563 }}</ref>

Studies of experimental treatments for PANS and PANDAS (IVIG, TPE, antibiotics, tonsillectomy, [[corticosteroid]]s and [[Nonsteroidal anti-inflammatory drug|NSAID]]s) are "few and in general have moderate or high risk of bias", according to a Sigra ''et al'' review published in 2018, which states:<ref name= Sigra2018/>{{blockquote| Nevertheless, there are 3 recent papers proposing guidelines for how to treat PANDAS and PANS using psychiatric and behavioral interventions (Thienemann et al., 2017), immunomodulatory therapies (Frankovich et al., 2017) and antibiotics (Cooperstock et al., 2017). These guidelines are proposed by a consortium of clinicians and researchers ... for children who fulfill criteria for PANDAS or PANS. We believe that our results are in line with the proposed guidelines, and that the lack of evidence for treatment is based not on the inefficacy of the treatments, but on lack of systematic research.|Sigra ''et al'' (2018)<ref name= Sigra2018/>}}

=== Guidelines ===
Following a 2014 meeting in the US of Swedo and physicians from [[Stanford University]],<ref name= BPNACon/> treatment guidelines for PANS and PANDAS were published in 2017, in three parts.<ref name=Thienemann2017>{{cite journal |vauthors=Thienemann M, Murphy T, Leckman J, Shaw R, Williams K, Kapphahn C, Frankovich J, Geller D, Bernstein G, Chang K, Elia J, Swedo S |title=Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I-Psychiatric and Behavioral Interventions |journal=J Child Adolesc Psychopharmacol |volume=27 |issue=7 |pages=566–573 |date=September 2017 |pmid=28722481 |pmc=5610394 |doi=10.1089/cap.2016.0145 }}</ref><ref>{{cite journal |vauthors= Frankovich J, Swedo S, Murphy T, et al|title= Clinical management of pediatric acute-onset neuropsychiatric syndrome: part II—use of immunomodulatory therapies|journal= J Child Adolesc Psychopharmacol |date= September 2017 |volume= 27 |issue= 7 |pages= 574–593 |doi= 10.1089/cap.2016.0148 |pmid= 36358107|pmc= 9836706|doi-access= free }}</ref><ref>{{cite journal |vauthors= Cooperstock MS, Swedo SE, Pasternack MS, Murphy TK |title= Clinical management of pediatric acute-onset neuropsychiatric syndrome: part III—treatment and prevention of infections |journal= J Child Adolesc Psychopharmacol |date= September 2017 |volume= 27 |issue= 7 |pages= 594–606  |doi= 10.1089/cap.2016.0151|pmid= 36358106 |pmc= 9836684 |doi-access= free }}</ref> In a 2018 review, Sigra ''et al'' said of the 2017 guidelines that treatment consensus was lacking and that results were inconclusive.<ref name= Sigra2018/> A 2019 review by Wilbur ''et al'' said that evidence for treatment of children with PANDAS/PANS is lacking, and remission rates in symptoms after treatment "may represent the natural history of [non-PANDAS pediatric OCD] cases rather than true treatment effect".<ref name= Wilbur2019/> The Wilbur ''et al'' 2019 review found no evidence to support [[tonsillectomy]] or [[Preventive healthcare|prophylactic]] antibiotics, recommended standard approved therapies known to be effective for OCD, and cautioned against immunomodulatory therapies except in clinical trials.<ref name= Wilbur2019/> Gilbert (2019) stated: "Skeptics have concluded that treatment studies do not support antibiotic or immunomodulatory interventions for PANDAS. Advocates published treatment guidelines supporting both."<ref name= Gilbert2019/> Gilbert adds that "... if PANS/PANDAS is really common, the best approach will have to be large, randomized, placebo-controlled trials. In addition, it would behoove skeptics and advocates to collaborate in pursuing both good science and sound patient care, while eschewing pseudoscientific approaches and calling out profit-seeking behaviors such as cash-pay clinics, Internet diagnoses, and expert witness testimony."<ref name= Gilbert2019/>

The guideline status in the UK is similar. The PANDAS and PANS Physicians Network published guidelines in 2018 on a private healthcare platform, e-hospital.<ref name= e-Hospital>{{cite web|url= https://www.e-hospital.co.uk/wp-content/uploads/2019/04/PANDAS-Protocol-V1.6.pdf |title= PANDAS & PANS Treatment Guidelines (v1.6) |author= UK PANDAS & PANS Physicians Network|publisher= e-hospital.co.uk |date= November 2018 |access-date= November 24, 2021}}</ref> In April 2021, the British Paediatric Neurology Association (BPNA) issued a consensus statement with the Child and Adolescent Psychiatry Faculty of the [[Royal College of Psychiatrists]] stating that there is an absence of evidence for recommending immunomodulatory or prophylactic antibiotic treatments.<ref name= BPNACon/> This consensus statement was issued in place of a guideline as the authors stated that there was insufficient evidence for developing a typical guideline.<ref name= BPNACon/> It noted no previous guidelines for PANDAS existed or had been endorsed by official bodies in the UK, including the [[National Institute for Health and Care Excellence]] (NICE), and that the 2018 guidelines available at a PANDAS/PANS UK charity website and the private platform (e-hospital) had been developed independently of the BPNA.<ref name=BPNACon/>

Similarly, the April 2021 treatment guidelines for Nordic countries (Denmark, Norway, Sweden and the UK) do not recommend tonsillectomy, antibiotic prophylaxis, or experimental immunomodulatory therapies outside of a specialist setting.<ref name= Nordic>{{cite journal |vauthors= Pfeiffer HC, Wickstrom R, Skov L, Sørensen CB, Sandvig I, Gjone IH, Ygberg S, de Visscher C, Idring Nordstrom S, Herner LB, Hesselmark E, Hedderly T, Lim M, Debes NM |title=Clinical guidance for diagnosis and management of suspected Pediatric Acute-onset Neuropsychiatric Syndrome in the Nordic countries |journal=Acta Paediatr  |date=April 2021 |volume=110 |issue=12 |pages=3153–3160 |pmid=33848371 |doi=10.1111/apa.15875 |s2cid=233234801 |doi-access=free }}</ref> A Swedish review published in 2021 found a moderate potential for [[adverse effect]]s, and a "very low certainty of evidence of beneficial effects", for treating individuals meeting the research definition of PANS with antibiotics, anti-inflammatory medications, or immunomodulatory agents.<ref name= Johnson2021>{{cite journal |vauthors=Johnson M, Ehlers S, Fernell E, Hajjari P, Wartenberg C, Wallerstedt SM |title=Anti-inflammatory, antibacterial and immunomodulatory treatment in children with symptoms corresponding to the research condition PANS (Pediatric Acute-onset Neuropsychiatric Syndrome): A systematic review |journal=PLOS ONE |volume=16 |issue=7 |pages=e0253844 |date=2021 |pmid=34197525 |pmc=8248649 |doi=10.1371/journal.pone.0253844|bibcode=2021PLoSO..1653844J |doi-access=free }}</ref> The Swedish review states that, "some researchers in the United States, on the basis of an assumption of an underlying neuroinflammation, recommend anti-inflammatory drugs, antibiotics and immunomodulatory treatment in the clinical management of these patients, Swedish national guidelines imply that these treatments shall only be provided within the framework of research and development".<ref name= Johnson2021/>

The American Academy of Neurology (AAN) 2011 guidelines say there are "inadequate data to determine the efficacy of plasmapheresis" and "insufficient evidence to support or refute the use of plasmapheresis", for treating OCD and tics "in the setting of PANDAS".<ref name=Cortese2011>{{cite journal |vauthors=Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A |title=Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology |journal=Neurology |volume=76 |issue=3 |pages=294–300 |date=January 2011 |pmid=21242498 |pmc=3034395 |doi=10.1212/WNL.0b013e318207b1f6}}</ref> The Medical Advisory Board of the Tourette Syndrome Association (now the [[Tourette Association of America]]) said in 2006,<ref name=Scahill2006>{{cite journal  |vauthors=Scahill L, Erenberg G, Berlin CM, etal |title=Contemporary assessment and pharmacotherapy of Tourette syndrome |journal=NeuroRx |volume=3 |issue=2 |pages=192–206 |date=April 2006 |pmid=16554257 |doi=10.1016/j.nurx.2006.01.009|pmc=3593444}}</ref> and reiterated in 2021:<ref name= Ueda2021>{{cite journal |vauthors=Ueda K, Black KJ |title=A Comprehensive Review of Tic Disorders in Children |journal=J Clin Med |volume=10 |issue=11 |date=June 2021 |page=2479 |pmid=34204991 |pmc=8199885 |doi=10.3390/jcm10112479 |doi-access=free }}</ref><ref>{{cite web|url= https://tourette.org/research-medical/pandas-pans-and-tourette-syndrome-disorder/ |publisher= Tourette Association of America |title= PANDAS/PANS and Tourette Syndrome (Disorder) |author= TAA PANDAS/PANS Workgroup|access-date= November 24, 2021}}</ref> {{blockquote|"Treatment with antibiotics should not be initiated without clinical evidence of infection and a positive throat culture. Experimental treatments based on the autoimmune theory, such as plasma exchange, immunoglobulin therapy, or prophylactic antibiotic treatment, should not be undertaken outside of formal clinical trials."}} The [[American Heart Association]]'s 2009 guidelines state that they do "not recommend routine laboratory testing for GAS to diagnose, long-term antistreptococcal prophylaxis to prevent, or immunoregulatory therapy (such as intravenous immunoglobulin, plasma exchange) to treat exacerbations of this disorder".<ref name=Gerber2009>{{cite journal  |vauthors=Gerber MA, Baltimore RS, Eaton CB, etal |title=Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics |journal=Circulation |volume=119 |issue=11 |pages=1541–51 |date=March 2009 |pmid=19246689 |doi=10.1161/CIRCULATIONAHA.109.191959 |doi-access=free }}</ref>

In [[Lyme disease]] guidelines released in 2020, experts from medical societies including the AAN, [[American College of Rheumatology]], [[Infectious Diseases Society of America]], and [[American Academy of Pediatrics]] agreed that "there are no data to support a causal relationship between tick-borne infections and childhood developmental delay or behavioral disorders (such as attention deficit-hyperactivity disorder, [PANDAS], learning disabilities, or psychiatric disorders)"<ref name="lyme-guidelines-2020">{{cite journal | vauthors = Lantos PM, Rumbaugh J, Bockenstedt LK, Falck-Ytter YT, Aguero-Rosenfeld ME, Auwaerter PG, Baldwin K, Bannuru RR, Belani KK, Bowie WR, Branda JA, Clifford DB, DiMario FJ, Halperin JJ, Krause PJ, Lavergne V, Liang MH, Meissner HC, Nigrovic LE, Nocton JJ, Osani MC, Pruitt AA, Rips J, Rosenfeld LE, Savoy ML, Sood SK, Steere AC, Strle F, Sundel R, Tsao J, Vaysbrot EE, Wormser GP, Zemel LS | display-authors = 1 | title = Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease | journal = Clinical Infectious Diseases | volume = 72 | issue = 1 | pages = e1–e48 | date = January 2021 | pmid = 33417672 | doi = 10.1093/cid/ciaa1215 | doi-access = free }}</ref> Some advocates had claimed that Lyme disease caused PANDAS, contrary to evidence.<ref name="lyme-guidelines-2020"/><ref name="Spectrum"/>

==Society and culture==
The debate surrounding the PANDAS hypothesis has societal implications; the media and the Internet have played a role in the PANDAS controversy.<ref name=Murphy2010/><ref name=Swerdlow2005/> The news and other media report the difficulties of families who believe their children have PANDAS or PANS.<ref name= Wilbur2019/> Attempts to influence public policy have been advanced by advocacy networks such as the USA-based PANDAS Network and Canadian PANDASHELP.<ref name= Wilbur2019/>

Swerdlow (2005) summarized the societal implications of the hypothesis, and the role of the Internet in the debate surrounding the PANDAS hypothesis:
<blockquote>...&nbsp;perhaps the most controversial putative TS trigger is exposure to streptococcal infections. The ubiquity of strep throats, the tremendous societal implications of over-treatment (e.g., antibiotic resistance or immunosuppressant side effects) versus medical implications of under-treatment (e.g., potentially irreversible autoimmune neurologic injury) are serious matters. With the level of desperation among Internet-armed parents, this controversy has sparked contentious disagreements, too often lacking both objectivity and civility.<ref name=Swerdlow2005>{{cite journal |author=Swerdlow NR |title=Tourette syndrome: current controversies and the battlefield landscape |journal=Curr Neurol Neurosci Rep |volume=5 |issue=5 |pages=329–31 |date=September 2005 |pmid=16131414 |doi=10.1007/s11910-005-0054-8|s2cid=26342334 |url= https://link.springer.com/content/pdf/10.1007/s11910-005-0054-8.pdf }}</ref></blockquote>

Murphy, Kurlan and [[James Leckman|Leckman]] (2010) discussed the influence of the media and the Internet in a paper that proposed a "way forward" with the "group of disorders collectively described as PANDAS":<blockquote>Of concern, public awareness has outpaced our scientific knowledge base, with multiple magazine and newspaper articles and Internet chat rooms calling this issue to the public's attention. Compared with ~ 200 reports listed on Medline—many involving a single patient, and others reporting the same patients in different papers, with most of these reporting on subjects who do not meet the current PANDAS criteria—there are over 100,000 sites on the Internet where the possible ''Streptococcus''–OCD–TD relationship is discussed. This gap between public interest in PANDAS and conclusive evidence supporting this link calls for increased scientific attention to the relationship between GAS and OCD/tics, particularly examining basic underlying cellular and immune mechanisms.<ref name=Murphy2010>{{cite journal |vauthors=Murphy TK, Kurlan R, Leckman J |title=The immunobiology of Tourette's disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: a way forward |journal=J Child Adolesc Psychopharmacol |volume=20 |issue=4 |pages=317–31 |date=August 2010 |pmid=20807070 |doi=10.1089/cap.2010.0043|pmc=4003464 }}</ref></blockquote>

==History==
PANDAS was first described in 1998<ref name=Sigra2018>{{cite journal |vauthors=Sigra S, Hesselmark E, Bejerot S |title=Treatment of PANDAS and PANS: a systematic review |journal=Neurosci Biobehav Rev |volume=86 |issue= |pages=51–65 |date=March 2018 |pmid=29309797 |doi=10.1016/j.neubiorev.2018.01.001 |s2cid=40827012 |doi-access=free }}</ref> by [[Susan Swedo]] and a group of researchers<ref name= BPNACon/> at the US [[National Institute of Mental Health]] (a branch of the [[National Institutes of Health|NIH]]).<ref name= Pichichero2009/> A similar clinical picture was proposed for PITANDs (pediatric infection-triggered autoimmune neuropsychiatric disorders) for those who met the Swedo ''et al'' criteria for PANDAS, but with symptoms triggered by an infection other than GAS.<ref name= Sigra2018/>

[[Michael Pichichero]] (2009) noted several reasons that PANDAS had not been validated as a disease classification. Its proposed age of onset and clinical features reflected a particular group of patients chosen for research studies, with no systematic studies of the possible relationship of GAS to other neurologic symptoms. There was dispute over whether its symptom of choreiform movements was distinct from the similar movements of SC. It was not known whether the pattern of abrupt onset was specific to PANDAS. Finally, there was controversy over whether a temporal relationship between GAS infections and PANDAS symptoms existed.<ref name=Pichichero2009/>

In light of controversies in establishing a basis for the hypothesis, a 2010 paper calling for "a way forward", Murphy, Kurlan and [[James Leckman|Leckman]] said: "It is time for the National Institutes of Health, in combination with advocacy and professional organizations, to convene a panel of experts not to debate the current data, but to chart a way forward. For now we have only to offer our standard therapies in treating OCD and tics, but one day we may have evidence that also allows us to add antibiotics or other immune-specific treatments to our armamentarium."<ref name=Murphy2010/> A 2011 paper by Singer proposed CANS, childhood acute neuropsychiatric symptoms—a new, "broader concept" in favor or requiring only acute-onset.<ref name=CANS/> CANS removes the requirement for GAS infection,<ref name= Sigra2018/> allowing for multiple causes, which Singer proposed because of the "inconclusive and conflicting scientific support" for PANDAS, including "strong evidence suggesting the absence of an important role for GABHS, a failure to apply published [PANDAS] criteria, and a lack of scientific support for proposed therapies".<ref name=CANS>{{cite journal |vauthors=Singer HS, Gilbert DL, Wolf DS, Mink JW, Kurlan R |title=Moving from PANDAS to CANS |journal=J Pediatr |volume= 160|issue= 5|pages= 725–31|date=December 2011 |pmid=22197466 |doi=10.1016/j.jpeds.2011.11.040}}</ref>

By 2012, with limitations of the PANDAS hypothesis published, the broader pediatric acute-onset neuropsychiatric syndrome (PANS) was proposed (also by Swedo and colleagues, following a conference<ref name= BPNACon/>) to create a better defined condition ''for research purposes''.<ref name=Wilbur2019/> It describes individuals with [[eating disorder]]s or rapid onset of OCD along with other neuropsychiatric symptoms,<ref name= Sigra2018/> and postulates that the causes can be other than GAS.<ref name= BPNACon/> Whether the PANS hypothesis defines a distinct entity is unclear {{as of|2019|lc=y}}.<ref name=Wilbur2019/>

Swedo retired from the NIH in 2019, but serves on the scientific advisory board of the PANDAS Physician Network.<ref name=Spectrum/> As of 2020, the NIH information pages (which Swedo helped write) do not mention the studies that do not support the PANDAS hypothesis.<ref name= Spectrum>{{cite web |author= Borrell, Brendan |url= https://www.spectrumnews.org/features/deep-dive/how-a-controversial-condition-called-pandas-is-gaining-ground-on-autism/ |title= How a controversial condition called PANDAS is gaining ground on autism |date= January 2020 |work= Spectrum News |publisher= Simons Foundation |access-date= November 23, 2021}}</ref>

==See also==
* [[Neurological disorder]]

==Notes==
{{notelist|32em}}

==References==
{{reflist|colwidth=32em}}

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{{Obsessive–compulsive disorder}}
{{Topics related to Tourette syndrome}}

[[Category:Central nervous system disorders]]
[[Category:Autoimmune diseases]]
[[Category:Tourette syndrome]]
[[Category:Biology of attention deficit hyperactivity disorder]]
[[Category:Biology of obsessive–compulsive disorder]]
[[Category:Psychiatry controversies]]
[[Category:Neurological disorders in children]]