This review and commentary is the product of an invited lecture called “Autoimmunity: PANS/PANDAS” presented at the 2018 Neurobiology of Diseases in Children Symposium in Chicago, IL. The talk addressed clinical and scientific questions and recently published data. At this time, among highly experienced and respected clinicians and researchers spanning relevant disciplines, there is substantial controversy regarding a role for inflammation in producing tics and obsessive-compulsive disorder. This commentary summarizes these controversies, discusses reasons for opposing views on best clinical practices, and concludes with suggestions for pathways forward.
GrausFTitulaerMJBaluRet al.A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391–404.
2.
SingerHS. Autoantibody-associated movement disorders in children: proven and proposed. Semin Pediatr Neurol. 2017;24(3):168–179.
3.
SigraSHesselmarkEBejerotS. Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev. 2018;86:51–65.
4.
GilbertDLMinkJWSingerHS. A pediatric neurology perspective on pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection and pediatric acute-onset neuropsychiatric syndrome. J Pediatr. 2018;199:243–251.
5.
SmithW. Case of insanity depending on syphilitic infection. Br Med J. 1868;2(393):30.
6.
CheadleWB. The various manifestations of the rheumatic state as exemplified in childhood and early life. Lancet. 1889;1(821):921–927.
7.
HobbsA. The role of wound infection as a factor in the causation of insanity. Am J Psychiatry. 1899;56(1):89–94.
8.
BriggsLV. A consideration of auto-intoxication and auto-infection as cause of various mental disorders. Boston Med Surg J. 1905;152(1):1–5.
9.
CottonHA. The Defective, Delinquent, and Insane; the Relation of Focal Infections to Their Causation, Treatment, and Prevention. Princeton, NJ: Princeton University Press; 1921.
10.
FrenchJG. Infection of the nasal sinuses in relation to insanity. Lancet. 1927;210(5418):13–14.
11.
SellingL. The role of infection in the etiology of tics. Arch Neurol Psychiatry. 1929;22:1163–1171.
12.
OslerW. On Chorea and Choreiform Affectations. Philadelphia, PA: P. Blakiston, Sons & Co; 1894.
13.
DiefendorfAR. Mental symptoms of acute chorea. J Nerv Ment Disord. 1912;39:161–172.
14.
EbaughFG. Neuropsychiatric aspects of chorea in children. JAMA. 1926;87:1083–1088.
15.
FreemanJMAronAMCollardJEMacKayMC. The emotional correlates of Sydenham’s chorea. Pediatrics. 1965;35:42–49.
16.
ShpitserI.Disease models, part I: Graphical models. Medical Imaging Informatics. Boston, MA: Springer; 2010:335–369.
17.
CoppenEMRoosRA. Current pharmacological approaches to reduce chorea in Huntington’s disease. Drugs. 2017;77(1):29–46.
18.
GewitzMHBaltimoreRSTaniLYet al.Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131(20):1806–1818.
19.
GerberMABaltimoreRSEatonCBet al.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. Circulation. 2009;119(11):1541–1551.
20.
GilbertDL. Acute and chronic chorea in childhood. Semin Pediatr Neurol. 2009;16(2):71–76.
21.
AxleyJ. Rheumatic chorea controlled with haloperidol. J Pediatr. 1972;81(6):1216–1217.
22.
AronsonNDouglasHSLewisJM. Cortisone in Sydenham’s chorea; report of two cases. JAMA. 1951;145(1):30–33.
23.
SchwarzH. Chorea gravis (Sydenham’s chorea) treated with cortisone and ascorbic acid. Can Med Assoc J. 1951;65(2):150–151.
24.
SigwaldJGirouxM. Very grave form of Sydenham’s chorea cured in a few days by cortisone therapy [in French]. Rev Neurol (Paris). 1951;85(4):278–280.
25.
PazJASilvaCAMarques-DiasMJ. Randomized double-blind study with prednisone in Sydenham’s chorea. Pediatr Neurol. 2006;34(4):264–269.
26.
SwedoSELeonardHLGarveyMet al.Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155(2):264–271.
27.
Swedo SE, Leckman JF, Rose NR. From Research Subgroup to Clinical Syndrome: Modifying the PANDAS Criteria to Describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr Therapeut. 2012;2:113.
28.
KurlanR. Tourette’s syndrome and “PANDAS”: will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Neurology. 1998;50(6):1530–1534.
29.
GilbertDLKurlanR. PANDAS: horse or zebra?Neurology. 2009;73(16):1252–1253.
30.
SingerHS. PANDAS and immunomodulatory therapy. Lancet. 1999;354(9185):1137–1138.
31.
BudmanCCoffeyBDureLet al.Regarding “antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders.”Biol Psychiatry. 2005;58(11):917; author reply 918-919.
32.
MinkJW. Intravenous immunoglobulin is not an effective treatment for pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2016;55(10):837–838.
33.
JohnsonDRKurlanRLeckmanJKaplanEL. The human immune response to streptococcal extracellular antigens: clinical, diagnostic, and potential pathogenetic implications. Clin Infect Dis. 2010;50(4):481–490.
34.
GabbayVCoffeyBJBabbJSet al.Pediatric autoimmune neuropsychiatric disorders associated with streptococcus: comparison of diagnosis and treatment in the community and at a specialty clinic. Pediatrics. 2008;122(2):273–278.
35.
PupilloJ. PANDAS/PANS treatments, awareness evolve, but some experts skeptical. AAP News. American Academy of Pediatrics; 2017.
36.
BejerotSHesselmarkE. The Cunningham Panel is an unreliable biological measure. Transl Psychiatry. 2019;9(1):49.
37.
PowersSWCoffeyCSChamberlinLAet al.Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med. 2017;376(2):115–124.
38.
GlauserTACnaanAShinnarSet al.Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010;362(9):790–799.
39.
SalleeFKohegyiEZhaoJet al.Randomized, double-blind, placebo-controlled trial demonstrates the efficacy and safety of oral aripiprazole for the treatment of Tourette’s disorder in children and adolescents. J Child Adolesc Psychopharmacol. 2017;27(9):771–781.
40.
MarchJSBiedermanJWolkowRet al.Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA. 1998;280(20):1752–1756.
41.
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS). Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. Mol Psychiatry. 2018;23(5):1181–1188.
42.
OttoMA. Antibiotics have a role in PANS even with no infection. Clinical Psychiatry News. 2017.
43.
BerendeATer HofstedeHJMVosFJet al.Effect of prolonged antibiotic treatment on cognition in patients with Lyme borreliosis. Neurology. 2019;92(13):e1447–e1455.
44.
Kurlan R, Johnson D, Kaplan EL; Tourette Syndrome Study Group. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics. 2008;121(6):1188–1197.
45.
LeckmanJFKingRAGilbertDLet al.Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry. 2011;50(2):108–118.e3.
46.
Cooperstock MS, Swedo SE, Pasternack MS, Murphy TK; for the PANS/PANDAS Consortium. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part III—treatment and prevention of infections. J Child Adolesc Psychopharmacol. 2017;27(7):594–606.
47.
SingerHSGiulianoJDZimmermanAMWalkupJT. Infection: a stimulus for tic disorders. Pediatr Neurol. 2000;22(5):380–383.
48.
SingerHSGilbertDLWolfDSMinkJWKurlanR. Moving from PANDAS to CANS. J Pediatr. 2012;160(5):725–731.
OrlovskaSVestergaardCHBechBHNordentoftMVestergaardMBenrosME. Association of streptococcal throat infection with mental disorders: testing key aspects of the PANDAS hypothesis in a nationwide study. JAMA Psychiatry. 2017;74(7):740–746.
51.
DileepanTSmithEDKnowlandDet al.Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells. J Clin Invest. 2016;126(1):303–317.
52.
MurphyTKParker-AthillECLewinABStorchEAMutchPJ. Cefdinir for recent-onset pediatric neuropsychiatric disorders: a pilot randomized trial. J Child Adolesc Psychopharmacol. 2015;25(1):57–64.
53.
MurphyTKLewinABParker-AthillECStorchEAMutchPJ. Tonsillectomies and adenoidectomies do not prevent the onset of pediatric autoimmune neuropsychiatric disorder associated with group A streptococcus. Pediatr Infect Dis J. 2013;32(8):834–838.
54.
PavonePRapisardaVSerraAet al.Pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection: the role of surgical treatment. Int J Immunopathol Pharmacol. 2014;27(3):371–378.
55.
WilliamsKASwedoSEFarmerCAet al.Randomized, controlled trial of intravenous immunoglobulin for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Am Acad Child Adolesc Psychiatry. 2016;55(10):860–867.e2.
56.
FrankovichJSwedoSMurphyTet al.Clinical management of pediatric acute-onset neuropsychiatric syndrome: part II—use of immunomodulatory therapies. J Child Adolesc Psychopharmacol. 2017;27(7):574–593.
57.
ChangKFrankovichJCooperstockMet al.Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2015;25(1):3–13.
58.
FrankovichJThienemannMPearlsteinJCrableABrownKChangK. Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. J Child Adolesc Psychopharmacol. 2015;25(1):38–47.
59.
CalapriceDTonaJParker-AthillECMurphyTK. A survey of pediatric acute-onset neuropsychiatric syndrome characteristics and course. J Child Adolesc Psychopharmacol. 2017;27(7):607–618.
60.
MurphyTKBrennanEMJohncoCet al.A double-blind randomized placebo-controlled pilot study of azithromycin in youth with acute-onset obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2017;27(7):640–651.
61.
Advisory Commission on Childhood Vaccines. Rockville, MD: Health Resources and Services Administration, Department of Health and Human Services; 2017.
62.
Decision on Entitlement, No. 15-1146 V. United States Court of Federal Claims OoSM. 2017.
63.
HornigM. The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr Opin Rheumatol. 2013;25(4):488–795.
64.
Bos-VenemanNGOliemanRTobiasovaZet al.Altered immunoglobulin profiles in children with Tourette syndrome. Brain Behav Immun. 2011;25(3):532–538.
65.
RaisonCLRutherfordREWoolwineBJet al.A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31–41.
66.
KohlerOBenrosMENordentoftMet al.Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71(12):1381–1391.
67.
KissingerBDwyerM. Illinois becomes 1st state requiring insurers to cover treatment for kids with PANDAS. WGN TV. 2017.
68.
TaylorRBMasonWKongKWennbergR. Reversible paraneoplastic encephalomyelitis associated with a benign ovarian teratoma. Can J Neurol Sci. 1999;26(4):317–320.
69.
DalmauJGleichmanAJHughesEGet al.Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091–1098.
70.
DalmauJTuzunEWuHYet al.Paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25–36.
71.
ArmangueTTitulaerMJMalagaIet al.Pediatric anti-N-methyl-d-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr. 2013;162(4):850–856.e2.
72.
ArmangueTSpatolaMVlageaAet al.Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760–772.
73.
GroseljUTansekMZBattelinoT. Fifty years of phenylketonuria newborn screening—a great success for many, but what about the rest?Mol Genet Metab. 2014;113(1-2):8–10.
74.
la MarcaG. Mass spectrometry in clinical chemistry: the case of newborn screening. J Pharm Biomed Anal. 2014;101:174–182.
75.
HesselmarkEBejerotS. Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS)—sensitivity and specificity of the Cunningham Panel. J Neuroimmunol. 2017;312:31–37.
76.
MurphyMLPichicheroME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002;156(4):356–361.
77.
KopeloffNKirbyGH. Focal infection and mental disease. Am J Psychiatry. 1923;80(2):149–197.
78.
PearlJMackenzieD. The Book of Why: The New Science of Cause and Effect. New York, NY: Basic Books; 2018.
79.
SwedoSEFrankovichJMurphyTK. Overview of treatment of pediatric acute-onset neuropsychiatric syndrome. J Child Adolesc Psychopharmacol. 2017;27(7):562–565.
80.
WakefordR. Association and causation in epidemiology—half a century since the publication of Bradford Hill’s interpretational guidance. J R Soc Med. 2015;108(1):4–6.
81.
IoannidisJPA. The proposal to lower P value thresholds to .005. JAMA. 2018;319(14):1429–1430.
82.
HellmuthJRabinoviciGDMillerBL. The rise of pseudomedicine for dementia and brain health. JAMA. 2019;321(6):543–544.
83.
Rae-GrantADayGSMarrieRAet al.Comprehensive systematic review summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):789–800.
84.
ThienemannMMurphyTLeckmanJet al.Clinical management of pediatric acute-onset neuropsychiatric syndrome: part I—psychiatric and behavioral interventions. J Child Adolesc Psychopharmacol. 2017;27(7):566–573.
85.
BrownKFarmerCFarhadianBHernandezJThienemannMFrankovichJ. Pediatric acute-onset neuropsychiatric syndrome response to oral corticosteroid bursts: an observational study of patients in an academic community-based PANS clinic. J Child Adolesc Psychopharmacol. 2017’27(7):629–639.
86.
BrownKDFarmerCFreemanGMJret al.Effect of early and prophylactic nonsteroidal anti-inflammatory drugs on flare duration in pediatric acute-onset neuropsychiatric syndrome: an observational study of patients followed by an academic community-based pediatric acute-onset neuropsychiatric syndrome clinic. J Child Adolesc Psychopharmacol. 2017;27(7):619–628.
87.
PaulKCLingCLeeAet al.Cognitive decline, mortality, and organophosphorus exposure in aging Mexican Americans. Environ Res. 2018;160:132–139.
88.
PezziniAGrassiMDel ZottoEet al.Influence of acute blood pressure on short- and mid-term outcome of ischemic and hemorrhagic stroke. J Neurol. 2011;258(4):634–640.
89.
TverskyAKahnemanD. Judgment under uncertainty: heuristics and biases. Science. 1974;185(4157):1124–1131.
90.
FeynmanRPRobbinsJSturmanHLöhnbergA. The Pleasure of Finding Things Out. Amsterdam: Nieuw Amsterdam; 2005.
91.
WingerterM. Oklahoma state-funded program sends out claim donkey milk treats disease. The Oklahoman. 2018.
92.
YvonSOlierMLevequeMet al.Donkey milk consumption exerts anti-inflammatory properties by normalizing antimicrobial peptides levels in Paneth’s cells in a model of ileitis in mice. Eur J Nutr. 2018;57(1):155–166.
