PANDAS: Too Narrow a View of the Neuroimmune Landscape

Back to table of contents Previous article Next EditorialsFull AccessPANDAS: Too Narrow a View the Neuroimmune LandscapeSteven E. Hyman, M.D.Steven HymanSearch for more papers by this author, M.D.Published Online:1 Jan 2021https://doi.org/10.1176/appi.ajp.2020.20111598AboutSectionsView articleView PDFView EPUB ToolsAdd favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail articleA subset children and adolescents with obsessive-compulsive disorder (OCD) have extremely rapid onsets, some occurring over course day. Swedo et al. (1) described 50 rapid-onset cases that were temporally closely associated group A ?-hemolytic streptococcal pharyngitis. The association neuropsychiatric symptoms strep infections was precedented Sydenham’s chorea, frequent manifestation rheumatic fever. Rheumatic fever is an inflammatory condition results from prolonged (and thus far common in preantibiotic era); it characterized fever, rash, arthritis, carditis, often, chorea—rapid jerking movements typically hands, feet, face. Notably, patients chorea are reported high prevalence co-occurring (2, 3). thought result molecular mimicry which antibodies directed against bind epitopes within basal ganglia (4), brain region involved not only movement disorders, but very likely also OCD (5).Taken together, these observations suggested possibility autoantibodies affecting could be responsible strep-associated when its absence. syndrome as pediatric autoimmune disorders (PANDAS). However, status PANDAS diagnostic entity has remained controversial want robust natural-history studies associating infection convincing evidence mechanism. In issue Journal, Xu (6) advance argument validity reporting IgG serum who meet criteria cholinergic interneurons (CINs) other interneuron cell types striatum (a component ganglia). CINs, utilize acetylcholine neurotransmitter, implicated regulation habit learning animal models (7), making them plausible substrate compulsive behaviors. authors had previously shown targeted ablation CINs mouse tic-like stereotypies (8), must recognized diverse genetic pharmacologic manipulations been produce OCD-like (9).Evidence would favor hypothesis pathogenesis includes 1) better documentation reliable temporal relationship between new or recurrent 2) replicable cross blood-brain barrier identifiable striatal (in human tissue). Ultimately, interaction autoantibody targets should alter circuit function manner produces obsessive-compulsive-like (research requires models). useful example comes investigation anti-NMDA receptor antibodies. These often arise response teratomas (not infectious agents), can reliably measured cerebrospinal fluid, psychosis, seizures, neurologic (10).One approach investigating pharyngitis prospectively follow two groups OCD—those whose initial presentation met those did not. Two such (11, 12) examined (laboratory validated) exacerbation recurrence tics. While one prospective (11) found few strep-OCD associations than expected chance, represented five 64 exacerbations. Together case-control find significant diagnosed PANDAS. complementary administration antibiotic prophylaxis goal preventing exacerbations symptoms. Clinical trials date yielded inconsistent (13).Studies immune system involvement both laboratory-based clinical. Antibodies sera on different rodent postmortem tissue (e.g., 14, 15). no pattern antibody binding emerged. Moreover, reportedly failed distinguish Tourette’s control subjects (16, 17).Despite pitfalls inferring diagnosis treatment psychiatry given, inter alia, etiological heterogeneity psychiatric several investigators attempted adduce mechanisms effects modulatory treatments patients. most studied interventions intravenous immunoglobulin (IVIG) plasmapheresis. Again, small number well-designed clinical published (13).Against challenging background, endeavor demonstrate immunologic mechanism Their study design complex, perhaps necessitated paucity rigorously research settings. any case, they report functional immunoglobulins (IgG) three separate cohorts subjects. Results cohort 1 (18), replication data assay study. (five subjects) 2 (six six obtained conducted randomized, double-blind, placebo-controlled trial IVIG where primary outcome measures improvement Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Global Impressions scale (19). achieve endpoint during double-blind phase. Nonresponders phase offered open-label after week 6 showed improvement; however, absence blinding placebo control, cannot interpreted indicate mechanism-based IVIG. third (N=16) (N=12) enrolled seen same clinic drawn. To complicate matters further, included selected positive either trial, whereas 3 response—indeed, receive IVIG.IgG each higher average subjects, albeit overlap levels patient groups. Assays performed immunohistochemistry tissue. Binding neurons examined. No difference observed, consistent selective targeting CINs. An ex vivo slices reduced marker (phospho-rpS6) spontaneous neural activity another type interneuron. Sera treated responded compared their baseline, longer phospho-rpS6 then correlated reduction CY-BOCS score. caution, given drawn show benefit responders used came continuation regression mean time. Additional interpretive bias introduced selecting alone putative response. Notwithstanding concerns, experiments usefully focus attention potential role production warrant follow-up using methodologies.Germane question specificity Given study, sensibly pursued hypothesis-driven bound sera. while replications literature may reflect methodological differences, represent target clinically defined cases, many situations influence construct proposed basis case series context extensive knowledge contrast, large epidemiologic (1,067,743 <18 years age followed 9,620,808 person-years) based Danish registers affirmed particular Severe required hospitalization 84% increase overall risk mental disorders. Less severe antibiotics 40% (20). cohort, non-streptococcal throat increased (N=11,315; incidence rate ratio [IRR]=1.08), including (N=316; IRR=1.28) tic (N=662; IRR=1.25). Partially supporting hypothesis, heterogeneity, elevated (N=15,408; IRR=1.18) produced greatest elevation (N=556; IRR=1.51) (21). Such findings suggest need broaden epidemiological investigations childhood adolescent include populations. It informative respect obtain DNA possible order test polygenic presence antecedent infection.A clear-eyed interpretation diversity molecular, cellular, (5, 9) premature assume unitary even individuals That said, argue well worth effort understand health disease we currently do. Finally, concerns I expressed about experimental designs commentary skepticism thinking anew, narrow our view prematurely. Autoantibodies play pathogenic roles syndromes (10), so complement factors (22), cytokines, mediators. conclusion nexus infection, immunology, illness inadequately explored. warrants significantly scientific investment received.Stanley Center Psychiatric Research at Broad Institute Harvard MIT, Cambridge, Mass.Send correspondence Dr. Hyman ([email protected]).Dr. received funding Stanley Family Foundation, he served advisory boards Brave Neuroscience, F-Prime Capital, Janssen Pharmaceuticals directors Q-State Biosciences Voyager Therapeutics.References1 SE, Leonard HL, Garvey M, al.: Pediatric infections: description first cases. 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Kalin, M.D.1 January 2021 | American Journal Psychiatry, Vol. 178, No. Volume 178Issue 01, 2021Pages 5-7 Metrics KeywordsPediatric Autoimmune Neuropsychiatric Disorders Associated With (PANDAS)NeuroimmunologyObsessive-Compulsive Disorder History Accepted 12 November 2020 Published online print