Research Information
Here you will find chronology and the short summary of each paper in case starting with early insights by Husby in 1976 and then the recent work on passive transfer in 2009. If you click on the underlined words, you'll be taken to the relevant papers.
Dicovery of anti-neural antibodies with GABHS
In 1976, Husby found that antibodies to GABHS bonded with neuronal tissue in the caudate nucleus (basal ganglia).
- He noted that this binding was found for strep of emm-type 6, 11, and 12.
- He also noted that the reaction did not occur in rabbit brains but only human neural tissue.
- 46% of sera from 30 children with rheumatic chorea showed IgG antibody reacting with neuronal cytoplasm of human caudate and subthalamic nuclei.
- The antibody was also detected in 14% of 50 children with active rheumatic carditis. 203 controls showed no such antibody response.
In 1977-1979, Husby found these antibodies were pronounced in Huntington’s Chorea and in Sydenham Chorea
ARF and the D8/17 marker
In 1989 Swedo published her study looking at 70 children with OCD over a ten year period where she noted the incredible similarity in symptoms.
By 1993, Bronze and Dale published their findings that neural tissue had cross reactivity with antibodies to the M protein from strep emm-type 6. This was essentially a rediscovery of Husby but with the further isolation that the antibodies were to the M protein.
In 1994, Swedo published a fascinating paper entitled “Speculations on antineuronal antibody-mediated neuropsychiatric disorders of childhood” where she proposed the hypothesis that neurological abnormalities of childhood may be caused by antineuronal antibodies resulting from a GABHS infection. This seemed to combine Husby’s and Bronze and Dale's theories together.
In 1995, Swedo and Allen found 4 children who exhibited sudden onset OCD symptoms coincident with infections. Two of the children had exacerbations coincident with GABHS infections and two with viral infections. Treatment with plasmapherisis, IVIG and prednisone were all found effective. They called this treatable subset of OCD, PITAND (pediatric infection-triggered auto-immune neuropsychiatric disorder).
In 1997, Swedo found that the D8/17 marker from Khanna (1989) work on Acute Rheumatic Fever seemed to correlate and support the theory of a distinct genetic pre-disposition for OCD and chorea. She labeled this distinct OCD subgroup PANDAS – in case you wondered where the term came in.
IVIG and Plasmaphersis
In 1998, Swedo published the landmark paper entitled “Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.” In which they separated and defined a clinical subgroup of OCD patients.
Challenges to the definition came out almost immediately, most notably from Singer and Kurlan who had been studying Tourettes Syndrome and did not think that the definition properly separated the group from children with TS. This has essentially been the argument for the last decade. Singer/Kurlan testing TS kids and Swedo testing the PANDAS subgroup of OCD kids.
In 1999, Perlmutter and Swedo conducted a blinded placebo controlled study that demonstrated that IVIG and Plasmapherisis reduced symptoms by some 45 and 50% respectively for the PANDAS subgroup. A later study by Nicolson showed no improvement for OCD and TS patients who did not fit the PANDAS subgroup (i.e., no post-streptococcal exacerbations).
Discovery of new antibodies (24.3.1)
In 2003, Kirvan and Swedo published the landmark Nature paper entitled “Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea” which pulled together all the above papers into a finding that there were three distinct antibodies that cross-reacted with Lysogangliosides in the brain. In addition, they found one of these antibodies caused significant CaM Kinase II activation in sera.
During this time, Dale , Church and others were making similar observations regarding anti-basal ganglia-antibodies (ABGA).
However, not all thought the research sufficient. Kurlan, Kaplan and Singer wrote many articles questioning whether the subgroup was sufficiently distinct. They were consistently unable to repeat Swedo's experiments and questioned therefore whether the diagnostic criteria was strong enough and whether causality was actually shown. Unfortunately, most of their studies were on kids with chronic tics and controlled OCD -- It is questionable whether they had any PANDAS subgroup in their proported PANDAS kids.
Clarifying the presentation differences of PANDAS (sudden onset, episodic course)
In 2004, Swedo responded to Kurlan and Kaplan’s comments explaining the different presentation of PANDAS from traditional OCD in that PANDAS presented with sudden onset and distinct episodes unlike the Tourettes presentation from Kurlan.
In 2006, Kirvan and Cunningham published their finding that children from the Swedo studies were distinct from Tourettes and traditional OCD/ADHD patients in that the Sydenham Chorea and PANDAS children had elevated CaM Kinase II activation in their sera.
In 2007, Kirvan further showed that Tubulin is a target of the anti-neural antibodies in patients with sydenham chorea.
Confusing TS subjects with PANDAS OCD subgroup
Despite all of this, in June of 2008, Kurlan and Singer published that their 2 year longitudinal study did not find any of the findings of Swedo or Kirvan. However, it appears that Kurlan was studying Tourettes children (i.e., individuals with relatively stable OCD symptoms) and Singer used rabbit brains for testing for cross-reactivity (despite Husby’s paper in 1977). Based on the very minor changes to OCD levels over the 2 year period, it certainly doesn't look like Kurlan had any PANDAS kids in his group.
Creation of a mouse model of PANDAS (EAE) and passive transfer
In August of 2009 Yaddanapudi showed behavioral abnormalities in a set of mice after innoculation with GABHS. These mice were especially bred to have high T-cell rates and be prone to blood-brain barrier disruption. Yaddanapudi showed that IgG transfered from innoculated mice to non-innoculated mice transferred the behavioral abnormalities. This is known as passive transferance and a key finding for proving auto-antibody effects.
Explanation of how the Blood-brain barrier is crossed
In November 2009, Bartholomäus et al unlocked a key part of explaining how the blood-brain-barrier can be breached. Using mice similar to Yaddanapudi (i.e., bred to have high T-cell rates and prone to blood-brain barrier disruption), they were able to watch individual T-cells cross the blood-brain-barrier. Once across, the T-cells produced inflammation recruiting other T-cells to the site of the breach. This could explain how antibodies in the blood stream cross the blood-brain barrier which has been the missing element since Husby's initial findings over three decades ago.
Research/References:
[Swedo1997] S Swedo et al, “Identification of Children With Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections by a Marker Associated With Rheumatic Fever”, Am J Psychiatry 154:1, January 1997 http://ajp.psychiatryonline.org/cgi/reprint/154/1/110.pdf
[Kirvan2006] Kirvan CA, Swedo SE, Kurahara D, Cunningham MW, "Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham's chorea". 2006 Autoimmunity 39 (1): 21–9. http://www.pandasnetwork.org/CunninghamJNICaMKinase.pdf
[Swedo2004] Swedo SE, Leonard HL, Rapoport JL.” The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction”, Pediatrics. 2004 Apr;113(4):907-11. http://pediatrics.aappublications.org/cgi/reprint/113/4/907
[Moretti2008] Moretti G, Pasquini M, Mandarelli G, Tarsitani L, Biondi M (2008). "What every psychiatrist should know about PANDAS: a review". Clin Pract Epidemol Ment Health 4: 13. http://www.ncbi.nlm.nih.gov/pmc/articles/P...5-0179-4-13.pdf
[Swedo1998] Swedo SE et al., “Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases”, Am J Psychiatry 155:2, February 1998. http://ajp.psychiatryonline.org/cgi/reprint/155/2/264
[Çengel-Kültür2009]Çengel-Kültür2009, et al. "The relationship between group A beta hemolytic streptococcal infection and psychiatric symptoms: a pilot study", The Turkish Journal of Pediatrics 2009; 51: 317-324, http://www.turkishjournalpediatrics.org/pe...pdf_TJP_674.pdf
[Murphy2004] Murphy TK, Muhammad S, Soto O, et al. “Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics”, Biological Psychiatry, Volume 55, Issue 1, Pages 61-68, January 2004 http://www.journals.elsevierhealth.com/per...0704-2/abstract
[Pavone2006] Pavone P, Parano E, Rizzo R, Trifiletti RR (2006). "Autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS, and PANDAS variants". J Child Neurol 21 (9): 727-36. http://jcn.sagepub.com/cgi/content/abstract/21/9/727
[Shet2003]Shet A, Kaplan EL, Johnson DR, Cleary PP, “Immune response to group A streptococcal C5a peptidase in children: implications for vaccine development”, J Infect Dis. 2003 Sep 15;188(6):809-17. http://www.journals.uchicago.edu/doi/pdf/10.1086/377700
[Storch2006]Storch EA, Murphy TK, Geffken, G et al, “Cognitive-Behavioral Therapy for PANDAS-Related Obsessive-Compulsive Disorder: Findings From a Preliminary Waitlist Controlled Open Trial”, Journal of the American Academy of Child & Adolescent Psychiatry: October 2006 - Volume 45 - Issue 10 - pp 1171-1178 http://www.ncbi.nlm.nih.gov/pubmed/17003662
[Murphy2006]Murphy TK, Storch EA, Strawser MS, “Selective serotonin reuptake inhibitor-induce behavioral activation in the PANDAS subtype”, Primary Psychiatry, 2006;13(8):87-89, http://mbldownloads.com/0806PP_Murphy.pdf
[Perlmutter1999]Perlmutter SJ, Leitman SF, Garvey MA, “Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood”, Lancet 1999; 354 : 1153 – 58 http://intramural.nimh.nih.gov/pdn/pubs/pub-5.pdf
[Snider2005]Snider L, Lougee L, Slattery M, Grant P, Swedo S. "Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders". Biol Psychiatry 57 (7): 788–92. 2005 http://intramural.nimh.nih.gov/pdn/pubs/pub-9.pdf
[Nicolson2000]Nicolson et al, “An Open Trial of Plasma Exchange in Childhood Onset Obsessive-compulsive Disorder Without Poststreptococcal Exacerbations. " J Am Acad Child Adolesc Psychiatry 2000, 39[10]: 1313-1315 http://www.ncbi.nlm.nih.gov/pubmed/11026187
[Yaddanapudi2009] K Yaddanapudi, M Hornig, R Serge, J De Miranda, A Baghban, G Villar, W I Lipkin Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection Molecular Psychiatry August 11, 2009 doi:10.1038/mp.2009.77 http://www.nature.com/mp/journal/vaop/ncur.../mp200977a.html
[Schneider2002]Schneider R., Robinson M., Levenson J., “Psychiatric presentations of non-HIV infectious diseases: Neurocysticercosis, lyme disease, and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection”,
Psychiatric Clinics of North America, Volume 25, Issue 1, Pages 1-16 http://www.ncbi.nlm.nih.gov/pubmed/11912935
[Martono2007]Martono D, Church A, Giovannoni, G, “Are antibasal ganglia antibodies important and clinically useful?”, Practical Neurology, 2007; 7: 32-41 http://pn.bmj.com/content/7/1/32.extract