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I was sorting through my papers on PANDAS and thought I’d package the chronology here and the short summary of each paper in case others are interested in some of the 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.
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, Bronze, Dale 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.
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, Bronze, Dale 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. Sigh.
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).
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. Sigh.
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 -- and thus I certainly have questioned whether they had any PANDAS subgroup in their proported PANDAS kids.
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 -- and thus I certainly have questioned 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 the "explosive onset and exacerbations of OCD symptoms" noted by Swedo. This begs the question of whether 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.
Th17, Autoimmunity and the blood brain barrier
Recently, Wang et al published a remarkable finding that repeated nasal innoculation with live (or dead) GABHS produced Th17 cell response in mice. Th17 was recently identified in 2006 (see Annunziato et al ) and is highly implicated in auto-immune disorders.
In 2007, Kebir et al published the paper "Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation" where it was shown that these Th17 cells are highly pro-inflammatory and promote blood-brain barrier disruption. Perhaps this is the missing link in how auto-antibodies are crossing the blood brain barrier (i.e., GABHS carriage triggers Th17, GABHS infection triggers anti-neuronal antibodies, Th17 disrupts the BBB allowing anti-neuronal antibodies (or B/T-cells) to cross). I certainly hope more research is done here.
While this is a mouse model and may not apply to humans, the study is noteworthy because only carriage was needed. This may explain why an apparent "allergic" reaction is seen in some children -- i.e., that only colonization is necessary on subsequent exposure and not infection.
What I find rather fascinating about all the above is the nice trail of good science leading up to the discovery of the antibodies and that the strongest counter evidence is the inability of Singer and Kurlan to duplicate the work of the other researchers. My belief is that Swedo or one of the others should ship Kurlan a control so that Singer and Kurlan can at least check their tests
.Quite a saga.
Regards,
Buster
This post has been edited by Buster: 24 July 2010 - 11:06 AM
