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Everything posted by Buster

  1. Hi Peglem, Fascinating article! In answer to your question, it seems that the cytokines are generated by B cells, Macrophages, and Dendrite cells. My understanding is that B cells and Macrophages can only activate Memory T-cells (i.e., ones that have already seen the presented antigen signature). Dendrites can activate memory T-cells and naive T-cells (i.e., those that could go either to Th1 or to Th2). So the dendrites seem to be the deciders of whether to send IL-10 or IL-12 to cause the naive T-cell to go to Th1 or Th2. You might want to look at http://en.wikipedia.org/wiki/T-helper_cell . What I found particularly interesting (with respect to PANDAS) was that multiple articles indicate that GABHS produces super-antigens that bind directly with the naive T-cells and thus cut the Dentrite and Macrophages out of the whole process. In one of the studies I was reading it indicated that Th2 (the inflammatory response) was being created even though there wasn't any IL-10 (i.e., that the super antigen was itself causing the production of Th2). So this got me thinking -- yeah, I know I'm out on a limb here, but see what you think. Suppose that the super-antigens are converting naive Th0-cells into Th2 but miscoding them --> causing inflamation, but also creating cells that aren't looking for things the macrophanges want them to find. Instead this super-antigen is causing the creation of Th2 cells that will destroy any Th1 or Th2 cells that would have attacked the actual strep. I know this sounds odd, but why else would the SuperAntigen attach directly to the naive Th0 cells? So now we bring azithromycin into the mix (or progesterone or NSAIDs or aktos or ...) and we get something that is slowing up the production of Th2 cells and rebiasing toward Th1 production. So if the strep were intracellular than the Th1 cells can now get it and not be killed off by these mis-programmed Th2. Anyway, just a theory, but wow! great paper. Regards, Buster
  2. Hi Peglem, Our daughter also did not exhibit high titers despite positive cultures (throat and perianal) for strep. We are pretty sure she got the strep infection 2 months earlier when 5 children from her class were out with high fevers and 2 were cultured positive for strep (we learned afterwards). She had an initial fever and sore throat (which we thought was viral). She appeared physically healthy the following week. However, she had a tooth extraction later in the month and bam! she started shouting and having very pronounced defiant behavior and stopped eating breakfast and had signficant irrational separation anxiety. She had another tooth extraction two weeks later and bam! she stopped eating almost all meals. She then exhibited huge OCD issues with ritualistic questions around food, fear of being > 50 lbs, concerns about body image (this is a 7 year old)! Then we noticed a verbal tic and an odd movement disorder -- a strange jerkiness in motion and clumsiness. Her handwritting had deteriorated into a scrawl. From this, she progressed to suicidal statements. It was horrible. She lost 15% of her weight and we were able to get her into the hospital for malnutrition and they took numerous tests and I insisted on a strep culture, ASO, AntiDNAse B, and B-12 depletion (I had read somewhere about B-12 depletion with nitrous oxide) The strep tests came back positive (both throat and perianal) but the ASO was not considered elevated (31) as was the Anti-DNAse B (149). We then had her sister tested and it turned out she was positive for strep. She was asymptomatic, but dx was willing to work on theory of PANDAS and we tried to clear both with Augmentin while also trying on dd refeeding therapy, CBT, and SSRIs. We had some issues getting sibling cleared of strep. At the 3 week culture, sibling came back positive for strep again (dd was on amoxicillan while we were trying to clear sister). Our dd was having all sorts of symptoms and checking with strep experts they indicated that dd could be recolonizing from the sibling even if on anti-biotics. We put sibling on azithromycin and 3 weeks later the strep test came back negative. We took new titers on dd and titers were down even lower ASO (29) and AntiDNAse(<60). We started searching everywhere for whether strep can exist while there is declining titers. There just wasn't any study showing the rate/circumstances of ASO decline. We reached streptococcal experts at WHO and they indicated that there really wasn't any study of titer behavior with long term strep infections. They indicated a recent study by Kurlan where there was a subject with strep for 23 of 25 months who had continuously declining titers. While we were researching this, we switched our dd to azithromycin since her sister's strep was eradicated with azith. We wondered if the strep was intercellular. On the 9th day of azith, we saw dramatic improvement in all symptoms -- and I mean dramatic (she went from not eating to eating, panic to calm, OCD questions to none, ...). I can fill in lots of other detail here, but the short summary is that we think this whole carrier state is less benign that dxs are making it out to be. Perhaps it was this particular strain/emm-type, but bottom line is dd's symptoms (all of them) that we had been fighting for 5 months were noticably down on day 9 and mostly gone by 30 days. Motion disorder was last symptom to disappear (took 40 days). Now there could be all sorts of reasons for what we saw. We had upped her SSRI during this window -- it could have been the SSRI. She was having headaches and we tried Advil during this time -- this seemed to have a positive effect. Lots of things going on, but definitely the strongest temporal correlation was the azithro. I posted a note at top level about what I've learned thus far about titers. It sure would be interesting to find out how many folks seem to be in this low titers state and potentially have had multi-month/year strep infections that haven't been caught (what is usually called carriage -- but maybe it's not so benign). Best regards, Buster
  3. In reading through multiple posts, it seems there is a lot of confusion about titers and carriage of streptococcal infection. As a parent struggling to understand the medical information, I wanted to post what I've learned thus far and I hope it will be of use to you. 1) Titers need to be compared to a baseline. Direction is much more important than absolute value. Some people produce very significant antibody responses, some don't. Some have high baselines, some don't. Since most often there isn't a test result from the prior month to compare against, most doctors (and labs) use a measure known as the "upper limit of normal" [uLN] as defining the baseline for ASO tests. Then if your single sample is > 130%-150% (depends on lab) of this baseline, they consider the test positive. 2) So this begs the question of what is the ULN for ASO? There are lots of studies here but what is important is that the studies have a very large range. For example in one study, kids not suspected of GABHS strep in the 5-10 year range, had 48% had titers below 100 6.8% had titers of 100 10.6% between 101-125 7.6% between 126-156, 22.1% between 157-195 and 4.5% in 196-244 Unfortunately, even in this study, there didn't seem to be a second measurement taken within 1-2 weeks to look for rise/decline. 3) This begs the question of "what level of response consistitutes a positive?." Could a result of <100 still be an indication of a recent strep infection? The answer appears to be yes, but only if you have a prior value done by the same lab, using the same technique. Most studies show that subjects will have a response 2-4x their baseline, this statistically could still fall within this "normal" range depending on the individual. So again, the importance is to look at trends and not absolute values. 4) What about falling titers? Does a high number indicate a current strep infection? The answer seems to be no. There is just no good study about how fast ASO titers fall and what drives the rate of fall. Thus a single sample really gives no good indication of direction. Most studies agree that the rise is within a week of infection with a peak at 4 weeks, but there isn't a study of whether this peak remains if the initial infection goes untreated. So could someone with an untreated strep infection have a declining ASO titer? -- the answer appears to be yes. For example, the most recent study by Kurlan [June 2008 - Pediatrics] has one subject that has positive throat cultures for 23 of 25 months but the ASO titers are falling within this entire time. What does this mean? No one knows. 5) Do all strains of strep produce an ASO reponse? The best study I've found on this is Kaplan's 2003 paper "Immune Response to Group A streptococcal C5a Peptidase in Children: Implications for Vaccine Development." What this paper shows is that despite positive strep cultures on day 1, at a subsequent visit 4 weeks later, 46% of subjects presented no ASO rise, 55% presented no Anti-DNAseB rise, and 37% presented no rise of either ASO nor Anti-DNAseB There also seems to be good research indicating that skin GABHS infections does not produce ASO response despite producing Streptolysin O. What does this mean? Does this mean that the test was bad? That some strains don't produce the streptolysin O protein? That some people don't mount a high immune response? That the individual is a strep carrier? That the strep was going on for some time and the ASO titers have already fallen? That skin GABHS infection differs from pharangytis GABHS? The answer is that the scientific community doesn't know. There has been no careful study of the decline rate of ASO titers and the entire field of "strep carriers" is not at all clear. So summarizing, a rising ASO titer (regardless of absolute value) is an indication of GABHS strep; however, you need a baseline to be sure it is rising. A falling ASO titer indicates that there was strep, but no one knows when. A high ASO titer could be anything including that the titer is falling, rising, or just a high baseline. Statistically it is likely to be a falling titer. Most will treat a titer of > 400 IU's as a falling titer (i.e., that there was once a strep infection sometime in the past). But the exact time of the infection is not known. The interpretation of a low ASO titer is unclear. There could have been an infection and the titer has already fallen, the baseline for the person could be low, the individual may not respond with a strong immune response, the strain may not produce significant amounts of streptolysin O. One final comment, Swedo does not require high ASO titers or even rising ASO titers to diagnose PANDAS. The titers are checked only when a positive strep culture is not available and you are retroactively looking for an indication of past infection. The flaw with using titers as an indication of prior strep infection is (as I stated above) that "low" values can still be associated with prior strep infections since the rate of ASO titer decline is not known, most people only have a single sample, and the ASO response is variable across individual and strep type. Regards, Buster
  4. Dear thnksmom: A couple of quick comments regarding Dr. Singer's paper in the June issue of Pediatrics. It appears that Dr. Singer is using (or provided) a subset of the sample data from the 2 year study summarized in the Kurlan paper appearing in the same issue. I have a long list of issues with both studies, but let me list the 5 big ones here. 1) This is not a study of sudden onset, but rather one of studying children who have chronic conditions. 75% of the subjects in the proported PANDAS group were diagnosed with TS (a condition requiring symptoms for > 1 year and requiring no remission for > 3 months), 87.5% of those in the control group were diagnosed with TS. Thus the critical item is what separates the PANDAS group from the TS group. 2) The separation critieria used by Kurlan for selecting the PANDAS patients was different from the diagnostic criteria proposed by Swedo. Kurlan used a "clinical course characterized by the abrupt onset of symptoms or by a pattern of dramatic recurrent symptom exacerbations and remission". Swedo used an "Episodic course characterized by acute, severe onset and dramatic symptom exacerbations." (emphasis added) While these sound similar, they are not. Indeed the episodic nature is the key distinguishing element in Swedo's studies as is the severity of the symptoms. Swedo wrote in her May 2003 response to Kurlan, "The episodic, relapasing-remitting course of the PANDAS subgroup is distinctly different from the undulating, waxing-waning course seen in other patients with OCD or tic disorders." In addition, Singer discloses that the average onset was over 4 years prior to his study. Kurlan discloses that the onset was not from documentation, but rather obtained through interviews thus being very prone to recall bias. So it is unclear whether the proported PANDAS subjects met the Episodic course, the severe onset, and the dramatic symptom exacerbations of the Swedo critieria. 3) The subjects attributed to be PANDAS subgroup in the Kurlan study had a CY-BOCS score that changed only 1.6 [-0.4 to 3.6] with controls changing 1.0 [-1.1 to 3.1]. This is hardly episodic given the baseline CY-BOCS scores and certainly does not indicate remission within the 2 year period but rather the small waxing and waning of OCD symptoms and the limited objective accuracy of the CY-BOCS measure. Swedo subjects often exhibited > 15 points of change in CY-BOCS score. Granted, I have some issues with these studies as well, but this 10 fold difference in CY-BOCS measured exacerbations definitely makes one wonder if these are the same subgroups. It is true that the subjects in the Kurlan study had YGTSS-tic exacerbations of 11 pts [4.2-17.9] and certainly this is significant, but most of the other papers on PANDAS focus on the OCD element and less on the tics. This begs the question whether tic-only exacerbations should be treated as the "episodic course" or "dramatic symptom exacerbation" when OCD scores did not move. 4) Many of the subjects in Kurlan's and Singer's studies were on numerous anti-psychotics, alpha-agonists, mood stabilizers, ... and it was very unclear how these variables were controlled. 5) The subjects in the Kurlan study were 11.0 +- 1.7 (i.e., older than almost all Swedo/Snider patients). In the Singer study, the children were listed as being 10.9+-2.5 with a full year difference in the controls 11.8 +-2.3. Almost all Swedo/Snider patients had a mean age of 7.5. So the key question is how many of the kids in Kurlan's and Singer's studies actually had PANDAS as opposed to being kids with severe Tourettes with the unfortunate waxing/waning of tics associated with Tourette symptoms. Please note, that despite my criticism of the studies, I am impressed with the Kulan's study and think the data collected from such a study will be extremely valuable to all sorts of post-study analysis. My difficulty is rather with the critieria of subject selection. No OCD episodic behavior, no documented sudden onset (recall bias only), chronic conditions existing in most cases for > 4 years, older children less prone to strep, ...). Hence the study is a great study of streptococcal relationships in Tourettes, but the lack of episodic OCD behavior makes me doubt that their net caught PANDAS cases. Regards, Buster
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