Buster

Alex, I think your explanation is very plausible. It is what we think was going on with our daughter. Augmentin did seem to help initially, but our prophylactic dose of amoxicillin was insufficient to prevent re-infection from her sister. Azithromycin was very effective but in our case it took 10 days of treatment before we saw benefit. At the worst, our dd9's CaM Kinase was 253. This was in the middle of an exacerbation. In our case, we did try prednisone in combination with azithromycin and this was effective. However, the effect we saw was at 2 weeks post burst. I mention this because others on the forum seemed to have immediate benefit. That was not the case for us. Similarly once we did IVIG it took 2 weeks before that took effect. Bottom line is that you read the papers the same way I did and I'd be happy to followup in an IM if there's anything we can answer for you. Best regards, Buster

Anyone know how to send a response to their request about how to help the girl? Seems someone should recommend checking for anti-neural antibodies and Cam Kinase II activation. Buster

Totally agree and wish they'd just repeat Kirvan's and Cunningham's work that explains a plausible pathogenesis that would be diagnostically useful rather than these needles in haystack experiments. The study is fine for what it is, but the reason for my post was to hopefully ensure that folks knew something about the study and in particular the quote that "untreated strep" has a higher correlation with OCD. Given that throat cultures were done in only 10% of the strep diagnosis -- this probably means that lots of strep went undetected (or wasn't coded). Regard, Buster

In the October 20th issue of Neurology, there is a new retrospective study entitled "Streptococcal infection, Tourette syndrome, and OCD: Is there a connection?" http://www.neurology.org/cgi/reprint/73/16/1256 The paper is a UK study paralleling the work by Mell in 2005 "Association between streptococcal infection and obsessive-compulsive disorders, Tourette's syndrome, and tic disorder" http://pediatrics.aappublications.org/cgi/reprint/116/1/56 The new paper looked at the coding records of 678,862 patients selecting 4784 patients for the study. The subset was selected by looking for OCD/Tourette's diagnosis and then matching for age. It seemed odd that a pediatrician would diagnose OCD (a psychiatric disorder) rather than referring the child to a psychiatrist, but that's what the study found. In any case, they isolating 129 cases of OCD and 126 cases of TS/tics and used 2211 age-matched controls for OCD and 2308 age-matched controls for TS/tics. Curiously the study found only 22 of the OCD cases had onset < 10 yrs old. The majority of cases (71) had onset > 16. This meant that they found the overall incidence of OCD to be 1:5000, and for children < 10 to be 1:33,000. What was also strange was that only 20 of the OCD or tic cases had a preceding strep infection within the last 2 years. 9 of these cases were not treated and 11 were treated with antibiotics. The study concludes that the data does "not support a strong relationship between streptococcal infections and neuropsychiatric syndromes" however, it did note with caution that incidences of OCD were more likely to have had an untreated possible strep infection (i.e., no antibiotics were prescribed). What I found amazing about the whole study was that in looking at 685 cases of likely strep over a 5 year period, there were only 67 throat swabs and only 6 ASO titers. Thus in > 90% of cases, strep throat was being diagnosed by clinical signs. If the sample on this forum is any indiction, there was probably a lot of undiagnosed strep. I'm not sure what to make of the study at this point. It did not look at suddenness of onset, did not apparently look for multiple strep infections, did not look at remission of symptoms. It is impossible to tell if the presented cases differ from traditional OCD. If we assume that the <5% of traditional OCD cases are actually PANDAS, then the study is underpowered and no PANDAS children were likely found. Kurlan and Gilbert have commentary about PANDAS and SC in the same issue but don't really help any (particularly as they fail to acknowledge the finding of higher incidence for untreated strep). Buster

I totally agree with you. When dd9 was at her worst, there was no way anyone could ignore it -- screaming psychotic suicidal statements right in the middle of the doctor's office. Horrible contamination fears with occular migraines and hallucinations (seeing ghosts). Okay that was really, really scary -- that was the peak. If we had only seen the minor vocal tic, movement disorder/hand tremor, deteriorating handwriting, defiant/compulsive behavior that we saw when on prophylaxic antibiotic (i.e., when she was 70% better), we probably would have thought it was "our version of normal kids -- kids get tics and stuff." By seeing the extreme and making daily logs, we could totally see the pattern. When dd9 was in an exacerbation (i.e., > 3 days), we would bring in dd6 (her sister) and her sister would be positive for GABHS (4 out of 5 times this past year -- and on the 5th one we think it was a bad throat swab ). Anyway, we definitely had a canary for GABHS in the house. We did culture her sister 3 weeks post treatment to ensure that she actually cleared. What a year.... In our case, we can totally say that there is a before IVIG an after IVIG child. We can absolutely say there is a correlation between GABHS in the home and exacerbations. We can absolutely say that we understand why if they had this in the 1800's they'd think the child was possessed. There is nothing benign about PANDAS. Regards, Buster

Quoting from the NIMH website: A positive throat culture is all that is necessary. ASO and anti-DNAse tests should be used only if you missed the throat (or skin) culture. Have you been able to clear your son with antibiotics (i.e., a negative throat culture 2 weeks post treatment with antibiotics)? Buster

Streptolysin-O is neutralized by cholestrol. This is why if you have a skin infection you generally won't have any ASO rise. In addition, in many with carrier state GABHS, it appears that several of the exotoxins are disabled and several of the proteins (such as M1) are also disabled. It is not known why this happens for carriers. Buster

Okay, deep breath, .... The antibody that is thought to cause PANDAS is NOT ASO or AntiDNase-B. These antibodies do not rise in over 37% of patients with streptococcal infections -- i.e. in more than a third of kids, the ASO and AntiDNAse-B measures are meaningless. The antibody that is thought to cause PANDAS is targeting a carbohydrate on the cell wall of GABHS. This antibody response can happen even if there is only a mild infection or mild invasion for children who's immune system is hyper-sensitized to GABHS (the bacteria). The PANDAS antibody can activate even if ASO and Anti-DNAse B don't. If you are wondering why Singer, Kurlan, Kaplan and the crew all focus so closely on ASO and Anti-DNAse B is that they basically have no other method to have a "definite" strep infection. So all their studies are about "definite" infections, they haven't bothered yet to test "probable". Oh, I could go on and on about sampling theory problems here....but let me just keep it simple, the Kirvan studies matter because they've found a differnet antibody that seems to rise in those with SC and PANDAS -- regardless of ASO titers when the PANDAS/SC child is exposed to GABHS. Regards, Buster

Yikes. Was her C8/C4 ratio also off the charts? No it doesn't mean that. The strep titers are measures of a response to two exotoxins of strep (so it isn't really a titer against strep but rather a titer against something that strep produces). About 46% of kids do not mount an ASO response even in the face of positive throat cultures. Was she positive on a throat culture each time (or the month before) she had the titers taken? If she didn't have a positive culture 4-8 weeks before the titers were drawn it would be unlikely they would be elevated. Well, usually when folks use the term strep titers, they mean ASO or Anti-DNAseB which test for the presence of the exotoxins Streptolysin-O and Deoxyribonuclease B. There are lots of antibodies created to strep and to the exotoxins of strep. The two above are just the most common commercially available tests -- despite a high false negative rate. The Cunningham antibodies are targeting a particular carbohydrate on the strep itself (known as GlcNAc). So the Cunningham antibodies have nothing to do with the ASO or Anti-DNAse B at all. Well, that's a bit tricky. Almost all titers are checks after an exposure -- for example, typically an immunologist is looking for a 4-10 fold increase in antibodies after a vaccination. The baseline titers may have meaning, but all studies I've seen look at titer responses after a challenge. Thus the difficulty with strep is that until the strep enters the blood stream (i.e., not on the skin or throat but an actual invasion like a shot) then there probably won't be a rise in titers. In terms of abnormally low titers, as far as I know it hasn't been studied. Even Ed Kaplan has said that 'carrier state' is likely much less benign than originally thought. Did you use Gammunex 10% before? We had very good results with that because of the low sucrous level. Buster

For CVID, the typical problem is that the child gets lots of illnesses and their immune system is insufficient to fight off even most bacteria or viral infections. The monthly IVIG is to ensure there is an immune system capable of responding. The dosing of IVIG is tricky here and I'm not sure it is exactly known how much is necessary to augment an existing (but incompetent) immune system. Was your daughter sick all the time with all sorts of diseases and having difficulty clearing the infections/illnesses? I remember way back the doctors thinking your child had childhood lupus. With respect to the high dose abx, what makes sense to me is that it's helping the immune system get rid of a lingering gram positive infection. If the immune system is really terrible, then just having high dose antibiotics by themselves are probably not enough. The high dose probably only helps those that can mount an immune response of some form, but the immune response is just not enough for clearing the infection. For those with an incompetent immune system, the "borrowed" IVIG antibodies can at least help to wipe out antigens (with or without the antibiotics). Antibodies tend to have a half life of 4-6 weeks, so dosing every 4 weeks will create a roughly stable immune system. I totally understand your concerns on blood products and we have that same concern... but if the alternative is severe CVID there's not many other options. Wishing you the best, Buster

We don't. But it seems given effectiveness of IVIG, it looks like the other antibodies from other parties are taking out the anti-host antibodies.

Cunningham was looking at heart disease (carditis) and Kawasaki's disease. You can consider that she came at PANDAS from the Acute Rheumatic Fever space. Back in 1988, she published: http://www.ncbi.nlm.nih.gov/pubmed/3049816...p;ordinalpos=49 In a sense, yes. The way the immune system works is that a macrophage engulfs a bacteria and then tries to find a "key" on the bacteria that is like a signature. In the case of PANDAS, it looks like the "key" used is a particular sequence of a carbohydrate on the cell wall of the bacteria known as GlcNAc. Now the macrophage runs into a T-cell and says "there's bacteria out there and it has a signature of 'GlcNAc'". If there's enough macrophages/T-cells, then some of these will connect with some activated B-cells (B-cells make antibodies). When macrophages run into a B-cell and say "there's more bacteria out there go send out scouts (antibodies)". The B-cells connect up with the activated T-cells and thus the "signal" is confirmed by two parties (i.e., both the B-cell and a T-cell found it) so the B-cell makes anitbodies targeting the key sequence. Just to make this clear, all sorts of keys are created when a Macrophage tries to find the "right sequence". Think of it as the macrophage is telling you the description of the bacteria but can only speak in DNA fragments. One says "it's got this carbohydrate sequence" another says "hey it has this protein sequence" and another finds yet another carbohydrate, .... There are thousands (possibly millions) of these "keys" on the edge of the bacteria. Each macrophage has to chose one key to present as their "identification of the bacteria". Thus the more macrophages, the more keys get presented and the better the chance that one of them is accurate as a real key for the bacteria. Anyway, if enough of the Macrophages presents the same sequence on the exterior, this turns into a memory B-cell and then the memory B-cell produces antibodies to that particular sequence. Now in the case of the four antibodies, Kirvan and Cunningham were looking at anti-lysogangliosides (meaning those antibodies that interfere with the bonding of lysogangliosides with neuronal tissue). They then isolated the bound antibodies and isolated four specific antibodies (one of which is known as 24.3.1). The point here is that there easily could be another 100 different antibodies also produced along with the anti-lysogangliosides. It just isn't known if the ones they isolated are the actual culprits. There is good evidence that 24.3.1 is the guy causing CaM Kinase II activation (i.e., opening of the Calcium channel). But whether it's leading to the wacky Basal Ganglia oddity, we don't know. I think that is true, but don't know. Yes. Although there may be other things that the B-cell recognizes and creates the faulty antibody for. Remember it is anything that presents the GlcNAc sequence (i.e., key) -- so if another bacteria has the same sequence then the B-cell will produce the same antibody. They aren't smart. I don't think there is an elevated Dop 2 -- all ranges on the test are currently treated as normal. Buster

I posted a bunch of stuff about ASO in this thread http://www.latitudes.org/forums/index.php?...art=#entry25312 The short summary is that ASO rises in only 53% of children with culturable throat GABHS (see Kaplan paper). GABHS that is on the skin does not have an ASO rise. So if the strep is skin strep or not in the thoat, you most likely will not get an ASO response. Regards, Buster Uggh....

Hi Faith, This is probably better for a different thread (since it doesn't have to do with the original topic). Let me try a short answer here and if it's not clear please start a new thread on the topic. SC and PANDAS are thought to be caused by 3 independent events: an immune response to GABHS that creates a faulty antibody a failure by the T-regulator cells to supress the faulty antibody a breach of the blood brain barrier In the initial presenting condition approximately 3-6 weeks occurs between the GABHS infection and the SC onset. This seems to be the time for the adaptive immune system to create memory B-cells and the antibody response. In subsequent exposures the onset can be immediate and even preceed the clinical symptoms of GABHS. This is thought to be because the recipe for the faulty antibody is now programmed into memory B-cells and thus the body's own rapid response system is now creating more faulty antibodies. The antibodies seem to have a half-life (turnover rate) of 4-6 weeks. This means in 4-6 weeks half the antibodies should disappear if there isn't more being made. If GABHS has gone intracellular, it is thought that when the cell bursts/dies it releases into the blood stream some GABHS that the immune system destroys -- however, in doing so, it makes more antibodies (since the B-cells recognize it immediately). This is why some think the higher doses of antibiotics are helping -- they are bacteriacidal at the high dose. This addresses the first two items above. However the opening of the BBB seems to be the real variable... The BBB seems to open from a variety of causes but severe inflammation and high stress seem to be two strong causes. This aspect is not well studied, but I think this explains the long delay from GABHS and the exposure of symptoms. With respect to steroids, they seem to have two effects. They reduce inflammation (and thereby may close the BBB temporarily) and they suppress immune response (such that the B cells don't produce so many antibodies). It is not known which effect is being seen, but I think given the brevity of time, it is likely the BBB closure. Steroids do not have an effect on GABHS. Steroids are anti-inflammatory and can help to suppress auto-immune responses. We tried steroids one time during an exacerbation and the steroids did have an effect 9 days later. We have only used steroids the one time, but it helped confirm it was likely related to inflammation or auto-immune. Regards, Buster

There are multiple things here: 1) For SC or RF, prophylatic antibiotics are used to prevent re-infection after the intial illness. Subsequent attacks are usually much more severe so the attempt is made to prevent or reduce the severity of re-occurance through long-term antibiotics. 2) In 1976, Husby http://www.ncbi.nlm.nih.gov/pmc/articles/P.../je14441094.pdf showed that emm-type 6, 11, and 12 were implicated in RF and SC. Subsequent studies by Wannemaker and Kaplan have implicated other strains (such as those exhibiting M1 and M18). 3) While penicillin is still effective invitro against GABHS, in early 2003 it was shown that strep can go intracellular (like a virus) http://www.journals.uchicago.edu/doi/pdf/10.1086/508773 . Penicillin is less effective at clearing for patients who have this strain (even in immune competent individuals) 4) The treatment dose and duration for antibiotics is based on studies of children who are not immuno-compromised. The objective of most of the studies investigating efficacy is to clear the disease in > 80% of children within a prescribe time window (typically 14 days). However in greater than 10% of cases, GABHS is not cleared. Now we get to PANDAS. Antibiotics do not in and of themselves kill GABHS, you need a competent immune system to do so. Some of the kids have low IgG levels and it is thought that they do not mount a sufficient response. While carriage may explain positive throat cultures in some children (with low ASO and antiDNAseB) it is not actually known whether carriage is benign or whether it is rather a lingering long term infection. Thus, the prophylaxis is intended to keep an infection from occuring (or if it does occur that it will be quickly curtailed). The high dose prophylaxis is (in my opinion) to clear intracellular strep or help an immunocompromized child fight an infection. There are also some anti-inflammatory and immuno-moculating properties of macrolides that help all of these items. The exact dosage needed to maintain prophylaxis in children is not really known and seems to vary by weight, immune response and GABHS strain. Long answer, but I hope it helps with your question. Buster

Isabel, If you are testing for clearing, you should test between > 14 days from final day of treatment (i.e., >24 days from start). The reason is that there is a high false negative for 10 days post treatment. There's a nice paper by Kaplan that shows the actual statistics. I'll try to get you the reference. In our house, we culture the others to ensure we don't have ping-ponging -- but sounds like you've got a full house so that may be impractical. Buster

I think it is more that the anti-D1 or anti-D2 are more messing with the feedback loop associating with regulating the amount of dopamine to use. The way I understand it is that there's a receptor that when hit releases dopamine and another that inhibits release. Similarly on the other neuron, there's one that receives a signal and another that inhibits a signal. The apparent mechanism is to release some dopamine and if some comes back on the feedback path to stop releasing dopamine. Similarly, on the other side, to receive some dopamine, but if you get too much then to stop receiving dopamine. Sort of like an overflow valve. So if someone is messing with the feeback loop, you either don't get enough or too much. So I don't think it is about having too much or too little, but rather that you are getting a ton and then none then a ton and then none so your system can't quite get it dialed in to get it controlled. Again, I may be way off, but that's how I understand it.

What I'm trying to say is that it is more like poor regulation (i.e., bad feedback loop) rather than too much or too little. I think that the problem is the randomness of the binding and that the "feedback loop" can't work because there's something other than dopamine binding to the site. It's sort of like trying to figure out your weight by standing on a scale that someone else is randomly putting other things on... The number sort of goes all over the place... That's how I understand it... not as a constant "too much dopamine" or "too little dopamine" but rather that the anti-lyso and anti-D1 and anti-D2 are screwing up the correction factors that figure out how much dopamine to use to cause a signal. Buster

No one knows yet exactly what the numbers mean -- that's why the study is a research study... they don't have yet a good handle on the accuracy or the specificity of the tests nor the exact correlation to symtpoms, but that's what they are looking for. I'm presuming that you have the Kirvan 2003 and Kirvan 2006 papers that present the CaM Kinase II results. If I understand the tests, higher CaM Kinase II is found in those with Sydenham Chorea and separate those with anti-neuronal antibodies from those with other causes of tics and non-PANDAS OCD. The sample size shown in the papers is pretty small, but the results seem representative. Anti-lysogangliosides measure interference with gangliosides and this doesn't mean they attack the gangliosides, but rather seem to bind to what the ganglioside was trying to connect to. This means they either cause more signalling (because they bind) or stop signalling (because they bind and the normal signal can't get through). I'm not sure they know which is occuring. There was one specific antibody that interferes with lysogangliosides known as 24.3.1. It is this antibody that is thought to cause the high Cam Kinase II activation. What has been interesting is seeing folks with high CaM Kinase II and low anti-lysogangliosides -- so it's possible something else is happening. My understanding is that for these tests, Cunningham is not isolating the 24.3.1 but rather testing the serum for all the anti-lysogangliosides at once. On the Tubulin -- there's a good paper by Kirvan in 2007 about this, but it seems to be about antibodies that interact with Tubulin (a dimmer protein) that helps and inhibits signalling. In this case the antibody appears to bond to certain parts of tubulin interfering with whether it "shuts down" or "turns on" messaging. For D1 and D2 -- this seems to be about two receptors in the basal ganglia. The receptors are part of a feedback cycle that regulates how a signal is sent across a synapse. As best as I understand it, some D2 receptors inhibit transmission of a signal and others increase the release of dopamine. My understanding is the combination is supposed to regulate the amount of dopamine released to cause a signal between two neurons. However, if the receptors get "plugged up" with anti-D1 or anti-D2 antibodies, then too much (or strangely too little) dopamine gets released and the signal gets weak. Sorry, that's the best that I know at this point... It would be great if someone else has more... but I think we're all more on a mission or expedition here rather than knowing an answer. But wow we are a lot further along than 2 years ago. Regards, Buster

Hi Peglem, As far as I can tell anti-D1 and anti-D2 are about binding to the dopamine 1 and dopamine 2 receptors on neuroblastoma cells. I think there are two D2 receptors (one called short and one called long) where one of them causes signalling and the other one causes inhibition of a signal. To the best that I understand it, when Cunningham says something is anti-lysoganglioside or anti-tubulin or anti-D1 or anti-D2 -- she's saying that the antibody in the blood is interfering with the normal lysoganglioside or tubulin or D1 or D2 bonding at that particular location. So anti-X doesn't mean it attacks X, it means it competes with X -- thereby leaving more X around. Essentially the antibody is mimicing X making it look like you've got more X even though technically you don't. It also seems though that just because the X binds to one of the receptors doesn't seem to mean it causes the same type of signalling. The way it was explained to me was that it's like interference on your car radio -- you still have the base signal but another signal interferes and makes it hard to hear the original signal. Hope that helps, perhaps someone else can add or clarify... Buster

I think what you are highlighting is that parents (and their doctors) should not double up existing prescriptions since that would raise the amout of clavulanic acid. Absolutely something to watch out for. I'm pretty sure the maximum amount of clavulanic acid is 10mg/kg/day. Buster

Wow, tough question. Yes, our daughter also didn't want to change. However, she is much younger. She didn't see the compulsive or obsessive thoughts as being foreign. In fact, for CBT to really work, they sort of needed her to name it. She couldn't externalize it but said that it was just her. She didn't feel it was outside. It wasn't until we got her on azith and her eyes cleared and she came back from the edge of starvation that we could talk about how she acted the 3months before. Then she saw it as really odd. So in retrospect she could see it, but not while she was in it. Your son is clearly much older and much more aware. Have you been to a psychiatrist? They have very good ways of helping to clarify this space. I say this because of all the time we actually did do with our psychiatrist -- despite the fact that until we got our daughter to 80% better we couldn't have a conversation about her obsessions. Buster

Kim posted a very nice summary here http://www.latitudes.org/forums/index.php?showtopic=5838 and referenced a good article http://www.physorg.com/news108987915.html The short summary is that regulatory T cells (Tregs) are T cells, but the Tregs watch for things that would be anti-host. If they find something anti-host, they don't react -- meaning they stop the feedback cycle. Think of it this way, a Macrophage comes along and found GABHS, the Macrophage comes along and tells a B-cell. The B-cell starts getting ready to mature and attracts T-cells. The T-regulatory cell attaches and goes "hold on, your antibody would be anti-host" and disables the B-cell. So the regulatory T-cells disable the feedback cycle and prevent more antibodies and macrophages from being produced for stuff that is antihost. Buster

Just ran into a very interesting 2004 paper -- http://www.pnas.org/content/101/21/8180.long from the folks in Rehovot Which says: "T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions " The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions. Hmm... Buster

I'm not sure. Certainly a T-cell deficiency would make it difficult for the body to create a sufficient response and thus the "tested effective dose" of antibiotic would probably not be very effective in people with either IgG or T-cell deficiencies. I haven't seen papers on this, but it seems to make sense. Antibiotics like augmentin (in high enough dosage) can be bactericidal. So if you really aren't raising enough of an immune response then I could see that helping out the immune system by actually breaking down the cell wall of GABHS. If the strep is hiding out intracellular, then when it bursts, it'll hit a the augmentin and be taken out. Similarly, antibiotics like azithromycin can go intracellular. If strep is hiding out intracellular, then azith would be effective by either preventing growth in the cell or becoming bacteriacidal for intracellular strep. The antibodies are actually created by the B-cells (when activated by a T-cell). So a T-cell deficiency should actually cause less B-cell activation and hence less antibodies. I suppose the actual deficiency might be the T-regulatory cells. In which case they don't detect the anti-host antibody. This seems very plausible in folks with low Igg. see http://en.wikipedia.org/wiki/File:B_cell_activation.png That was a long way of saying that I don't know... Regards, Buster