Buster

Hi LLM, There are so many things wrong with the NIMH website that I keep wanting to scrap it and rewrite it. Let me start with some simple changes I hope they can do and then I'll hit last the most damaging section (about treating PANDAS like non-PANDAS OCD/tics -- arggh!): Symptom Description The web site states that "children may also become moody, irritable or show concerns about separating from parents or loved ones. " Unbelievable. Please just delete that line. This so understates what the symptoms really are. A 20+ change on a CYBOC scale is *not* being moody. I doubt anyone on this panel would claim that their child is just moody, a little irritable, .... Arrggghh. Statement that NIMH believes that PANDAS is a variant of Rheumatic Fever This whole section needs to be re-worked. NIMH actually believes that PANDAS is a variant of Sydenham Chorea and explicitly has studied that it is not a subset of RF. Throat culture is sufficient to demonstrate Streptococcal infection The web site needs to add a simple Q/A about throat cultures and say: Q. Is a throat culture sufficient to demonstrate association with streptococcal infection? A. Yes. The AMA treats a positive GABHS throat culture as demonstration of an infection and warrants treatment of the strep infection. The site needs to drop the emphasis on ASO and add a statement about rule-outs Q. Does a negative ASO titer rule out PANDAS? A. No. A rising ASO titer can confirm a preceeding strep infection if no throat culture was available. A negative ASO titer could be due to many variables and one study found that 46% of culture positive children presented with a negative ASO titer. Arrgh the section regarding "Q. What are the treatment options for children with PANDAS? " This just must be fixed. The Answer states that PANDAS should be treated like any other form of OCD or tic disorder. But there is no science to support that statement. None. There is actually science pointing the other way -- that PANDAS is a separate pathogenesis from non-PANDAS OCD and tics and thus has to be treated differently. It just makes absolutely no sense for NIMH to be recommending anti-psychotics for PANDAS children with NO studies and not recommending antibiotics, IVIG or PEX despite the studies of efficacy. This MUST be changed. Perhaps I'll post back here a version of the web site that we can discuss as I do agree that helping NIMH correct their website would really help. I appreciate the difficult situation they are in, but I sure wish they'd fund the research to end the debates rather than claiming "more research is needed". If it's needed, fund it. Grrrrr. Buster P.S. I'll find a way to make this into more concrete suggestions. It seems the best approach is to challenge the web site on facts. Give me a day to think about what to do here.... I too have been unbelievably frustrated by the website.

I'm so glad you thought to check. With our dd9's sister we had to use azithromycin due to needing to stop augmentin early due to a rash. Bottom line is check again post treatment. If she does test positive again, please see if they'll get an emm-type for the GABHS. Might be too advanced for most clinics but it would be great to know why it's not clearing. Really glad the rest of you are getting tested. Buster

That's a really significant C-Reactive protein level, ESR and neutrophil level. He is having significant inflammation going on. It would be consistent with RF (especially with the CRP and Anti-DNAse . Wow! I see now why you are taking these three cases in together given the RF and KD... wish they had done an emm-typing. Buster

That is a great question. I have sent emails to the webmaster at NIMH, have contacted various perceived owners of content, all without success. I tried calling one day and just gave up. If you find a way in, I'd sure be willing to provide a marked up copy of the NIMH website with corrections based on the current research. Buster

Hi Wendy, I'm pretty sure Dr. Lewis won't value comments off the internet by parents even if backed with good scientific data. It just doesn't seem to be the nature of immunologists :-) Usually a good paper on a topic, particularly one in a notable journal (like JNI or Nature), is more effective. If it's not a paper he's already read, he'll scan it in the 15 min before the appointment. I think he, like many specialists, are looking for a reason to treat --but they want to have a reason and not just be experimenting. Unfortunately, the science (and funding) here is still 5-10 years away from the conclusive evidence that is really needed. I think you've met with with him before, right? He is extremely well versed in Kawasaki's disease and has his own research around T cells. My strongest recommendation would be to consider what you want done, and why you think it will help, and then ask him what he'd need to see in tests or otherwise to support you? I presume he's already done his own lab work, discovered nothing particularly unusual, so he's not finding a way yet to support you. My memory is that you have a ~3 year old diagnosed and treated for Kawasaki's. A ~6 year old diagnosed and treated with IVIG (Sept 21) for PANDAS and a playmate who had peeling hands and lymph issues of KD but likely has PANDAS. So, just wondering if you are trying to dangle a good research direction in front of Lewis (i.e., a good topic for one of his grad students to work on) or trying to get him to do something? Best wishes and hopes, Buster ASO is a test of the body producing an antibody to Streptolycin-O (an exotoxin of GABHS). Deoxyribonuclease B is also an exotoxin of GABHS. Anti-DNAseB is a measurement of antibodies to this exotoxin. Other known exotoxins are known as A, B, C, ... Z, Stretokinase (SK), Hyaluronidase (HA) and Cysteine proteinase. There are undoubtedly many more that haven't been found yet. A..Z are usually written as Spe A, Spe B, ... standing for streptococcal pyogenes exotoxin A, .... Deoxyribonuclease B is also known as Spe F, although it was only recently these were found to be immunologically identical. So with so many exotoxins why do doctors use Streptolycin-O? The reason doctors like Streptolycin-O is that it is generated by all known emm-types of GABHS in vitro (i.e., outside the body). While this is true, it isn't as true in the human body. Kaplan discovered that cholesterol seems to neutralize streptolycin-O (so if you have strep on the skin, or in an area with high concentrations of cholesterol, you won't see an ASO response). This appears to be contributing to the >46% false negative rate even on perfect timing of taking ASO samples. About 85% of the strains produce cysteine proteinase (aka SPE B ) but this seems to be neutralized in many and so is not in general tested. Streptokinase is the next most popular test (it's found on 71% of strains). Some laboratories run this test if requested. Spe A is found in 25% of the GABHS strains (primarily those expressing M1 or M3). Hyaluronidase was found in only 10% of the strains. You can find out about others at http://www.ncbi.nlm.nih.gov/pubmed/9361388 The bottom line is without knowing the emm-type of the strep, there's not good concensus on what exotoxin to measure. Hope that helps, Buster

ASO is a test of the body producing an antibody to Streptolycin-O (an exotoxin of GABHS). Deoxyribonuclease B is also an exotoxin of GABHS. Anti-DNAseB is a measurement of antibodies to this exotoxin. Other known exotoxins are known as A, B, C, ... Z, Stretokinase (SK), Hyaluronidase (HA) and Cysteine proteinase. There are undoubtedly many more that haven't been found yet. A..Z are usually written as Spe A, Spe B, ... standing for streptococcal pyogenes exotoxin A, .... Deoxyribonuclease B is also known as Spe F, although it was only recently these were found to be immunologically identical. So with so many exotoxins why do doctors use Streptolycin-O? The reason doctors like Streptolycin-O is that it is generated by all known emm-types of GABHS in vitro (i.e., outside the body). While this is true, it isn't as true in the human body. Kaplan discovered that cholesterol seems to neutralize streptolycin-O (so if you have strep on the skin, or in an area with high concentrations of cholesterol, you won't see an ASO response). This appears to be contributing to the >46% false negative rate even on perfect timing of taking ASO samples. About 85% of the strains produce cysteine proteinase (aka SPE B ) but this seems to be neutralized in many and so is not in general tested. Streptokinase is the next most popular test (it's found on 71% of strains). Some laboratories run this test if requested. Spe A is found in 25% of the GABHS strains (primarily those expressing M1 or M3). Hyaluronidase was found in only 10% of the strains. You can find out about others at http://www.ncbi.nlm.nih.gov/pubmed/9361388 The bottom line is without knowing the emm-type of the strep, there's not good concensus on what exotoxin to measure. Hope that helps, Buster

If you are interested in the exotoxins of GABHS, a good reference is http://books.google.com/books?id=k_gROZ_xu...SPE&f=false The short summary is that the exotoxins are thought to cause more leakage across epithelial cells (i.e., the BBB). The common tests of Anti-Streptolycin-O and AntiDNAse-B are actually tests of the amount of antibodies to these two exotoxins. What I'm getting at is that the tests currently performed don't test for strep, they test for antibodies to exotoxins of strep. Buster

as far as I know that trial is still ongoing http://clinicaltrials.gov/ct2/show/NCT00409747 Yes, the early tests isolated the antibodies in the CSF for those patients who were in significant exacerbations. She also showed that such antibodies were absent during remission. It is not known whether the antibodies are a cause or a byproduct. They are correlated but not shown to be causal at this point. Buster

Yes, there are macrophages and phagocytes on the brain side of the BBB. However, what's unusual about these cells is that they can present pieces of neuronal tissue sequences in addition to normal antigens. I don't think we know yet. There are two good theories here: T-cells create a breach through which existing antibodies cross T-cells create a breach through which B-cells cross (creating antibodies) What I got from their paper was that the effector T-cells seem to be attracted to weak spots in the BBB. The T-cell seeks out the weak spot using the footholds on the epithelial cells. When a T-cell slips through, it connects with one of these "brain-side" macrophages/phagocytes and gets activated. Once activated it releases more inflammatory cytokines recruiting still more T-cells to the spot. This causes more inflammation and essentially a breach in the BBB through which other cells/antibodies can cross. I personally think (due to size) it is more likely that the pre-existing antibodies cross rather than the B-cell crossing. What has been on my mind is that it seems equally plausible that one of the T-cells comes back across the breach and connects up with a B-cell causing more antibody production. In theory, IVIG and combined PEX/IVIG should affect both #1 and #2. Plasmapherisis (i.e., without IVIG) would likely affect only #1. What I was struggling with was "if we got rid of the strep, why is there still antibody production in the blood?" There seem to be three explanations here: we didn't actually get rid of the strep and there is some still in the system the T-cells and B-cells are self activating and don't need the original antigen the macrophages present more neuonal tissue and the T-cells confuse this with strep and activate All of these theories seem to have merit. The first is the paper by Kaplan around intracellular strep and how strep can act more like a virus (invading a cell and then bursting forth to reinfect). The second is from a paper by Voss http://www.jimmunol.org/cgi/reprint/180/3/1362 indicating that T-cells can stay activated if they find cooperative B-cells. This is basically a failure of the B-regulatory/T-regulatory mechanism. The third seems supported by Kirvan's papers about the cross-reactivity with neuronal tissue. The good news is that (with PANDAS) we don't seem to see demyelination, so it looks like there is antibody interference with neuronal tissue but not destruction of neuronal tissue. If it is #3, then it is limited to a few macrophages. It takes very little antigen to produce a lot of antibodies so any of the above would explain the scenario This is a long way of saying that I think the Nature paper is significant and perhaps the explanation as to why IVIG, prednisone, and PEX break the cycle by reducing the inflammatory cytokines and letting the BBB close. Buster

Hi Charlotte, My personal opinion is that momtocole1 child could be considered to have low Igg subclass 1 and the finding with other symptoms might be consistent with CVID. There is a nice chart of Igg1 plotted against age groups in normal children (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1554695/?page=2 ) While this is a small sample it indicates that Igg1 should be > 500mg/dl for a 7-12 year old. I'm not quite sure of what age group was used for "normal" in mom2cole1's child. This would be a good question for the lab and easy to check. The expected value for a 5 year old is quite different than for a 12 year old. Can't say from the insurance side, but I think there's a good argument there. Definitely worth nudging the doctor to see if the clincal symptoms are consistent with a CVID diagnosis -- along with the measured Igg1 low band. Regards, Buster

From the paper it seems like LFA-1 (lymphocyte function-associated antigen 1) was implicated in recruiting the T-cells to the site. LFA-1 is produced by Eicosanoids and by Leukocytes that are on the "brain" side of the BBB. The endothelial cells then seem to present "footholds" known as ICAM-1 (intercellular adhesion molecule-1) on the inner surface of the bloood vessel (see fig22b ), and then the T-cell seems to squeeze through similar to the leukocytes (see fig22c). My guess (no data/reference yet) is there is some chemical near the site of the macrophage on the brain side that has high concentration of the chemical near where the T-cell should push through. I think it is still the permeability of the BBB. It is true that certain antibodies and MS medication seems to stop the creeping behavior and limit the ability of the T-cells to creep with the ICAM-1. I can't speak to NAG, but NAC seems to be studied and seems to down regulate the LFA-1 I agree and think it likely that it is a chemical getting across the BBB that "attracts" the T-cells to use the ICAM-1 to try to find the source. I keep thinking of it like one of those tom and jerry movies where the scent draws them toward the source. Buster

Looks like the hospital requested that we not give Advil during the day before or the day of her IVIG.

Hi Elizabeth, Yes, I do think that the key is whether the blood-brain barrier opens or not. I think you need all three events: The initiating strep infection, the unusual immune system response, and the breach of the BBB. I think we'll find lots of kids get #1 and #2 without having #3. With respect to controls, I too think this is the area that will need careful study. Right now we have numbers but no clear understanding of what the number means. We might be measuring a side effect rather than a cause. One of my old teachers was telling me about his search for causes of certain cardiac diseases and he thought he had found that certain patients had lower temperatures -- instead he found that the non-controls were being wheeled through a cold part of the hospital. Essentially until we know why something happens, the number is just a number. At present, having a parent on this forum seems to cause elevated CaM Kinase II scores (that's a joke). Buster

I found another person had done a nice translation of this paper. See http://www.rdmag.com/News/2009/11/Life-Sci...vade-the-brain/ Buster

I'm not sure we exactly know, but yes, I think the principal impact of other viruses/illnesses is to weaken the BBB. Yes, the B-cell engulfs a possible antigen and presents parts on the surface of the B-cell. A T-cell recognizes the fragment and the two compare notes and decide it's something worthy to "destroy" and so release the B-cell antibodies. It's hard to say who is at fault, the B-cell (for presenting a bad fragment) or the T-cell (for recognizing the host fragment), but the result is the same -- more antibodies released. More macrophages go out and find more cells tagged with the antibody and reactivate more T-cells causing the cycle to continue.

Y'a know it, but of course I was officially a geek a long time ago :-) Happy Thanksgiving.

Your question really touched me as I too felt that same sense of despair when we were at the height of our dd symptoms. Our psychiatrist was encouraging our daughter to try to externalize the OCD and name it (like you would with any normal OCD -- if there is such a thing as normal OCD). She couldn't see it as being odd. She was saying it was part of her. I was thinking about this on the evening of June 13th 2008. We had just given our 9th day of azithromycin. I was tearful thinking how she was wasting away. She had OCD and Anorexia Nervosa with body image morphology in a 7 year old. She looked up at me from the couch and a cloud had passed from her eyes. She said "I want to get better" -- that was it, she got up and sat down at the table and ate dinner. Her movement disorders, vocal tic, contamination fears, OCD questioning, ... all disappeared over the next month. We had a blessed summer. We did have issues 5 months later when she was re-exposed to strep multiple times -- but she is now fully back! We once more have the lovely, caring, sensitive and insightful child. I wish you and your family the same recovery. It does get better. Buster

Without a doubt, one of the coolest papers I've seen recently -- and I've read a bunch. It explains and documents (with movies) how T-cells can cross the blood-brain barrier. This should have huge impact on MS, SC and frankly on PANDAS too. kim you are going to LOVE this one. Wow. Buster http://www.nature.com/nature/journal/v462/...ature08478.html Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions Nature 462, 94-98 (5 November 2009) | doi:10.1038/nature08478; The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks1. Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce proinflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations. Translation (by Buster): The blood brain barrier keeps out white blood cells and other large items such as proteins, nucleic acids, carbohydrates, and lipids (fats) that are circulating in the blood stream. However, the blood brain barrier is vulnerable to autoimmune attacks. Using a really cool technology, we studied rats that have a weakened blood-brain barrier and made a video of how T-cells interact with the blood-brain barrier. The T-cells can squeeze through the BBB (diapedesis) and once on the other side encountered macrophages and phagocytes that had found bacteria (antigens) and other stuff (including myelin proteins). The phagocytes showed parts of these antigens to the T-cells and the T-cells recognized some of the fragments as "foreign" and produced inflammation chemicals. The inflammation caused a breach in the blood-brain barrier. To see the movies: http://www.nature.com/nature/journal/v462/...ature08478.html

Hi Angela, Let me try a response here, but please post again if this isn't clear. Q: What is the trigger for symptoms in PANDAS? The key item in PANDAS appears to be a break down in the blood-brain barrier such that antibodies circulating in the blood stream can interact with neuronal tissue. I write it this way because that seems to be the actual trigger of symptoms. As long as the blood brain barrier remains closed, symptoms seem to not emerge. Q: "What opens the blood-brain barrier?" It turns out that stress, infections, high-blood pressure, epinephrine, .... all can cause leakage across the blood brain barrier. Also certain exotoxins (for example those from strep) can cause leakage across the BBB. Q: "What closes the blood-brain barrier?" This is the central question in Multiple Sclerosis (and other) studies. If the BBB breach is due to inflammation, removing the original antigen or reducing the "pro-inflammatory" chemicals help. This is why antibiotics, prednisone, and IVIG are all thought to work. Antibiotics help the immune system get rid of bacteria. Prednisone is anti-inflammatory and immuno-suppressant. IVIG is highly anti-inflammatory. PEX is also anti-inflammatory by removing antigens and removing antibodies that might cross the BBB. Q: "What gets rid of the anti-bodies?" Time removes antibodies -- if the antigen goes away, then the antibodies decline in 4-6 weeks. Unfortunately, they can come back if the B or T-cells encounter a similar antigen. In addition, PEX removes antibodies by filtering. IVIG removes antibdodies but we aren't exactly sure how. It looks like IVIG resets what are called regulatory cells. Once reset, these cells seem to remove faulty antibodies. Prednisone also suppresses B-cell activation so at least new antibodies aren't created. Q: "Does everyone get these antibodies?" Apparently not. The kirvan and cunningham tests have isolated a number of antibodies that are thought to be the culprit in the above scenario. These antibodies are created by some individuals in response to GABHS infection. A specific antibody (24.3.1) interferes with neuronal messaging and dopamine levels. Q: "Why does there seem to be exacerbations even without strep?" The current theory is that the antibodies are already in the blood stream. Some other event (stress, infection, ...) opens the blood brain barrer and the symptoms re-emerge. Q: "Why high doses of antibiotics?" First, it is important to know that antibiotics don't kill GABHS. Most antibiotics (especially at common dosage levels) inhibit the growth of bacteria, but the body's own immune system has to come along and get rid of the bacteria. For people who are immuno compromised, higher doses of antibiotics are needed so that the antibiotic becomes bacteriacidal. In addition, it appears that some forms of strep go intracellular (like a virus) and thus can't easily be eradicated except when the cell bursts. The high antibiotic level helps ensure that no growth is occuring by the "bursting" bacteria before the immune system can remove them. Hope the above helps... Regards, Buster

Hi Michael, Hopefully you already got your answer, but if not, please repost. The issue is not thought to be the strep bacteria, but rather the antibody produced in response to the strep bacteria. These antibodies seem to have a half-life of between 4-6 weeks from an initial exposure. There may be another condition that is also auto-immune in pathogenesis, but PANDAS by its definition is a pediatric condition. It requires the onset to be before puberty. Buster

The symptoms you describe sound similar to peripheral neuropathy -- the tingling/itching in toes and fingers. There are a lot of things that can cause that. Did she have full-on chorea? Did she have ventricular issues from the ARF? Was she on metronidazole by any chance? There are also a number of sensory processing disorders (sensory integration, sensory defensiveness) which can manifest in the "not feeling right" items you are mentioning. We had to cut labels out of a lot of clothes in the past. That issue did seem to go away for us over time. My reason for raising the peripheral neuropathy is that it seems to only affect the very long nerves and then only the small fiber nerves. The tingling should be checked. Feeling uncomfortable is one thing, having tingling, numbness or feelings of heat is another. Regards, Buster

Hi Worried Dad, I haven't looked at that path but will now. It might be worth a check with Dale, Church or Giovanni who are in the UK and probably more familiar with the treatment. Thanks for the reference. Buster

I decided to pull this to a new thread... The best research at this point indicates that PANDAS is a subgroup of children with OCD/tics where there is : an immune response to GABHS by B-cells creating an anti-neuronal antibody (see http://www.pandasnetwork.org/Cunningham.NMpaper%5b1%5d.pdf ) a failure of the immune system (T-reg/B-reg) to stop the anti-neuronal antibody (see http://www.journals.elsevierhealth.com/per...0804-3/abstract ) a breach of the blood-brain barrier that allows the antibody to interact with neuronal tissue (see http://www.jimmunol.org/cgi/reprint/178/11/7412 ) Antibiotics can help to prevent an infection that might lead to #1 (see http://intramural.nimh.nih.gov/pdn/pubs/pub-9.pdf ) PEX and IVIG can both help to address #2 (see http://iai.asm.org/cgi/content/abstract/64/12/5395 ) Macrolide antibiotics are anti-inflammatory and can help #3 : see http://jac.oxfordjournals.org/cgi/reprint/55/1/10 Advil is anti-inflammatory and can help with #3 : see http://www.jneuroinflammation.com/content/...2-2094-1-21.pdf IVIG is highly anti-inflammatory and helps #3 : see http://www.sciencemag.org/cgi/content/abstract/320/5874/373 On the blood-brain barrier, there is some work that indicates that the exotoxins of GABHS itself can change the permeability of the blood-brain barrier. It isn't known if this is through inflammation or some other mechanism: (see http://iai.asm.org/cgi/reprint/21/3/753.pdf and http://www.neurology.org/cgi/content/abstract/54/7/1433 ). Of interest, there was a recent paper that indicates that IVIG neutralizes the exotoxins and super-antigens of GABHS : see http://iai.asm.org/cgi/content/abstract/64/12/5395 Finally, there are a few studies that if it isn't PANDAS (i.e., isn't autoimmune) then the treatments above don't work because there aren't any antibodies to go after (see http://www.ncbi.nlm.nih.gov/pubmed/11026187 ) Buster

Wishing you the best.

Also in our dd9's case, it took 14 days from start of pred burst until we saw a noticable effect. We did 6 days of a burst, on day 14 we had improvement until day 18, then back to where we started. Buster