Buster

peglem, First, sorry, last thing I wanted to do was add more weight to the worries we all feel. Let me go with the good stuff first: 1. There is no evidence of any permanent damage in PANDAS -- no demyelination, no plaque, no .... 2. The studies seem to indicate it is interference and not aptosis occuring (i.e., the antibodies are acting like neurotransmitters and not like antibodies) 3. The antibodies seem to have a half-life of 4 weeks (as best as I can figure out -- still searching) 4. PEX, IVIG, pred, and antibiotics all seem to work And yes, I too am not thrilled by the prospect of the antibodies being in the brain, but I'm sort of stuck figuring out how they get there. Without that piece explained, I'm not sure whether this one time treatment will hold or not -- was it an immune failure, a genetic pre-disposition, a BBB failure or all three. I've been struggling with how would so many antibodies cross into the brain -- I mean you need a fair amount to compete with dopamine receptors on neurons. Well, this would be an explanation... not sure it is "the" explanation.... I'm happy to label these types of posts as "WACKY THEORY" posts if that helps lower the concern level -- this is definitely not science yet -- it's speculation. Buster

FANTASTIC! Really truly great segment. I actually like how the reporter phrased that the immune system misfires. Nicely explained. I'm also so very glad to hear that Lauren is doing better on antibiotics -- that's great to hear. Buster

If that is the case, than she is one lucky girl.... she has no ocd, no other issues up till now at 12 yrs old, then how could she have had PANDAS episodes in the past? I would think something would have been noticed. ... In our own case, we missed the first two episodes when our daughter was 4.5. She had daytime urinary frequency and frequent handwashing until her hands were raw. The daytime urinary frequency, we took her in for a possible bladder infection but they found nothing. It turns out she was put on an antibiotic two weeks later for an upper respiratory infection and interestingly all the symptoms disappeared 2 weeks after that. We never made the connection at that time -- although it was in her medical history. I bring this up because it's actually pretty easy for the early behavioral symptoms to be missed -- or rather we sure missed them in our child till all ###### broke loose in March 2008. Buster

Hi Faith, I think it is technically referred to as a provisional diagnosis. I'm sure Dr. T did a full history checking for prior symptoms, checked for other tell tale neurologic signs and perhaps the improvement on antibiotics is swaying him towards PANDAS. Typically there was a preceding episode that shows up in a retrospective of medical records (as I think pretty most of the parents here can attest to -- ourselves included). Dr. K uses short burst pred as a diagnostic tool since if the child improves it is likely auto-immune. At this point, I'm just glad she's getting the word out and I really do hope that Lauren finds the calm that many on this forum have found post antibiotics. Buster

I just ran across another paper that now has the B-cells crossing the BBB. The paper from Nature that started this thread shows that T-cells are attracted to weaknesses in the BBB and recruit other T-cells there. We've been wondering if antibodies to strep (i.e., 24.3.1) then cross at this point and interfere with neuronal tissue Now this paper indicates that if the breach is wide enough, B-cells can cross and if responsive to neuronal tissue, can activate antibodies on the brain side I have no idea if this applies in the PANDAS case, but this would explain the rapid onset -- because a B cell on the Brain side of the BBB that happened to be there with an activated T-cell would propogate a whole bunch of antibodies all at once. http://www.jimmunol.org/cgi/reprint/170/9/4497 I'm looking for followups to this work .... Buster Determinants of Human B Cell Migration Across Brain Endothelial Cells Andrea Alter et al Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-- inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking. The Journal of Immunology, 2003, 170: 4497–4505.

Hi Wendy, Gosh, so much to talk about and so little good science here.... Let's start with the known... Yes, GABHS can produce all the exotoxins you mention plus the super-antigen/exotoxins named Spe A through Spe Z as well as a bunch we haven't found yet. Different GABHS strains produce different exotoxins. For the moment, let's assume that the exotoxins cause the inflammation. So either the immune system can't get rid of the GABHS and so there continues to be exotoxins causing strep -- or-- the exotoxins aren't getting removed and so they just keep causing inflammation. The improvement (anecdotally) by so many on high dose azith and augmentin leads me to think it really is the strep and not the exotoxins that aren't getting removed. The antibiotics really don't have a lot to do with exotoxins. Yes, the azith can modulate Th1/Th2 response, but largely augmentin and azith don't do a lot to exotoxins themselves. So, this makes me think that the real culprit is either: there is some strep that's gone intracellular and like a virus (e.g. chicken-pox) can come out under stress or other illness a reinfection has occured and the T-cells go nuts and a B-cell finds a tiny, tiny bit of the antigen (GABHS) there's leakage across the BBB and the T-cells go nuts and a B-cell finds a tiny, tiny bit of neuronal cells that look like GABHS I keep coming back to why does PEX, IVIG and prednisone all seem to work and why does high-dose antibiotics work. IVIG will close #3, pred will close #3 and slow down the T-cell recruitment. Antibiotics helps #1 and strangely can prevent T-cells recruitment in #2. PEX breaks the cycle and assuming no more GABHS, removes the offending antibodies. Also, and this may be really really significant, a lot of times blood thinners are used (Warfrin) with PEX. In reading about this, the blood thinners prevent T-cells from collecting on the epithelial hand holds. This might mean that the concentrated breach in the BBB is cleared by not letting the T-cells congregate. Literally this might be what is going on. If so, then PEX is essentially closing the BBB too. So, my gut (wish I had more good science to play with and why I thought that paper on T-cell crossing the BBB was SOOO cool) is that the real culprit is the BBB and any inflammation that causes a breach in the BBB is really at fault here because the B-cells are recognizing neuronal cells just as much as GABHS. I'd be really interested if you get good insight from your immunologist.... Buster

Yup, and frankly I don't think anyone knows the answer. We too are hoping it is the first and not the second. PEX only removed a percentage of antibodies -- but doesn't get them all... it's logically a dilution effect. So that sort of leads me to think there were some still there... and just a closed BBB due to lack of inflammation... but no science behind that statement. Just trying to see explanations that might explain what we're seeing. Buster

Hi Eileen, Fundamentally we don't know but there could be several answers. My guess is it is one of the following: There was still strep (or a strep exotoxin) in the body and a T-cell got activated causing inflammation and then bound with a B-cell to produce antibodies. That the BBB was still open and the B-cell got across or a macrophage got back presenting neuronal tissue That there was some residual antibodies and the BBB got opened due to some other illness That there was a re-exposure to strep and while the antibiotics prevented a full out infection, he had a response Based on our experience, I'd say it was #4. Our dd always went into an exacerbation when her sister was colonized with strep. Buster

Here's a table and perhaps it will answer your question. Sometimes there are more headaches with Gammagard but it is less expensive. http://www.ashp.org/s_ashp/docs/files/DSho...pdatedDec07.pdf One mild caution is that we had to remind our nurse to use Dextrose 5% for the flush since they don't usually use Gamunex 10%. Gamunex is incompatible with Saline flush. Buster Thanks for posting this question! We too are getting ready for IVIG - either next week (if insurance approves) or the week after. Thanks for all the information Buster! Any thoughts on Gamunex 10% vs. Gammaguard? We were told he'd be given Gamunex 10% "if it was available," otherwise it would be Gammaguard.

One mild caution is that we had to remind our nurse to use Dextrose 5% for the flush since they don't usually use Gamunex 10%. Gamunex is incompatible with Saline flush. Buster

Hi Mom_MD, Not quite sure what you are asking here, but happy to answer any question regarding our experience.... In our case, we split the IVIG over 2 days. It took about 6 hours per day for each infusion. The protocol we followed was for 1 gm/kg/day (I think Dr. K and others use .75 gm/kg/day): provide age/wt appropriate tylenol and benadryl 1 hour before going to hospital (make sure to tell them what you did or they'll repeat) ask for EMLA cream to be applied when you arrive (helps lessen pain of IV insertion if child is sensitive) go to room and get settled and order something for lunch -- you're going to be there a while wait 30 min and then get IV -- in our case they did this in another room our doctor used Gamunex 10% (due to low sucrose level and good success by others) infusion rates differ by weight and total dosage so the pharmacy will likely tell you the rate. in our case, it was: infuse at a low initial rate (like 12 cc/hr for 30 min) -- watch like a hawk for any reactions throughout. Most adverse reactions are within 30 min of change increase infusion rate to 25 cc/hr for 30 min -- again watching for changes increase infusion rate to 54 cc/hr for xx min -- infusion rate is calculated by total amount given use dextrose 5% flush at end -- saline is incompatible with Gamunex 10% [*] make sure to eat lunch and drink fluids. IVIG can be dehydrating. [*] it is likely your child might get a headache. Consider a second dosage of tylenol at the 4 hour mark. [*] remove IV [*] if you can, get your child a snack because it is really likely your child will fall fast asleep after the anxiety of being at the hospital [*] get as much sleep as possible and repeat the next day. Please post or IM if questions. Remember it takes a while so cards, good book, or TV whatever to pass the time would be good. Best wishes, Buster

Tears well up in my eyes when I read your post. I can't believe how terrible your history has been. We too had that moment in the hospital where the "kind nurse" took us aside and told us we were likely looking at long term care at a psychiatric center. I still remember arguing with the doctor that "he will test her for strep." I was so insistent that when I later pulled the hospital records, the doctor's notes say "At parental demand, we tested for B12 defiiciency and GABHS." The doctor was really shocked that the test came back positive and even more shocked when our dd7 got better on Augmentin -- she wasn't back, but 24 hours after Augmentin she smiled. It took us a while to realize that Amoxicillin was *not* a good prophylaxis choice for us/for this strain, that 10 days of "normal" dosing didn't clear her, .... It took azithromycin to really change the situation for us (and maybe high dose Augmentin would have worked). Bottom line is the NIMH website just has to change. It just is unbelievable that doctors are willing to put kids on atypical antipsychotics with horrible side effects and won't try 30 days of an antibiotic. Argghhh.... My point in all this is please, please, please find a doctor who will listen to your story. Dr. K or Dr. Triffiletti or Dr. Latimer -- all will listen to you and give you good guidance. There really is hope and there really is a parting of the storm clouds.... Buster

Oh goodness, Of course strep can colonize elsewhere than the throat. Impetigo is one such condition, Intertrigo is another. http://pediatrics.aappublications.org/cgi/reprint/112/6/1427 Erysipelas is yet another, and of course the great atopic dermatitis. Let me know if you really need references as this is classic red-book material. In terms of the exacerbations due to viral or other bacteria infections. There are three explanations I have heard: The anti-neuronal antibodies are still in the blood stream and the viral/bacterial infection is just causing further inflammation of the BBB causing leaking of the pre-existing anti-neuronal antibodies (i.e., its been < 6 weeks since GABHS exposure). There still remains some strep in the system (perhaps intracellular) and this keeps the antibodies active There is something superantigen from the viral/bacterial infection having nothing to do with strep causing antibody proliferation #1 and #2 make the most sense to me. Buster

In our case, for 9yr old dd, we saw dramatic improvements 10 days post burst. They only lasted 4 days though. Buster

I know, I know, not my most helpful answer and I too stared at the numbers for hours wondering what they meant and wasn't it bad or not... All I can say is that my daughter still has anti-lyso at 1280 anti-tubulin at 8000 anti-D1 at 16000 anti-D2 at 16000 and yet has no symptoms now. So while the numbers are interesting, at least anecdotally, they aren't the "cause". Hoping this post saves you some fretting as I certainly did my share. Buster Every laboratory experiment uses a positive and negative sample as part of a "run" to verify that the test really is working. Normally, you would never report these -- they are internal measures for the lab that they used the right chemicals and got known answers. Typically they use a prior known good sample and check that the result this time matches the result last time. Buster

Every laboratory experiment uses a positive and negative sample as part of a "run" to verify that the test really is working. Normally, you would never report these -- they are internal measures for the lab that they used the right chemicals and got known answers. Typically they use a prior known good sample and check that the result this time matches the result last time. Buster

That was definitely true in our case. I think that's good... I modified the post. Buster

Short summary is all the numbers were within range for controls -- meaning nothing is dramtically high. If you still have questions, you can send a note back to the lab and they'll try to explain what they know. At the moment, it just isn't known how to treat these detailed antibody tests because we don't have a correlation yet with symptoms. Buster

That's interesting... anyone look at it yet?

The short answer is they don't really mean anything at this time. The CaM Kinase II values have some comparatives for PANDAS and non-PANDAS kids and SC and non-SC kids, but the others are antibodies they are checking and at this point it's not known what these values actually mean or whether they are correlated with any symptoms. Sorry, that's the frustration with this stage of research trials. Usually, they wouldn't release the measures to us until the end of the study, but I'm glad for any info :-) With respect to the results, the numbers are saying that when they checked your child's draw, they had slightly elevated anti-tubulin (but only one dilution away) and slightly elevated anti-d1 (i.e., antibodies that would bond with dopamine receptor 1 if given the chance). Again both are only slightly elevated versus the other samples she's seen. They don't yet know whether certain medications affect these values or not which is why they've been asking for more history from parents. I'd recommend not worrying too much about these values. The CaM Kinase II seems to be correlated (especially when > 170) but again, it's still early to know how to read the results. Buster

Here's an odd thought... I was going through all the other diseases listed on the NIMH website http://www.nimh.nih.gov/health/topics/index.shtml (Anxiety Disorders, ADHD, ADD, Autism, Bipolar Disorder, Borderline Personality Disorder, ...) For all of these the format of the page is: What is it? Signs & Symptoms Treatment Getting Help: Locate Services Related Information Perhaps the real problem with the NIMH website on PANDAS is that they spend so much time in Q/A that they've lost the basic stuff about symptoms & treatment. I can fill out the following with all the citations, but what about something like the following: What is PANDAS: PANDAS is a pediatric autoimmune disorder characterized by the dramatic onset of neuropsychiatric symptoms such as obsessions, compulsions, motor or vocal tics. PANDAS is thought to be similar to Sydenham Chorea where there is dramatic symptom exacerbation following a strep infection. Signs and Symptoms: Children with PANDAS are first diagnosed with Obsessive Compulsive disorder or a tic disorder. In addition, these children may have emotional lability (sudden unexplainable rages), personality changes, anorexia, age inappropriate bedtime fears/rituals, separation anxiety, tactile/sensory defensiveness and marked deterioration in handwriting. When a child has primarily vocal and motor tics, the symptoms have apparent overlap with symptoms of Tourette Syndrome; however, the children can be differentiated by observing symptom exacerbations over time. In PANDAS children, a streptococcal infection precedes symptom exacerbation and once treated the exacerbation remits in 4-6 weeks. The rapid onset with significant remission is characteristic of PANDAS. For children who have primarily PANDAS/OCD, the abrupt onset and remission after treatment for streptococcal infection separates the child from non-PANDAS OCD. A throat culture at time of exacerbation onset is recommended to diagnose a streptococcal infection. Treatment: Streptococcal infections are treated with antibiotics. Cognitive Behavioral Therapy has been shown to be effective on some children with PANDAS/OCD and to provide families with coping strategies. Caution is recommended for using SSRIs with PANDAS/OCD as there are reports of higher activation rates in such cases. Several reports have shown effectiveness of immunomodulating therapy (IVIG and PEX) in combination with prophylactic antibiotics. These treatments are still considered experimental and have several risks. Immunomodulating therapies are not effective for Tourette Syndrome or other non-PANDAS OCD cases. Getting Help: You're pretty much on your own as this is a very recent disease and a lot of the doctors won't know about it. Hopefully you'll connect with another parent on the internet who has navigated the research and can help. Oh, you might consider an IEP for your child too ;-) Research: PANDAS is thought to be caused by three independent events: the production by the immune system of an antibody that can interact with neuronal tissue. a failure of the immune system to suppress this antibody a breach of the blood brain barrier such that the antibody reaches neuronal tissue All three areas have active research results and require duplication of experiments to help reach concensus in the research community.

I'm probably opening a dangerous topic here where there is lots of energy but not much control... but... I've been frustrated by sections on the NIMH website that eventually conclude that PANDAS should be treated the same way as non-PANDAS OCD. This is just not in keeping with the current research and I worry is doing more damage than good -- where a child has an easier time being prescribed SSRIs and atypical anti-psychotics but can't get a 3 week trial of antibiotics. I'm working on another angle recommending that NIMH focus on the auto-immune aspect of PANDAS rather than the streptococcal aspect of PANDAS. I think that NIMH needs to focus on the research indicating treatment and symptoms while letting the research continue on pathogenesis. Here's a start... To NIMH director: In reading the NIMH website regarding PANDAS, I strongly disagree with the wording of the section regarding the recommended treatment for children with PANDAS. In this section, labeled “treatment options for children with PANDAS,” the website refers to a recent study (without citation) indicating that combined CBT and SSRI medication is the best treatment for OCD. Assuming this is referring to March et al (2007) this study did not recruit patients matching the PANDAS sub-type. Given that the NIMH research is indicating a different pathogenesis for PANDAS there is insufficient evidence to state that SSRIs are appropriate for children with PANDAS. Indeed, in 2006, Murphy et al in “Selective Serotonin Reuptake Inhibitor-Induced Behavioral Activation in the PANDAS Subtype” indicate that there is a high potential for increased behavioral activation at common dosing of SSRIs. The recent research by Kirvan and Cunningham (2003, 2006) support the pathogenesis of an auto-antibody interfering with neuronal signaling and that remission of symptoms comes from the decline in the antibody. Yaddanapudi ‘s research (2009) on passive transfer also indicates that it is antibodies that are causing behavioral change. Given the black-label warnings on SSRIs, the increased activation level on SSRIs for PANDAS children, and the increasing evidence that symptoms are due to interference of antibodies and not to levels of serotonin or dopamine, it is improper to recommend SSRIs without a very clear warning regarding activation and the symptoms of activation. Buster

In our case it was Group A beta-hemolytic strep on the skin in the peri-rectal area.

That was true for our daughter too. It's a great point. I think we can reference Kaplan's paper that skin strep doesn't cause an ASO rise. I'll group these together into a series of recommended changes. Buster

Are you kidding me? With CRP at almost 26 and an ESR at 20? They should either have been immediately looking for lyme disease or RF. The Anti-DNAseB should have driven them to RF. Amazing. I'm not sure whether it is the exotoxins, certainly some of them act as super-antigens and recruit/activate 20+% of T-cells. With that many activated T-cells all sorts of things can go wrong. Why I'm asking about the emm-type is I think this is likely a key that may even help us determine the right exotoxins to track. I wonder if we could recruit Ed Kaplan at WHO to run emm-types on culture samples... He was the one who found that GABHS changed its M protein expression when moved from person to person. Perhaps there is something going on there. Buster