Buster

Our dd9 gets a lot of bloody noses too -- particularly during exacerbations. We weren't sure if it was dry skin, seasonal allergies turning into congestion turning into blowing nose/bloody nose. Hard to say. Symptoms were correlated with bloody nose -- but so was giving advil :-) So could have been a number of different factors. Bottom line, yes we got them too. Oh, and we live in a pretty humid place so unlikely to be dry air. Buster

Amy, If they are subcutaneous nodules rather than hives, then that could be one of the signs of ARF. Did she have strep during this time? Alternatively, they could easily be a skin allergy. Recommend taking to the doctor to have them take a look. If you send me a PM, I'll send you a note on how to post a picture if you wish. Buster

We had three main things that caused us to go ahead: Our child's baseline symptoms (i.e., during the time between exacerbations) was getting worse. When plotting symptoms over the 18m period, her baseline symptoms were not remitting The anorexia nervosa and restrictive eating symptom returned A prednisone burst had full remission of symptoms for 4 days I guess it depends on the severity of the residual symptoms. IVIG is a blood product with the risks associated with blood products. You really do have to weigh benefits. In our case the symptoms were severe enough we felt it was the right thing to do. Improvement occured at 14 days post IVIG. The first 2 weeks were substantially worse with a significant exacerbation. It was on the 14th day that symptoms remitted with a dramatic improvement in mood for another 20 weeks. We will likely keep her on prophylactic antibiotic for a long time. It is our belief that the potential for the condition remains in her system but that IVIG closed the blood brain barrier and suppressed the antibody. We think that she might be re-exposed to strep and get a similar antibody response and with sufficient inflammation, the BBB might open. While antibiotics do not prevent GABHS infections, they do help the body fight off the infection and as such we hope her antibody levels will not be elevated. We discuss this regularly but want a period of sustained remission before changing meds or adding another variable.

Hi Amy, Our child had fairly chronic bloody noses and this did seem to be correlated with symptoms. It wasn't possible for us to determine if this was just high blood pressure and then "picking" at the nose or something else. It seemed correlated with giving Advil but again tough to tell. Anyway, yes, on the bloody nose. On the hives/nodules, there's a lot of things that could be. Are they very pink or are they sort of soft and movable? Do they seem mostly over the bones/joints or spread out. Did you notice a rash on the body? About how big were/are they -- are they about 1/2 inch or about an inch or smaller. Often hives are from an allergic reaction to new soap or detergent or ... -- but if you also have symptoms of strep the hives could be tied to ARF and hence something to pay a lot of attention to. Regards, Buster

I find that interesting too.... I'm on a weird research direction looking at the Eosinophil #'s. Buster

I've now listened to Kurlan's webinar. LLM captured Kurlan's basic argument quite well. In addition to LLM's post I'll raise a few things here: Kurlan stated that the breadth in symptoms (i.e., things like daytime urinary frequency) was a strike against PANDAS. This statement is without merit and without research. More importantly, he confused statements made by foundations with statements made by researchers. Finally, he did not seem to be aware that many of the symptoms were actually manifestations of compulsions and therefore a unifying symptom (and helpful comorbid indicator) rather than separate manifestations. He stated that the "sawtooth course is common in TS". This statement is also without research merit. The use of the word sawtooth does not appear in TS literature prior to the comparison to PANDAS. Reviewing his paper, his kids did not have a baseline change in tics or OCD (meaning no child went into remission in the 2 years). Also no child had a major OCD exacerbation during the 2 years. By definition, none of his subjects had sawtooth OCD symptoms. He spent a great deal of time on his study -- however, it was very odd how he represented the research. In the presentation, he showed that they found definite and probable GABHS infections in 31 cases in the PANDAS group versus the controls that had 12. This is statistically significant. In addition, if you just take the culture positive for GABHS this was 36 cases in PANDAS subgroup whereas controls had 16. This indicates that in their study 5 PANDAS kids and 3 controls did not have a rise in ASO titers and were asymptomatic despite a positive culture. He did not disclose on the webinar that he informed the children's doctors when the kids had positive GABHS. As such he easily could be repeating the study that showed that treating GABHS prevents severe exacerbations. He presented the hit ratio of how many kids got an exacerbation within -4 to 4 weeks from a definite or probable GABHS infection. This was statistically significant and significantly above mere chance. He dismissed this by saying that children meeting the PANDAS critieria were just more suceptible to GABHS infections and therefore hit more of the window than mere chance. The point is actually valid, but is not the simplest explanation of the data. It was just amazing that he showed the correlation and then dismissed it. His final comment on the research was that most of the exacerbations recorded (i..e, 75% of them depending on definition) were not correlated with a preceeding or occuring GABHS infection. I would have loved to see this on a patient by patient basis as he just mixed individual results with a blended population. He's got 25% correlated (which is a huge amount in a study with 40 patients). For me, the single biggest issue was that Kurlan did not recruit children who had exacerbations that were temporally correlated with GABHS and then compare that selected group with controls over a 2 year window. Instead, he took Tourettes kids with tics and tried to see if their tic exacerbations were correlated with GABHS. Uggh. The second to last question in the session was "Are we any closer to understanding the causes of TS than we were 10 years ago." Response: "I think from 10 years ago, we're not a heck of a lot closer. I think 10 years ago there was actually a lot of excitement about the possibility that genetic studies would in fact give us the answer. But I think the last 10 years has been pretty disappointing in that we still don't know which genes in the brain are involved and if we don't know which genes are involved [then] we don't know about the basic molecular mechanisms in the brain. There also has not been a great advance in terms of available treatments for Tourette Syndrome. Perhaps the most dramatic advance is that deep brain stimulation might be useful for patients with very severe Tourette Syndrome. But unfortunately I think the past decade has not been too kind to Tourette Syndrome and we're not too far ahead really [in] understanding things. I think there needs to be a large push in research to understand things better." I thought about this comment and sort of screamed at the screen -- then stop spending money on trying to disprove PANDAS and go repeat Kirvan, Cunningham, Snider and Swedo's experiments exactly (I mean exactly) -- replicate the results and see if they are right. Sigh, Buster

I can't believe I missed this post much less the webinar. Feb/March was such a busy time. The notes are really helpful. I wish I had heard exactly what he said -- does anyone know if the "webinar" is available online? Let's start with Kurlan's selection process: Kurlan selects his subjects from children diagnosed with Tourettes Syndrome and typically selected from the Tourettes study group. The diagnostic criteria for 307.23 requires: Both multiple motor and one or more vocal tics have been present at some time during the illness, although not necessarily concurrently. (A tic is a sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization.) The tics occur many times a day (usually in bouts) nearly every day or intermittently throughout a period of more than 1 year, and during this period there was never a tic-free period of more than 3 consecutive months. The onset is before age 18 years. The disturbance is not due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington's disease or postviral encephalitis). So technically, if PANDAS is a disease, then a child with PANDAS couldn't have Tourettes Syndrome because of the exclusionary comment in the last bullet. In Kurlan's reports, 90% of the children were diagnosed with Tourettes. Presuming this was an accurate diagnosis, this means these children had no remission in at least one year and no tic-free period of more than 3 months. Comments in the study and the delay from initial recruitment to execution indicate that the children had been diagnosed with Tourettes for > 3 years with no remission with many post-pubescent at the time of the study. This means Kurlan was not looking at kids at the onset, but only after many years of unremitting tics. Also looking at his recent 2008 study, none of the children had any variation in OCD symptoms over a 2 year run. This means these children are quite different from Swedo's kids. Swedo was observing children with +/- 17 points in CYBOCS scores around an exacerbation. Kurlan noted variances of 1.6 (i.e., nothing) over a 2 year window. In addition, in Kurlan's 2008 report, he broke the blind to inform pediatricians if the child was diagnosed with GABHS. While technically his team didn't know that a child had been treated, the child/mother/... sure did. If anything, his study confirmed earlier studies which are that prompt treatment of GABHS with antibiotics prevent sequelea (including PANDAS).[/b] Anyway, I'd love to hear what he says directly and it annoys me to no end that the peer group reviewing the 2008 papers didn't pick on these results and the conclusions given the holes in the study. By the way, in case it isn't obvious, Leckman's kids were in the same study. Singer's kids were pulled from the same study. Schulman's ridiculous write up was claiming these were three independent studies (when they were all the same kids). Arggh. Buster

The NIMH website isn't quite up to date. Dr Swedo clarified her position and diagnostic critieria in 2004 when she explained what "episodic course" meant (see my comments in the research papers). She defined that episodic was a noticable beginning with a noticable remission and was not similar to the normal waxing and waning of symptoms associated with traditional OCD. Now it should be noted that she is defining a subgroup for purposes of research, the same pathogensis (cause) could apply to those who don't have the "sudden" onset or the episodic nature, but she's studying the smaller group first and then will broaden. Buster Interesting! So am I mistaken in understanding that "sudden onset" was part of the initial criteria following Swedo's first study? It has certainly been cited to me by our psych more than once. Has the NIMH changed its criteria over the years as more information and evidence has come to light? Then why do we continually hear and see "sudden onset" identified in the press and by current practitioners like Leckman?

This was a bit tough to answer. In our dd9's case, I would say overnight. When she was 7.5 her symptoms came on literally overnight following a 102 degree fever. We went downhill fast and had to hospitalize her to get her stable. However, in going back over all our notes, we discovered that when she was 5, she exhibited what could be seen as OCD traits coincident with being treated for an upper respiratory infection. We think this was her real first PANDAS episode. At that time, she exhibited excessive hand washing and worry about getting sick. A friend's child had died of a rare cancer and she was worried she too could get sick. We actually thought this a normal childhood fear that could be addressed with reassurance. She also exhibited the symptom of needing to walk 15 feet behind an older neighbor (who was ill at the time). Again, she was worried about contamination. It took about a month but she recovered. Curiously, that was one of the few times she (and her sister) had gotten antibiotics to cure an upper respiratory infection. Regards, Buster

Well, this won't have any statistical significance until a lot more votes... always the danger with data -- so many other things can cause all the effects, I was just wondering if one of them stood out. On the note regarding Eosinophils -- usually they are associated with parasites or allergies.

Good question. I guess I meant during an exacerbation -- but was more trying to see if the Eosinophils were off for a lot of people. In PM's from a lot of folks it looks like Eosinophils are high and that made me wonder whether this was a common trait -- even for those on antibiotics.

That's not good. If he has PANDAS, then you likely have another source of strep in the house. Go get the family throat cultures. No, antibiotics do not kill bacteria nor do they "ward off" bacteria. Yup, prophylactic antibiotics do not prevent colonization nor prevent infection. They just slow down both. You must have an intact immune system for prophylaxis to have any effect. By the way, you can't believe how many doctors don't know this. Even while on antibiotics, you can still get strep colonization. However, the antibiotics slow the speed at which the colonization/infection can spread so you body can generally kill off the strep without having to mount a full out assault. This means that there will be some antibody rise but not severe. This is the real problem here, prophylaxis (i.e., preventative use of antibiotics) don't stop an immune reaction, they just minimize how much the body has to create an immune reaction. In PANDAS and Sydenham Chorea, this is thought to be effective because these diseases have three components: the initial strep infection the creation of the abnormal antibody by the immune system a breach of the blood-brain-barrier -- likely due to inflammation So the antibiotics are likely preventing #3 and minimizing #2 and shortening the window of #1. So if your child has symptoms correlated with streptococcal infections, prophylactic antibiotics will likely minimize the symptoms and minimize the duration and may prevent the response entirely by keeping inflammatory cytokines low so that the blood-brain barrier is not breached. If your child has something other than PANDAS then the above will likely have no effect. Regards, Buster

Hi Folks, If you've had a differential CBC done on your child -- could you take a quick look at the poll and see if any of the monocytes, lymphocytes, eosinophils were out of range? Buster

While a simple question, the answer is a bit complicated. Antibiotics don't kill strep. The immune system kills strep. Antibiotics work by slowing the progression of the strep replication allowing the immune system to catch up. Penicillin works by eroding the cell wall. Azith and macrolides work by inhibiting an enzyme used in rapid replication. Antibiotics are only really helpful in rapidly replicating bacterial infections. Antibiotics are not particularly helpful in slowly replicating infections. The immune system has to recognize the GABHS bacteria and attack the bacteria with macrophages. In some people, the immune system doesn't recognize GABHS or has trouble clearing it. It is not known why. Kaplan refers to the carrier state as "an enigma" because GABHS is generating exotoxins but the immune system seems not to respond in some people. To test for clearance, you have to check 14-21 days post last treatment. The dosage for antibiotics is set to treat 80+% of people effectively (i.e., lowest dose that will help 80+% of people clear an infection). so, to answer your question, the term "carriers" usually is short hand for "asymptomatic carriers" and means that there is no apparent immune response to the presence of GABHS. For these asymptomatic carriers, the use of antibiotics does not help the immune system overcome the infection because for reasons not understood the infection is being held in check through some other mechanism -- lots here about other throat flora, but the short answer is they don't know why. So yes, for asymptomatic carriers, they would typically not clear strep on normal dosage of antibiotics. I probably just caused you to have more questions, but hope this helped. Buster

PANDAS is thought to have a different pathogenesis (cause) than traditional tic or Obsessive Compulsive disorders. The cause for Tourettes Syndrome and other tic disorders is not known and thus symptoms are generally treated for these disorders rather than underlying condition. PANDAS is thought to be a disease (i.e., defined cause) where Tourettes and OCD are syndromes (i.e., collections of symptoms whose cause is not known). Studies in since 1998 (see PANDAS FACT Sheet) indicate that PANDAS has an auto-immune component that is not present in traditional tic and OCD presentation. Research by Kirvan indicates that in genetically susceptible individuals, the immune system produces an inappropriate response to GABHS with antibodies targeting the GlcNAc carbohydrate on the GABHS cell wall. These antibodies appear to cross react with neuronal tissue causing fluxuations/interference with dopamine levels and neuronal signalling. That sounds odd on multiple levels. If it said your son had a strep infection, then he should treat the strep infection to head off possibility of ARF or SC. What an odd comment. However, usually a throat culture is an effective first level test to check for active strep colonization. Throat colonization is typically treated since in most cases (>90%) it turns into an infection. PANDAS does not have a recognized blood test. Swedo found elevation in ASO titers in some children that presented with sudden onset and severe OCD. Other studies have shown the ASO titers rise in only 64% of children who had culturable GABHS. Kirvan and Cunningham have found an elevation in CaM Kinase II activation in children who fit the PANDAS profile. However, this is a research trial and the sensitivity and specificity of this test is not known. Today, PANDAS must be diagnosed from clinical symptoms and the correlation of clinical symptoms with a GABHS infection precursor. Bottom line, exacerbation with GABHS infection and remission with antibiotics is a pretty strong indicator of PANDAS. Similarly, for severe cases, remission with a burst of pred or remission with IVIG/PEX strongly implicates an auto-immune component. Recommend looking at the PANDAS fact sheet at: http://www.latitudes.org/forums/index.php?showtopic=6265 Best regards, Buster

Thanks for this info. I will ponder over it a while. Sounds like it is possible for titers to come down fast naturally. Andrea Let me be more specific. Yes, it is possible for titers to drop quite rapidly with or without antibiotics. Antibiotics slow an infection so the body's immune system can catch up. Antibiotics (especially at low dose) do not "kill" bacteria. Only the immune system kills bacteria. Azith is bacteriostatic which means it prevents replication of bacteria -- it doesn't kill it -- it just slows it down. So as long as you have an intact immune system your ASO will come down. However, for lot of people, they can't quite kill off the bacteria faster than it can replicate. For these folks antibiotics are a life saver (literally). Let me know if there is something deeper in your question -- happy to answer or point you at papers. Buster

Hi Santi, There is no good controlled study on the rate of decline of ASO titers. However, IgG has a half-life of 21-28 days. On the assumption that you got a sample of ~1000 at or near the peak of the ASO response (i.e., 4 weeks post infection) and your body is able to stop the infection (either with or without antibiotics), then the values would be expected to be: 840 at one week 707 at two weeks 594 at three weeks, etc If the sample was taken before the peak, then the rate of decline will obviously vary. Hope that helps. Buster

Well, a Kinase is an enzyme that causes a state change in a cell. In neuronal cells, Cam Kinase II causes activation of the neuron. I'm happy to go into the science, but what you are probably asking is what does it do. Well, to the best of my knowledge, CaM Kinase II (when applied to neuronal cells) regulates dopamine release. So if you have excessive amounts of CamKinase II you likely have a disfunction in dopamine processing and production. The problem isn't really whether you have too much dopamine or too little, but rather that it isn't regulated so the body can't quite get the right signal through -- think of the excessive CaM Kinase II as being interference. While the normal signal should be producing some of the signal, if a foreign substance creates it (say the antibody 24.3.1) then the neurons have a hard time regulating the release of dopamine. SSRIs tend to increase the amount of available dopamine, other psychotropic drugs reduce the amount by also mucking around with CaM Kinase II activation. The analogy I use is that its like those terrible commercials that come on 40% louder than the show you want to watch. When they come on -- too much volume. You try to adjust but then when the regular shows back on, too little. It's just hard to get it right. Best regards, Buster

Hi folks, I got several emails asking if I was okay with material from this post (and others) being posted on other web sites. Yes, however, people should create a link back to this post for the latest material as that means I don't have to try to keep multiple sites up to date :-) My goal in writing this stuff is to get good summaries of the scientific literature out there in a way that is hopefully easy to understand. Buster

It appears PANDAS is not in the current draft of DSM-5 either.

I know you are saying that there isn't a specific separate code for PANDAS -- but that's because there is still debate about whether PANDAS is a set of symptoms or a disease. As a set of symptoms, PANDAS has a bunch of codes. For example, children with PANDAS have either a tic disorder (307.20 : Tic disorder unspecified) or OCD (300.3). The problem is not characterizing the symptoms, but rather coding the symptoms in such a way that the treatment is actually beneficial and covered under the code. Doctors (and insurance) associate standards of care with each code. Thus you can get strong anti-psychotics for 300.3 but can't usually get antibiotics. This in essense is the debate in PANDAS -- not whether the kids are sick, but whether the code used to describe their symptoms has good evidence (i.e., double-blinded studies) of efficacy. Unfortunately, the "standard of care" is usually based on research from 15-20 years ago and despite the very strong set of papers from Yaddanpudi (2009), Kirvan (2004, 2006, 2007), Cunningham(2006, 2007), Perlmutter (1999), Church (2004), ... the studies have not been replicated sufficiently to have a proven set of results. A simple repeat of Perlmutter would do wonders. For reasons I can't figure out the Turkish and Russian studies don't seem to count. Tourette's Syndrome, for example, is not a disease (because its cause is not known). It is defined by a set of symptoms. OCD is a syndrome because its cause isn't known. Most believe that the basal ganglia is involved in OCD and Tourettes, but exactly what is wrong and what will help correct the disorder is not known. In terms of treatment options, PANDAS can be characterized by ICD9 348.39 Other encephalopathy -- if you have evidence of inflammation of the brain 279.00 Hypogammaglobulinemia unspecified -- some children have unusual IgG levels 279.03 Other selective immunoglobulin deficiencies -- again if they aren't raising a IgG response 279.09 Other deficiency of humoral immunity -- again because of the faulty antibody creation 279.10 Immunodeficiency with predominant t-cell defect unspecified -- again because of the high T-cell recruitment or the old standby 279.3 Unspecified immunity deficiency or better yet 279.4 Autoimmune disease not elsewhere classified Thus far Kirvan and Cunninham tests established anti-GM1 antibodies. Swedo/Perlmutter demonstrated that IVIG and PEX had dramatic improvement on severe cases that had sudden onset. Swedo also demonstrated that IVIG and PEX had no effect on children who did not fit the PANDAS subgroup. While this is strong evidence, what is actually required is for Swedo's tests to be repeated and confirmed. Anyway, I know your point which is that PANDAS doesn't have it's own code, but thought I'd lay out all the codes that apply so that folks know it is codeable. Buster

Dr T, I thoroughly agree. In fact, one of the reasons I put together the fact sheet and FAQ sheet was explicitly to accelerate the path of parents in coming up to speed as I wish I had had that information in March 2008. What frustrated me so much about certain research by a very specific organization was that they were propogating their opinion in their title and not in their study. Titles like "PANDAS: Is It Important?" or "The PANDAS hypothesis: losing its bite?". Things like selecting patients who had 3+ years of continuous tics without remission and then making some statement about PANDAS. Only buried in their report can you find that they didn't repeat other people's experiments but decided to use rabbit brains (despite Husby's warning from 1977). Or that their children had zero fluctuations in their OCD severity (1.6 actually), when Swedo, Snider, etc explained fluctuations of 18pts. While I appreciate that their studies didn't confirm prior studies, I wish they had spent their time confirming/repeating the prior experiements rather than creating new experiments that could neither confirm or refute prior findings. Best regards, Buster

Looks like I'm a bit late to the party here. The science is: Cunningham and Kirvan isolated 3 antibodies 24.3.1, 31.1.1 and 37.2.1 that interacted or inhibited binding of Monosialoganglioside GM1. These antibodies also had epitype for N-acetyl-beta-D-glucosamine. Finally, 24.3.1 was found to cause activation of Cam Kinase II when presented to neuroblastoma cells. N-acetyl-beta-D-glucosamine is the dominant carbohydrate on GABHS. Now translating: Cunningham and Kirvan found 3 antibodies that interfered with neurotransmitters in the brain. These antibodies target a particular molecular sequence which happens to be a part of the Group A Beta Hemolytic cell wall structure. In neuro-blastoma cells Cam Kinase II activation regulates the amount of dopamine released. So what Cunningham was studying was the disregulation of dopamine due to the introduction of antibodies. While CaM Kinase II can occur elsewhere in the body (i.e., muscles etc), Cunningham was testing the level of Cam Kinase II activation with neuro-blastoma cells and the interaction with dopamine. Now to the question about Strep: What was unusual about 24.3.1 was that it was targeting a particular carbohydrate (GlcNAC). This carbohydrate is the predominantcomponent of the GABHS cell wall; however, this carbohydrate does exist elsewhere in the body (in particular in joints) and thus it's possible for some other event to cause the activation of the B-cell for the production of the anti-GlcNAC antibody. Kirvan and Cunningham are not yet able to discuss causality but only correspondence -- i.e., that the antibodies exist in more quantity in children with certain symptoms and if exposed to neuroblastoma cells cause CaM Kinase II activation. So, no they do not know whether the antibody is produced only in response to Strep -- but can show that the antibody is produced in a group of children in response to GABHS.

I went down this path for quite some time and ended up wondering if the kids were actually MyD88 deficient. TLR2 and TLR4 both trigger MyD88 in response to bacteria. But clearance required MyD88 support. http://www.sciencemag.org/cgi/content/abstract/321/5889/691 Buster

My understanding is that the cell line that produced this marker died out so this test is no longer available. Dr. Swedo mentioned this in one of her lectures. Buster