Buster

Actually Cunningham is testing for 24.3.1 but only under the general category of anti-lysogangliosides (i.e., she's looking at competitive inhibition but is using the whole serum -- she's not isolating the antibody first). This is likely a cost issue. I'd imagine isolating the antibody would be quite expensive. The presumption is that the anti-lysogangliosides found in competitive inhibition are the 24.3.1, 31.1.1 and 37.2.1. Of these 24.3.1 is the only one that seems to really drive CaM Kinase II. So I suppose your question is "if the anti-lysogangliosides are low, why is her CaM Kinase II high?" Frankly, I'm not sure. CaM Kinase II can stay active for a while, but it is surprising that it's remaining high. I would have expected the anti-lysogangliosides to be elevated if the CaM Kinase II is activated. I guess that's the whole purpose of the current study. It may mean there is another cause. In terms of blood level and brain level, it looks like this is only correlated during an exacerbation. The nature paper reports CSF and Serum levels and these correlate in exacerbations. Hence the thought that there's a BBB problem. Regards, Buster

Hi T.Mom, On the evidence that 24.3.1 falls at same rate as other two antibodies. There are essentially three elements: Swedo showed that system exacerbations tracked ASO titers for those PANDAS kids that had ASO response Kirvan showed that CaM Kinase II activation was substantially reduced in convalescent serum (see fig 3a in http://www.pandasnetwork.org/CunninghamJNICaMKinase.pdf) finally, Kirvan showed that antibody 24.3.1 activated Cam Kinase II (see figure 4a in http://www.pandasnetwork.org/Cunningham.NMpaper%5b1%5d.pdf) What's interesting about fig 3a in the JNI paper is that 25% of the kids did not have a substantial change in their CaM Kinase II -- to me this indicates that perhaps their blood brain barrier closed rather than the antibody going away -- however, that's just conjecture. Okay, so what is CaM Kinase II, well, that's a tough topic. Let's see if a short answer works: Upon activation, CaM Kinase II turns on glutamate receptors on synapses. This changes the electrical property of the synapse. So if CaM Kinase II is happening incorrectly, it interferes with how the synapse works -- sort of like interference on a radio. So, if 24.3.1 causes CaM Kinase II activation, then if it crosses the blood-brain barrier, it could be causing incorrect signalling in the region of the brain sensitive to lysogangliosides and glutomate signalling (namely the basal ganglia). I realize that is 3 if's in a row, but that's about as far as the research has gotten. Hope that helps -- I can point you to papers if you really want details, Regards, Buster

if you can't see the replies in this thread, set the options button to standard rather than outline. Try this link for an explanation of ASO and AntiDNAse B http://www.latitudes.org/forums/index.php?...ost&p=25312 Just as a quick reminder, PANDAS is not thought to be caused by ASO or Anti-DNAseB, but is thought to be caused by another antibody known as 24.3.1 (great name huh). 24.3.1 showed up in the kids who had PANDAS in Swedo's studies and was not elevated in controls. ASO and anti-DNAse B showed up in both PANDAS and controls. However, ASO and Anti-DNAse B was elevated in PANDAS kids with sudden CY-BOCS score exacerbation. The 24.3.1 gives a new differential between the PANDAS kids and the controls. I say "thought to be caused" because causality is still not yet shown. There could be yet another antibody/protein not yet found or perhaps the antibody doesn't matter until something else opens the blood brain barrier. So, what is the usefulness of ASO and Anti-DNAse B? Well, I don't think there is much use (especially since PANDAS exacerbations seem to happen when the blood-brain barrier is disturbed and not just when a child gets strep). However, given the educational state of doctors, having a rising ASO or antiDNAse B sure helps convince them -- since they don't seem to read the research papers :-) The emphasis on ASO and Anti-DNAse B is largely because of Swedos original study where she only selected kids with rising ASO and AntiDNAse B as opposed to kids with just positive throat cultures. Swedo's study chose to use a strong definition of "associated with strep" which was to define "associated with strep" as "immunologic response to known strep antigens". The discovery of 24.3.1 wasn't until 2004 (8 years after Swedo's study). 24.3.1 is thought to be an unusual antibody response to a strep antigen that isn't suppressed in kids with PANDAS (i.e., others seem to suppress 24.3.1) -- I think this is why IVIG might work. It is unknown what the rate of fall is for ASO or AntiDNAse B or for the PANDAS antibody 24.3.1. The current research by Kirvan/Cunningham indicate that the concentration of 24.3.1 is important and so its rate of fall matters. There is some evidence that CaM Kinase II stays activated even with falling 24.3.1. There is apparently some hysterisis for some kids. There is good evidence that 24.3.1 falls at the same rate as the other two antibodies in 75% of kids. Perhaps for kids who show a rise in ASO, the fall is also a good indicator of T-cell regulation/suppression. There is mounting anecdotal evidence that colonized strep (rather than infection) is sufficient to trigger antibody response in PANDAS kids. So it could be that colonization is sufficient to cause a rise of 24.3.1 -- or that some kids just don't have rising ASO/Anti-DNAseB during infection (Kurlan indicates 36% of kids don't have a rise of ASO and Anti-DNAse B ) . Hope this and the above reference help. Regards, Buster

Our dd9 says "that's exactly what I was feeling. I didn't want to be alone because it felt like someone was watching me and I felt like they wouldn't if you [mom or dad] was there." She explained it's like the back of your neck can feel eyes on it. It's that creepy feeling that something is out there. She later said that during the worst exacerbation she thought it was ghosts watching her and had seen ghosts coming out of the tap -- we think that was an occular migraine from the description. She was definitely seeing things. She was also scared of spiders at night because she felt watched and once saw a spider so then thought it was watching her. She said it didn't make sense but she couldn't get "not scared". Bottom line she really wanted someone else with her so she didn't feel watched. I should mention this only happened for her at night -- for some reason during the day, she didn't feel watched. She likes spiders by day, but not at night. By the way, there were places where she felt safe (like her bed) where she didn't feel watched so could be alone. However, getting to the safe spots was a big deal. There were a lot of weird comments that the above explains -- she'd say things like "I want to be alone, but you have to be here." The contradictions were funny at face value, but she was truly terrified and was quite serious. Regards, Buster

In terms of prednisone, in our case we did a 6 day burst and it wasn't until the 10th day post-pred that we saw a noticable difference. I suppose looking back, she had better mood, but on the 10th day, her basic symptoms disappeared and she was doing things (like talking to adults) that she hadn't done in years. This lasted 4 days and then back we went to before prednisone behavior. Not sure what to tell you. 10 days is an awfully long time to think that it is causal, but we have no other explanation. Regards, Buster I completely agree with you....we used it for six weeks...and the last four weeks it was only 5mg daily...DD6 is almost completely recovered...just some really minor issues now... ~Karen

Michele, Wow, 7 years. We're exhausted at just 1 year. We're post-IVIG by one week and things are actually getting worse, not better. It's very scary. Despite all my reading, I'm not at all feeling qualified to advise you because we are really not through it ourselves. In terms of your questions, yes, prednisone did have an effect. However, in our case, the effect was 10 days after the burst. It was noticable with a complete absence of social anxiety, tics, chorea, measurement rituals or any other symptoms. We were amazed. Then 4 days later, our dd9 was back to her withdrawn self. My gut is that Latimer and others are responding to the long length of illness. We don't know if PANDAS becomes something else long term (such as classic OCD and TS) and in our own child we've seen an increasing baseline when plotted over the past year that isn't corrected with antibiotics. She never seems to fully reset from an exacerbation so the baseline of symptoms between exacerbations just gets higher. I guess the real question for you is whether you see episodes now correlated with strep or whether you are seeing more mild variations. In Kurlan's study of long-term TS/OCD patients -- he saw OCD changes of +/- 1.6 points over 2 years. In Swedo's studes of sudden onset, she saw OCD changes of +/- 20 points (i.e., 10 times larger). I'm not sure whether Kurlan had any PANDAS kids at all, but he'd say they met all the criteria. I'd say they didn't have Swedo's criteria of episodic exacerbations with dramatic onset and fall (i.e., the 20 pts CY-BOC score changes). Perhaps that is what Latimer is responding to if your child is demonstating mostly constant OCD behavior. Of course this could also be the meds doing what they are supposed to. I don't think anyone knows. It seems a really reasonable question to ask your doctors what led them to one diagnosis over another especially since they actually are supporters of treating PANDAS. My gut is that they just haven't seen a kid with 7 years of suffering and are thinking that treating the symptoms will likely require other methods than with onset PANDAS kids. I really wish I knew what to advise you here. Perhaps an email with Dr. K could help as he's probably seen more patients than anyone else and might have a sense for whether the same treatment has been helpful on longer term sufferers. Best regards, Buster

Just as a reminder, the new paper is a followup to work by the same author in 2004 http://www.jneurosci.org/cgi/reprint/24/7/1780 that was entitled "A Murine Model for Neuropsychiatric Disorders Associated with Group A -Hemolytic Streptococcal Infection" that heavily cited Kirvan/Cunningham's work on GlcNAc. what was different here was that the authors transferred the created antibodies from immunized mice into non-immunized mice and showed that the transfer of serum caused the movement/behavior issues. The push back on the paper will be similar to the prior paper that "mice aren't people", but wow, it's very good work and very consistent with the findings of Kirvan and Cunningham. It would be fascinating to know whether the innoculated mice have an antibody similar to 24.3.1. Regards, Buster

Yeah, dw definitely makes fun of me about getting a kit. She says I'm really a frustrated chemist :-) Our true canary is our PANDAS dd -- historically when she starts to flair up, a throat culture on non-PANDAS dd (ie., her sibling) is positive and then negative 3 weeks post antibiotics. Anyway, I still claim it saves time -- even if dw makes fun :-) Buster

The worry with broad antibiotics is that you might be knocking out some good bacteria -- and in that sense weakening the immune system -- or that you create a strain of antibiotic-resistant bacteria. These two worries are why we're more comfortable with a very narrow spectrum antibiotic for our non-PANDAS daughter (she's 6). Penicillin (for example) is pretty narrow and really only disables strep. I can see why you'd be concerned giving anything to a toddler as their immune system is still forming. The reason we aren't using penicillin on our PANDAS dd9 is that we didn't see curative effects from penicillin/amoxicillin before and we're trying to minimize the number of variables we introduce (change only one thing at a time). Over time, we'd sure like to move off azithromycin, but that won't be for a while as we try to get back to a stable baseline.

The Cunningham tests are quite different from the ASO or Anti-DNAse B tests. ASO and anti-DNAse B are commonly used to look for a prior strep infection that occurred in the last 2-6 weeks. ASO and anti-DNAse B both require a baseline as they are only meaningful when rising. A falling titer means nothing. A stable titer apparently means nothing. Most people don't have a baseline, so many labs indicate that a high value is positive -- but that's not always true as you could be on the downramp. Cunningham's tests are not checking for strep, but rather are testing for a specific antibodies in the blood stream (24.3.1) that seems to interfere with neuronal signalling by competing with a brain chemical (lysoganglioside GM1) and memory formation (by triggering CaM Kinase II). In addition, Cunningham runs some other tests for additional antibodies that compete with other brain signalling chemicals (tubulin and dopamine). The Cunningham tests are not testing for Strep. They are testing for residual antibodies that could cause problems in brain signalling if the blood-brain barrier is breached. There are longer write ups about this in this forum -- let me know if you need to post #. Regards, Buster

If you are interested, you can find out about the SJL/J mouse at http://jaxmice.jax.org/strain/000686.html These mice are engineered to have elevated circulating T cells and are highly susceptible to experimental autoimmune encephalomyelitis (EAE). EAE is thought to be similar to multiple sclerosis. Essentially, these are mice who have problems with the blood brain barrier and have really active immune systems. So when they are innoculated with GABHS, they produce a lot of antibodies and these antibodies end up crossing the BBB. Regards, Buster Maybe a mouse that is known to be prone to an autoimmune response that was immunized with GlcNAc? They call it an autoimmune mouse model.

Hi Folks, I posted this within another thread but figured I'd pull it out to its own topic. We went ahead with IVIG this past week for dd9. We were able to convince our immunologist to treat locally. We did a short run of prednisone for 6 days. We saw no effect until 10 days post-burst. At 10 days we had a noticable reduction in movement disorder, social anxiety, separation anxiety, measurements, and restrictive eating. The effect lasted for 4 days and then we returned to baseline. We decided to do IVIG because exacerbations were continuing despite propholaxis azith and dd9's baseline of symptoms had risen significantly over past year. We decided on IVIG over PEX in hope that there is something to IVIG resetting T regulatory cells (per article below by Aharon). We're really hoping it is curative versus just reducing the antibodies. Unfortunately, we won't know for a while. dd9 did great and had no apparent adverse effects from the IVIG. We were concerned because of high dose and moderate flow rate (52 ml/hr). It took a long time (7 hours/day for 2 days). We're 2 days post IVIG. dd9 had a slight fever (100 degree) and a slight headache, but oddly is in a good mood and headache is addressable with tylenol. We'll post as we learn more. For those tracking, dd9's CaM Kinase II was 183% in April without exacerbation and 253% in July during exacerbation. Buster

Hi Folks, Just a quick note that we went ahead with IVIG this past week for dd9. We decided to do IVIG because exacerbations were continuing despite propholaxis azith and dd9's baseline seemed to be rising significantly over past year. We decided on IVIG over PEX in hope that there is something to IVIG resetting T regulatory cells (per article below by Aharon). We're really hoping it is curative versus just reducing the antibodies. Unfortunately, we won't know for a while. dd9 did great and had no apparent adverse effects from the IVIG. We were concerned because of high dose and moderate flow rate (52 ml/hr). It took a long time (7 hours/day for 2 days). We're 2 days post IVIG. dd9 had a slight fever (100 degree) and a slight headache, but oddly is in a good mood and headache is addressable with tylenol. We'll post as we learn more. For those tracking, dd9's CaM Kinase II was 183% iin April without exacerbation and 253% in July during exacerbation. We did a prednisone burst in July. We saw a positive change 10 days post pred. It lasted about a week (same as length of burst). Buster

Hi Folks, Just a warning that Cunningham might be a bit slower in responding to requests around PANDAS. They didn't get funding for the brain/PANDAS research. They did get funding for their heart research but this means they sort of have to get back to that research. Best regards, Buster

Hi folks, Just a quick warning that Cunningham's lab did not get the funding for continuing brain/PANDAS research. They did get funding for continuing their heart research but this means they might not be able to run a lot of CaM Kinase II tests until funding for PANDAS comes in. Best regards, Buster

** edited 8/8 ** I'm not sure yet what this test means. I'm reading some doctors take a base line, then re-vacinate, and then check antibodies 3 weeks later. There are other web sites that indicate a 10 year antibody response to challenge. If someone talks with an immunologist I'd sure appreciate an explanation. I'm wondering if the difference is those that were born pre 2000 (i.e., were not likely vaccinated) and those post 2000 (who probably got 4 vaccinations). In our case, our dd had a response on serotype 19, 6B (26) with weak 18C(56). The rest (1, 3, 4, 7F(51), 8, 9, 12, 14, 23) were negative. I didn't see values for the other serotypes. The items in () are alternate names for same serotype. I found the following web sites with the pre/post vaccination values but it doesn't appear to test multi-year post vaccination: http://cvi.asm.org/cgi/reprint/13/8/905.pdf Regards, Buster Buster, out of curiosity, which did your dd "pass"? My dd was not low on 23F and 19F and 5 was a 2.0. Susan

We too had low PREVNAR reaction for 11 of the 14 seratypes. Our immunologist wasn't particularly concerned with this despite our pointing out that our dd had been vaccinated 4 times. I think this is sure an interesting coincidence and worth seeing if others have had similar results. Regards, Buster

On the why advil... The theory is that the blood brain barrier opened and some anti-neuronal antibodies are crossing causing the tremor/OCD by interfering with lysogangliosides or causing CaM kinase II. Azithromycin (in addition to slowing the replication of strep) is immunomodulating (shifting the Th2 to Th1 response) and is also anti-inflammatory. Our immunologist thinks that we're probably seeing more the effect of anti-inflammatory rather than the antibiotic traits of azith at this stage. Of course, if it isn't an open BBB, then it probably isn't helping more than for a headache :-). Buster

(edited 7/27/09) I originally posted that I didn't think azithromycin would have an effect, but now I'm not so sure. There's a very interesting article (see http://www.jleukbio.org/cgi/content/abstract/78/6/1397) where it's possible that increased maturation of dendritic cells might cause higher CaM kinase activation. I'll keep searching to see if there's a study on CaM Kinase II and macrolides. The anti-inflammatory property of prednisone is probably not an issue, but prednisone can also reduce activation of B-cells and this could reduce the concentration of antibodies. While that would normally be a good thing on theory of anti-host antibody, it would likely mess up the test. Buster

Hi ShaesMom, Our dd had a similar results on the PREVNAR test. Our immunologist didn't feel the supressed PREVNAR was significant in and of itself so we did keep looking for other elements. In studying this, I did find the following paper that indicated that azithromycin did supress PREVNAR titer response in mice. http://www.journals.uchicago.edu/doi/pdf/10.1086/425038 So if your daughter is on long-term azithromycin, that could affect the PREVNAR titer tests; however, there doesn't seem to be a good study on people. So we've been keeping an eye on it and adding it to the list of unusual results. In terms of your other study, our dd had CD3 and CD4 percentages at the top of the range of normal while her CD8 percentage was at the bottom of normal. The CD8 is essentially the Cytotoxic response (i.e., T-cell suppressors). Whereas CD4 drives the helper cells (such as inflammatory Th2 response). As an interesting note, Azithromycin shifts Th2 response to Th1 essentially increasing the cytotoxic response and reducing the inflammatory Th2 response. Very interesting the similarity in what you found with our own situation. Thanks for posting. Buster

Kelly, I recommend sending in spun down serum (as that is what they request) -- certainly check with the lab if there's a reason your lab can't spin it down. It transports better than whole blood. In addition many states have tighter restrictions on transporting whole blood. Serum is like a rock.

Just to clarify how to read results from Cunningham. The Positive Control is just a value that is used in the lab from a prior sample that indicates that the test actually worked. The % is checked to verify that it matches a prior run (i.e., within experimental error). In Mom_MD's case, it appears that Cunningham used an SC positive control. Checking with Dr. Cunningham, they use a prior serum to verify repeatability when they test your child's serum. When they run out of one, they move onto the next positive control. They do this to verify that the test worked, but the result on the positive control is largely irrelevant -- it sort of is an internal lab measure that the test worked.. You can safely ignore the positive (plus) control. On the CaM Kinase II %, it is a measure above the basal amount. So you should add 100% to it. Hope that helps, Buster

The Kirvan/Cunningham tests distinguish PANDAS from straightforward OCD and Tourettes. Church and Dale (from the UK) see these anti-neuronal antibodies as diagnostic for PANDAS. In terms of your question, the tests do indicate that something is odd in the immune system because the antibodies should not normally be there. The presense and cross-reactivity with lysogangliosides indicates either a defective B-cell or a defective T-regulatory cell. The T-regulatory suppress anti-host anti-bodies. We don't know what the exact defect is here, but the existence of the anti-neuronal antibodies is the symptom. Regards, Buster

Kirvan and Cunningham isolated three monoclonal antibodies that are present in the blood serum and spinal fluid of children with sydenham chorea and in children with PANDAS and these antibodies were not present in their controls (who had Tourettes and non-PANDAS OCD). These antibodies are not the ASO or Anti-DNAse B antibodies, but rather related to interaction with lysogangliosides (such as GM1) which affect signalling of neurons in the brain. Kirvan and Cunningham were seeking whether there was a way to distinguish children with SC or PANDAS from others and seem to have found a way. Church, Martino, and Dale (in the UK) found similar results to Kirvan and Cunningham and published their results in 2006. Singer (2006, 2008) was unable to reproduce the results -- however, there are numerous problems with Singer's studies -- it was not clear he had any PANDAS children in his study (he pulled from Tourettes children who had onset 3 years previous), he used older kids, and he tested using lysogangliosides from rabbit muscle rather than human brain. Let me just say that I don't think Singer's research justifies the title of his papers -- grrh. There's an excellent commentary from Dale about Singer's research in the June 2006 JNI. So, the long and short is that Cunningham's research shows that CaM Kinase II activation and anti-GM1, anti-dopamine and anti-Tubulin occur with SC and to a lesser degree with PANDAS and that these two groups are separated from Controls. Their research does not show causality, just concurrance. The presence of these antibodies seems to be a diagnostic symptom. The theory is that these antibodies are created (incorrectly) in response to a strain of strep and are not being surpressed by the body's T-cell regulators. There remains the question of how these circulating antibodies cross the blood-brain-barrier, but given that Kirvan was finding the antibodies in CSF, clearly the antibodies or their antigens are crossing the BBB during acute conditions. What I found exciting about Cunningham and Kirvan (and Church and Dale's) work is that this diagnostic tool seems much, much more concrete for doctors for separating out the condition and recommending an appropriate treatment. Regards, Buster

I think Alex is correct. The hope is that IVIG neutralizes the anti-GM1 and anti-lysoganglioside antibodies -- this is probably testable by checking anti-GM1 and anti-tubulin antibodies pre/post IVIG. In terms of the "reboot" highlighted by Vickie -- my understanding is that IVIG seems to suppress the B-cell activation allowing the furnace of anti-host antibodies to cool. It still isn't clear that there is long term protection here since the B-cells can get reactivated (presumably by Strep) reproducing the anti-GM1 antibodies again. Regards, Buster