Buster
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A two day IVIG ended last night. Since 4:30am my daughter has had head pain, stiff neck, tired, and upset stomach. Tonight she also has a fever of 101. The IVIG instructions say to call if, among other things, she has a stiff neck or fever. We left a message for the doctor. She is alert sitting in the bathroom in case she vomits. Since we couldn't get a hold of the doctor, we gave Tylenol, Benadryl, and a pedialyte popcycle. I think the fever is coming down. Should we be concerned?
I say head pain not headache only because my daughter says it is not the same as her usual migraine headache. This one feels like pressure around her scalp and on top of her head.
One hour later: The fever is not reducing and she refuses to take motrin.
The fever definitely happens. Our dd9 had the fever after both IVIGs. Headache too. Advil was very effective for our daughter with Tylenol being less so.
In our case, fever lasted 1 day, headache lasted 2 days, symptoms worsened for first 2 weeks post IVIG then rapid fall off.
Buster
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You said that #3 was probably the most likely - that there is inflammation (from whatever virus/infection) and that causes the BBB to open. I get that part but how do those bad anti-neuronal antibodies get triggered again to even cross the BBB if strep is not there to trigger them - just some other random immune system challenge. Is it because these anti-neuronal antibodies can now just be made again and again in the absence of strep because the immune system has a memory of them?? Like for as long as the BBB is open (or when it becomes open) they think they have a job to do (when they encounter the neuronal tissue they believe they should attack??)
That's my theory -- the antibodies think they are connecting with a true antigen when actually they're just finding host cells.
Essentially, I think the BBB is the real culprit here and the critical item is getting the BBB closed. After that you can address the antigens or the antibodies.
But that's just a theory -- rather than fact from some study.
Regards, Buster
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If the antibodies go away after 3 months, why do so many kids seem to have exacerbations with any kind of immune system challenge??
Frankly, I'm not sure. I've heard three good explanations that warrant further investigation:
- there is a targeted antigen that keeps the B-cells activated
- there is a superantigen that has incorrectly recruited the B-cell
- there is inflammation that causes the BBB to open
The first one is sort of saying that the T-cells/B-cells are finding a tiny bit of the real antigen (say GABHS) and generating a bunch of antibodies.
The second one is saying that GABHS (and other infections) can cause the release of antibodies even though the exact signature of the bacteria wasn't present -- there are a lot of reasons this happens in the immune system.
The third one is probably the most likely.
Is it because as soon as the immune system starts to work, it brings out all of the antibodies in its memory (both good and bad) while it tries to figure out how to deal with this new assault - even if it is not strep (because our immune system keeps a memory of all of our antibodies right)??
There are sort of two types of immune response. Normally, T-cells/Antigen Presenting Cells (APC) come along and find something not quite right and present fragments of that to B-cells. If the key fits, the B-cell "unlocks" and releases/creates a bunch of antibodies. A second type of immune response occurs when there is a super antigen. These can activate a lot of T-cells and a lot of B-cells directly (i.e., sort of exhausting a person's immune response). Lyme seems to work this way.
And then if the BBB is open when our immune system "kicks in", these bad ant-neuronal antibodies (originally caused by untreated strep) find what they think they should attack (brain tissue) - and as a result more of these bad antibodies are made because they think they have found a job to do??
That is actually a theory -- in the case of 24.3.1 it targets GlcNAC which is a pretty common carbohydrate and on the GABHS exterior wall.
- there is a targeted antigen that keeps the B-cells activated
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Hi Priscilla,
I think the post you are referring to is : http://www.latitudes.org/forums/index.php?showtopic=6685
The graph is no longer active (too much time since that post) but the paramaters are still good.
What I found most helpful was to have a wall calendar or daily log where you wrote down anything really odd that happened on that day. And then plotted the symptoms on a weekly basis (daily was, well, just too much data).
You have to use some judgement, but it works pretty well. What you want to catch are REALLY bad times and really good times and get a sense for whether certain symptoms went into remission or were pretty constant. What we found was that the sum of symptoms was more important than looking at any one symptoms. When things were bad, it was really bad. When things were good, all symptoms (but 2) were good.
Buster
I read a post that said Buster has a checkist to help track daily progress/ regression. Can anyone direct me to it? and thanks for making that Buster.
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Sure, I'll do my best....
The antibodies are just "normal" antibodies (meaning they have the typical Y shape pattern of antibodies) and are released by B cells into the blood stream. -- let me know if you'd like an explanation of B cells.
The antibodies are called "anti-neuronal" because the antibodies seem to interfere with signalling of neurons. I know they should have called this "neuron interfering antibodies" but for reasons lost to me they call them anti-neuronal. This interference is found through a technique called competitive ELISAs which means they add the antibodies and then add stuff that should bind with the neuronal cells. If the normal stuff doesn't bind like it should when the antibodies aren't there, they assume that the antibodies interfered with the binding.
Okay, so are anti-neuronal or neuronal interfering antibodies bad? -- well, actually, not really. There's this part of your brain called the Blood brain barrier. The whole purpose of the BBB is to keep proteins in your blood from interfering with stuff in the brain. Stuff does cross the BBB but it's a pretty good filter.
So now we call anti-neuronal antibodies "things that could interfere with neuronal signalling if they ever got across the BBB". A bit long...
If the antibodies don't reach the brain they don't do anything... they just hang out in the blood stream for about 2-3 months and then disappear as the blood is cleaned by the liver.
So are the antibodies damaging -- so far the evidence is no. They just sort of interfere, but don't cause permanent damage.
Do we really know it's these antibodies -- well, sort of. The antibodies (such as this funny one called 24.3.1 was found in Sydenham Chorea kids in the spinal fluid). Whether this antibody is actually causing the symptom or just a byproduct is really not known.
On your final question of what sends them to the brain -- that's really a great question. It's not that they go "to the brain" it's more that they are getting distributed throughout the body but have nothing to attach to. The pattern in the Y that makes up monoclonal antibodies has to find a very specific sequence. That sequence seems to be similar to lysogangliosides and similar to a portion of dopamine. Essentially, the antibodies are floating around going sort of everywhere but when they finally get across the BBB, they find some dopamine receptors in the basal ganglia and bind there.
Let me know if this was too much detail or not enough (i.e., please ask again).
Very best regards,
Buster
The antibodies thought to cause PANDAS are not the ASO or Anti-DNAseB, but rather a set of antineuronal antibodies to GABHS (e.g., see Kirvan2006 with antibody 24.3.1).
Sorry to veer a bit off topic here, but could you please explain exactly what antineuronal antibodies are, Buster? I know they're the bad antibodies that think they're attacking our strep when they're really just attacking out brain.. But that's about it. What makes them different? Why are they called "antineuronal"? & what sends them to the brain, of all places?
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Hi folks, just a comment that I've updated the research papers to include some recent papers by Wang and Cleary in 2010. http://www.latitudes.org/forums/index.php?showtopic=5144&st=0&p=36300entry36300
Th17, Autoimmunity and the blood brain barrier
Recently, Wang et al published a remarkable finding that repeated nasal innoculation with live (or dead) GABHS produced Th17 cell response in mice. Th17 was recently identified in 2006 (see Annunziato et al ) and is highly implicated in auto-immune disorders.
In 2007, Kebir et al published the paper "Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation" where it was shown that these Th17 cells are highly pro-inflammatory and promote blood-brain barrier disruption. Perhaps this is the missing link in how auto-antibodies are crossing the blood brain barrier (i.e., GABHS carriage triggers Th17, GABHS infection triggers anti-neuronal antibodies, Th17 disrupts the BBB allowing anti-neuronal antibodies (or B/T-cells) to cross). I certainly hope more research is done here.
While this is a mouse model and may not apply to humans, the study is noteworthy because only carriage was needed. This may explain why an apparent "allergic" reaction is seen in some children -- i.e., that only colonization is necessary on subsequent exposure and not infection.
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With respect to your question...
If titers take time to rise... does that mean that when you are first seeing what you think is a problem that there is likely a current infection.
Not exactly. It is possible you are seeing a breach of BBB rather than an active infection. Just as a reminder, the antibodies thought to cause PANDAS are not the ASO or Anti-DNAseB, but rather a set of antineuronal antibodies to GABHS (e.g., see Kirvan2006 with antibody 24.3.1).
Current thought is that symptoms are due to the combination of three events
- rise in anti-neuronal antibodies
- anti-neuronal antibodies hang out in serum for ~3 months
- breach of the blood brain barrier
The breach of the BBB just seems to take inflammation -- that can come from an infection or stress.
The rise in anti-neuronal antibodies seems to take about 1-2 weeks to occur -- however, the antibodies have a half-life of around 28 days. This means they hang around a while (i.e., the 3 months). So any disruption to the BBB could in theory cause symptom exacerbation.
if you didn't have evidence of a current infection and were going to just check titers (aware that titers don't tell the whole story) would you want to wait a few weeks out from the start to see a rise
Yes. However, timing is really tricky. I would strongly urge a throat culture within 3 days of symptom exacerbation. For 53% of people, ASO will rise 1-4 weeks after symptoms of strep throat.
or by time you are seeing symptoms if your kid is a titer rising kid in the past would you suspect it would already have risen.
No, in Swedo's studies (see http://www.ucdmc.ucdavis.edu/mindinstitute/events/toxicology_recorded_events.html ) for those kids who did have rising titers, their titers rose 1-2 weeks after symptom onset (i.e., correlated with a preceding strep infection).
I hope that came out as clear on here as it did in my head.
Hope my response is equally clear.
Now there are a few complexities here...
Nasal carriage might be enough to trigger a breach of the BBB. There are a couple of really nice papers on Th17, GABHS and breach of BBB. Probably the most impressive are Kerbir (2007) "Human Th17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation" http://www.nature.com/nm/journal/v13/n10/abs/nm1651.html. Here he showing that the BBB can be disrupted by Th17 cells in the blood.
Recently (2010), Wang and Cleary publish "Induction of TGF-β1 and TGF-β1-dependent predominant Th17 differentiation by group A streptococcal infection" (see http://www.pnas.org/content/107/13/5937.short). Where they show that Th17 autoimmune and highly inflammatory response can occur with only nasal colonization in mice.
Now Mice are not people, but this was a fascinating finding that might explain why colonization may be all that is necessary in PANDAS kids who already have the anti-neuronal antibodies in the serum.
What I'm trying to highlight is that ASO and Anti-DNAseB rises will just tell you if strep got into the blood. However you could have symptoms if the antibodies are still in the blood and the BBB is opened due to other causes (such as Th17).
I think this circulation of antibodies with breach is what makes this so darn hard to isolate -- two factors rather than just one.
Buster
- rise in anti-neuronal antibodies
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Hi Kerry,
The question tried to get after the IVIG information by looking at who had 400mg/kg, 1.5g/kg and 2g/kg and whether those had efficacy > 3 months or there had been recurrance. Only about 50% of the people answered this section of the material, so I've got about 50 children to run stats on. Given the 3:1 boy/girl ratio, the studies are all going to be underpowered for any age variance (which is why I was looking there first). If we have different trends in boys/girls on symptoms (or efficacy), then I have to split on sex for trending.
Unfortunately, this means that I'm really looking at something more like 15 girls and 45 boys for this section of the study. Drawing trends on only 15 girls with other random factors will just confound -- but I'll pull what I can.
Buster
Buster,
Thank you so much for all the work! I've been thinking about our sample group, and while its frustrating that we probably aren't surveying any people who's kids had one ivig and got better (what I hope is approx 80% of the pandas population!) we probably have a large number for whom one ivig failed (I'm guessing that those folks stick around this forum longer, and I'm praying of rht day I don't feel compelled to check in because ds is doing so well!), so maybe there is an opportunity to learn something about those kids? I guess we are seeing that untreated lyme can cause it to fail,what about age, sex, IGG levels?
I know that Dr K claims that the older they are, the less likely to respond to treatment (or maybe they just need 2 or 3 treatments?). Do we have enough data to see if that is true?
THANK YOU!!! While I'm really excited about the ivig study they will be doing in the fall, I'm feeling like by the time its done and published could be too late to help ds..I'm trying to figure out if ds is in a higher risk category for ivig "failure". Dr K also mentioned that food issues have higher chance of relapse with re exposure. I can't recall if your survey asks about number of ivig's..I took it prior to ours (a week ago).
Kerry
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Here is another cut of the data from the survey. Here we're looking at the answers to the questions regarding symptoms and their presence at onset, at exacerbations pre-treatment and during exacerbations post-treatment (whatever treatment meant to folks).
Not everyone answered this question so I only have data on about 55 kids. Also please remember that this should still be treated as anecdotal since this was not a formal research study with a formal control.
The way to read the slide is that this is the number of respondents who said their child had these symptoms at the three time windows.
What is striking on the slide is that Urinary symptoms, tantrums, vocal tic, social anxiety issues resolved for 54%, 45%, 40% and 35% of the cases (respectively) post treatment. I didn't ask intensity questions so there may be more here than is obvious in the slide, but the overall trend if very interesting.
Similarly, the following symptoms seemed to linger post treatment: bedtime rituals, mood issues, obsessions, motor abnormalities, separation anxiety. These moved 13%, 17%, 20% and 22% respectively. This probably means I needed to have asked severity questions rather than whether the sympom existed. Given all the huge numbers of variables here (such as time elapsing, different treatments, different interpretations, ...) I was hesitant to post this graph, but thought it a good summary of what I've heard anecdotally on the forum.
Please remember that the survey does not have a control and so the information really should be treated as more things for followup surveys/case studies to study.
Buster
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Buster, Has anyone ever looked at whether teenager with anorexia, had saw tooth symptoms since childhood? Just wonder since food is a big issue for my dd and has been Very relapsing remitting since she was 7 years old? Thanks!
Clinically, Dr. K has studied this group and finds that there seem to be 3 classes of anorexia
- sensory -- restriction due to color, texture, odor, ...
- obsession -- restriction due to fear of choking
- dysmorphia -- restriction due to body dysmorphia or fear of weight gain
He sees the first 2 in younger kids and the last one in kids post puberty. Our child had the third type at age 7. Dr. Mae Sokol studied these three groups and as far aas I know her work wasn't pursued after her death. Here is one of her early papers:
http://www.ncbi.nlm.nih.gov/pubmed/10933123
Buster
- sensory -- restriction due to color, texture, odor, ...
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Hm. I look at the chart and what my SON had as his strongest symptoms falls into what the girls experienced strongest. For him, the exacerbations I referred to while taking the survey was when he was between just turning 5 until almost 6 years old. Could his age play a factor in it? Meaning, are hormone levels different in a 5 year old boy vs say a 9 year old boy? But, then, I cannot remember the average age of the boys in this survey.
This is actually the problem in the survey. I have the data, but even with 100 participants it would be considered underpowered for cutting for factors like age.
The mean age of onset for girls (5.7 years) -- median 6
mean age of onset for boys (4.96 years) -- median 4
Many of the symptoms are not distinguishable in the younger set.
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CaM Kinase II was not correlated with male/female (that I could determine). Anti-neuronals also did not seem correlated with symptoms or with sex. This surprised me. I wonder if I didn't make the question tight enough to ensure symptoms could be correlated with CaM Kinase II. I think the only way to really get at this would be to run as longitudinal studies.
Buster
Thanks buster. Poor girls without tics and titers, I'm
Sure there are so many out there not getting help. Dr k thinks vast majority of anorexia is really pandas, he mentioned Swedo working on it too, but did not talk about her opinions as related to infectious disease.
Did any of the anti neuronal Cunningham test have a sex correlation?
Sorry to keep badgering for more info. I find it fascinating.
Btw-I know your ds had relapse, did you happen to do another Cunningham test when she relapsed?
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Some other results from the survey:
First, please remember that this is not a controlled research study and is anecdotal -- but I sure would like a followup on this. For 35 girls and 65 boys:
Only 15% of girls had elevated ASO or Anti-DNAseB over the course of the illness
Whereas 54% of boys had elevated ASO or Anti-DNAseB
In addition, 23% of girls did not have a rise in ASO or Anti-DNAseB despite a positive throat culture
whereas 14% of boys had this situation.
What I'm raising is that boys were ~4x more likely to have a rise in ASO or Anti-DNAseB
Whereas girls were ~2x more likely to be labeled as "carriers"
If we look over the whole of the illness, people indicate the following symptoms:
There are differences between overall symptoms over entire course, symptoms at onset and symptoms pre and post interventions.
In this data set, you'll see that boys have more tics/vocal and girls more restrictive eating.
Buster
P.S. AI: stands for "Age Inappropriate" in the graph
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Okay, here's a very interesting result in the data... (I might have to pull this out to its own thread)
First, please remember that this is not a controlled research study and is anecdotal -- but I sure would like a followup on this. For 35 girls and 65 boys:
Only 15% of girls had elevated ASO or Anti-DNAseB over the course of the illness
Whereas 54% of boys had elevated ASO or Anti-DNAseB
In addition, 23% of girls did not have a rise in ASO or Anti-DNAseB despite a positive throat culture
whereas 14% of boys had this situation.
What I'm raising is that boys were ~4x more likely to have a rise in ASO or Anti-DNAseB
Whereas girls were ~2x more likely to be labeled as "carriers"
I'm doing other scrubbing on data, but these ratios seem to hold true despite filtering on other criteria.
Buster
I wonder if more girls have OCD and food issues and more boys tics... Maybe that is why more boys diagnosed. It would have taken us much longer to figure out it was pandas if ds wasn't ticcing.
Just not convinced boys more likely to get it. I remember our neurologist gave me info on Touettes, and primarily male disorder while OCD primarily female.
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On July 2nd, I started a survey to generate a map of potential PANDAS cases.
(see survey : http://www.surveymonkey.com/s/PANDASMAP )
Today, I noticed that we had over 190 respondents to the survey. Wow!
You can zoom in here:
http://www.batchgeo.com/map/ca5449d55ccb94010dd9dbfbc0fdd870
Buster
Has anyone else put this map next to a map of reported lyme cases? Check on the second (blue) map at this link. http://www.aldf.com/usmap.shtml It could be due to density of population or some other factor.. but it is very interesting... but I am reading "cure unknown" right now so everything looks like lyme and I am questioning everything I read or hear from the medical establishment...
Map of PANDAS is correlated with population density -- almost perfectly. This could be because of a lot of reasons (like people in such populations are more likely to be on this forum :-))
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Can you tell us what some of the "other" responses were? Were there any consistent write in answers that suprised you?
Bloody noses, hallucinations and shouting very loud all stood out in the OTHER responses.
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There was a second survey that about 99 people responded to. There were a lot of issues in getting the questions right, and this was not a formal research study with controls. However, with all those caveats, I thought I'd post snippets from that survey here:
65% were male children and 35% were female.
Buster
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On July 2nd, I started a survey to generate a map of potential PANDAS cases.
(see survey : http://www.surveymonkey.com/s/PANDASMAP )
Today, I noticed that we had over 190 respondents to the survey. Wow!
You can zoom in here:
http://www.batchgeo.com/map/ca5449d55ccb94010dd9dbfbc0fdd870
Buster
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I added the definitions of "normal" to the survey. Lots of good information in the comments. I'll pull a few of the graphs out and post them.
Buster
This is amazing.
Can you clarify re: the Cunningham tests, if above normal refers to the range or the mean?
Also, wasn't sure how to deal with the symptom list. DS9 has primarily motor and vocal tics. He has some of the other, but they are so mild that if I didn't know to look for them (thanks to this group) I would either never see them or pass them off as minor quirks of childhood or personality. I guess I'll put them in as co-occurring.
And, as for the trigger - I think that his was a tooth extraction that occurred w/o prophylactic abx. Can you add/expand the trigger question?
Maybe you could add what the range is for each category- that way we could just look at our numbers and see where they fit. I get the impression from people who have reported their results recently, that they are reported a bit differently than when I got the test a year ago. I was not told what the mean score was when I got my results. Also, would be cool to see the CamK scores categorized to correspond to Cunningham's graph- ie...sydenham's range, PANDAS range, etc.
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Thanks Tenacity, this is great. I'll incorporate in next round.
Buster
Dear Buster,
I am engaged, excited, even inspired, by this survey project! At the same time, I am reminded why I was never able to finish a multiple-choice test in school, because I was always the one sitting there, when the clock stopped, with an incomplete form, thinking, "None of these choices is right!..."
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This was there before.
What really annoyed me was the site update did not address the controversy section.
I would have loved a section like:
Q: What is the controversy in PANDAS?
A: The controversy in PANDAS is really 4 things:
a) whether strep infections cause PANDAS or children with PANDAS just have more strep infections
B ) whether the production of anti-neuronal antibodies are genetic or a byproduct of a particular strain
c) whether colonization is sufficient to trigger anti-neuronal antibodies
d) whether PANDAS is only triggered by untreated strep infections or also triggers for treated strep infection
(d) is by far the most important because the studies keep breaking the blind to "treat" strep infections. This would be like trying to prove a relationship between strep and acute rheumatic fever and treating anyone you see with strep and then complaining that your study was underpowered because you found no ARF.
Literally that's what's going on in the controversy.
I suppose an (e) is that researchers at Johns Hopkins can't seem to repeat a test run elsewhere. I suppose you could doubt either party, but I sure wish we'd get funding for replicating the research rather than just letting both parties fight it out in papers.
Buster
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Here's one on people's experience with medication -- please treat this appropriately -- the survey data is way underpowered for any real conclusions here. I didn't pull dosage or duration or anything else and people have lots of different co-morbid conditions. Still, interesting trending and I'll see if we can get more from it.
Buster
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Another cool diagram
Of particular interest seems to be the reported difference in some symptoms post-antibiotics:
* urinary issues
* separation anxiety
* age inappropriate tantrums
* sensory issues
Vocal tic was interesting because it seemed to arise after intial episode.
Very hard to tell the strength of the correlations here because of the age spread in the data, but interesting.
Strep "carrier"
in PANS / PANDAS (Lyme included)
Posted · Edited by Buster
Usually carrier is a shorthand for "asymptomatic carrier". This means that someone is carrying the bacteria and can be cultured positive (colonization) but does not have immunologic signs of an infection (no classic sore throat, no rise in ASO, no rise in AntiDNAseB, etc).
Dr. Kaplan (world health organization) refers to carriage as an "enigma" because it isn't exactly known what is happening in those who only get colonization and don't progress to infection. Several theories have been presented that perhaps the GABHS is "starved" by other competing flora in the throat. Others think streptolysin gets neutralized in some people due to differences in pH (or cholesterol levels), and there's lots of other items.
There's actually very little study of carriage and while many doctors think it is benign, there really isn't any evidence that this is true. There is some evidence that those with chronic carriage do not progress to acute rheumatic fever, but that might just be that the strain being carried is not a rheumatic strain.
Asymptomatic carriers have been harder to clear than symptomatic carriers. One strong reason is that most of the common treatments (Pennicilin and derivatives) only work when the bacteria is growing quickly -- if the bacteria is slowly growing amoxicillin, penicillin, augmentin are less effective. So asymptomatic carriage may merely be an inability of the immune system to really take out the bacteria -- sort of a chronic light colonization.
Buster