Buster
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I remember someone posting (but can't remember who, sorry) a link that talked about titer testing and said that ASO and Anti-DNase B alone were not enough that there are more that should be tested for and that you can't rule out PANDAS without these.
Hi Dut,
Here was my prior post on ASO titers: A little bit about ASO titers
Regards,
Buster
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Hi Myrose,
I am wondering if everyone can give me their story or explanation of the differences between Pandas, Tics and Tourettes.Tics can be verbal or motion abnormalities and are actually pretty common in kids. Many tics are self limiting and go away on their own.
Tourettes is diagnosed as:
1) having both multiple motor tics and one or more vocal tics that must be present at the same time (although not necessarily concurrently).
2) the tics must occur many times a day (usually in bouts) nearly every day or intermittently over more than 1 year, during which time there must not have been a tic-free period of more than 3 consecutive months;
3) the age at onset must be less than 18 years;
4) the disturbance must not be 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).
Thus to diagnose Tourettes you have to wait a year with monitoring and have no remissions.
PANDAS is diagnosed as (Swedo):
1) presence of obsessive-compulsive disorder, tic disorder, or both;
2) with prepubertal onset (typically between 3 and 12);
3) sudden, severe symptom onset and an episodic course characterized by remissions and abrupt exacerbations;
4) a link in time between either the symptom onset or exacerbation and a GABHS infection;
5) Presence of Neurologic Abnormalities During Periods of Symptom Exacerbation (movement disorder, choreiform movements, ...)
It is the episodic and severe exacerbations of PANDAS that is so telling. Swedo and all of us can tell you this isn't the normal waxing and waning of OCD symptoms, this is like your kid is possessed. Almost all of Swedo and Snider studies were on OCD kids with CYBOCs scores changing +15 pts over the exacerbation.
Tourettes is defined by the presence of tics and not OCD. Many Tourettes kids do have OCD, but it is not part of the diagnostic criteria. Recent studies on Tourette kids seem to indicate that their exacerbations are primarily in Tics and have low changes in CYBOC scores (usually 1-3 pts).
I know the titers play a big part in Pandas but from what I understand until someone knows their baseline level, than its hard to tell if its elevated or not.Acutally titers are not part of the diagnosis of PANDAS. They are techniques for looking for the evidence of a prior strep infection. A positive throat culture is sufficient to meet the PANDAS criteria. People with positive throat cultures that are left untreated can still have falling ASO titers with colonization and invasion of strep.
Pandas in her case was ruled out by her neurologist becasue of the titer issue alone. She has a history of sore throats and tested positive for strep when she did not even have any symptoms of it.Asymptomatic strep is often referred to as carriage. Experts on GABHS now think that carriage is not as benign as previously thought. In the carriage state, there is colonization and adhesion with production of exotoxins and particularly streptolycin O (which enables invasion). It is extremely likely that there is some invasion but this may be small or controlled. Rising titers are a good indicator in the 1-4 week (up to 8th week for AntiDNAse-B ) ; however, outside of that time, it is just not known what the titers mean. You can have an active infection with falling titers if the infection is not treated. So carriage that goes to infection (such as with a tooth extraction or dental work) could yield very odd titers since there has been long term exposure.
As a reminder, it is not the streptolycin O that is thought to be the problem for PANDAS but rather a failure to supress an antibody that goes after GlcNAc -- a carbohydrate on the strep A. The problem is that carbohydrates/patterns similar to GlcNAc are all around the body, so the antibody can go after the wrong stuff. What is thought to be the problem is that the normal suppression T cells and B-cell suppressors aren't taking out this antibody to GlcNAc so once triggered with a little bit of strep carbohydrate, the B cell starts replicating like crazy causing attacks on non-strep cells.
Before she started on Topamax she did have the ocd signs that came on one day out of no where while attending pre-school. It showed every once in a while after that. All different degrees. She had anxiety thats for sure. She used to bite her inside lip and always picked the skin at the side of her fingers. Urge to urinate was there as well.These are all consistent with the CYBOC scoring criteria for OCD. However, the question would be the severity of the symptoms. Everyone with OCD has good and bad days. What is telling in PANDAS is the severity. Fear/need to constantly urinate is a documented precursor. It again depends on the severity and the temporal locality to a positive culture/signs of strep.
Lastly, other than the steroid burst being a sign of pandas if it shows benefit....is there any other way that would lead one to lean towards Pandas??Thanks ahead for everyones input. This Pandas thing is really bugging me. Especially about the brain after time not being able to repair.
What would someone do to be sure then????
Well, certainly the steroid burst helps to show that it is an immune response (or an inflammatory response). In my dd case, we got a throat culture (she was positive throat and perianal) and then after trying a couple of antibiotics to wipe out the strep, finally put her on azithromycin. At time of culture her ASO was 31 and her anti-dnase B was 149 and she was asymptomatic. Many doctors would have said this was a carrier condition. But PANDAS doesn't say anything about such a condition nor about how high the titers are, but rather evidence of an infection. The culture is enough. If you dd is positive, I'd certainly recommend having her treated.
In our case, we found our dd got infected almost 2 months before. At the time of the throat culture she was absolutely psychotic with full fledge anorexia nervosa and suicidal statements. It was a nightmare. When we had titers drawn a month later her ASO was steady 28, but her anti-dnase B was now < 60. What I mean here is we were already on the falling side of the titer. No one (and I mean it, I've checked) knows how long these titers stay elevated or what keeps them elevated or how quickly they fall. If your symptom severity is high, then I'd recommend getting a culture. If that is positive and you had sudden onset OCD, then treat the strep! My dd is now on propholaxis antibiotics given the severity of her situation.
We had very good success on azithromycin after not clearing the strep on amoxicillin. I can post more about what we went through if it helps, but bottom line if you have doubts, get a culture and act on that.
Regards,
Buster
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Anyone have an idea of why IVIG, PEX and Azithromycin seem all to affect PANDAS?
I'd be particularly interested if Dr. K has offered any explanation.
I've been wondering whether the similar factor is the supression of an antibody. Yes, I know that Swedo's theory was that PANDAS was an auto-immune disorder but it didn't make sense to me that both PEX and IVIG both worked -- because PEX removes antibodies and IVIG adds antibodies.
However, I just ran across a very interesting paper by Kawikova at Yale:
"Decreased numbers of regulatory T cells suggest impaired immune tolerance in children with tourette syndrome: a preliminary study." http://www.ncbi.nlm.nih.gov/pubmed/16996487
and then Matsushita paper at Duke in Sept 2008, found the elusive regulatory/suppressor B cells:
http://content.jci.org/articles/view/36030
and Tedder's paper on regulatory B cell effect http://www.biochemsoctrans.org/bst/030/0807/0300807.pdf
So perhaps the problem is that PANDAS kids are just missing the regulatory B cells (i.e., the suppressor B antibodies) that get rid of antibodies that would otherwise attach to host cells/cause inflamation. Could it be this simple?
- PEX removes the generated antibody that attacks self.
- IVIG adds a suppressor antibody (a suppressor stops antibodies that attack self)
- and Azithromycin shifts the Thelper response, thereby acting as an anti-inflammatory and immunomodulator/suppressor.
I'd be very interested if anyone has any other collaborating or contradicting documentation on this.
If this is really the key, then Azithromycin would be a temporary suppression (like Prednisone) because
a ) the underlying self-attacking antibody is still there and
b ) there is no long term suppressive agent to prevent replication of the antibody
I've gone to look at Kirvan's paper again on GlcNAc but was wondering if anyone had heard from one of the IVIG folks why IVIG is supposed to work. I'm now thinking these regulatory B cells are very likely the missing culprit.
Regards,
Buster
- PEX removes the generated antibody that attacks self.
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How kids react to strep while on antibiotics ...
Hi Diana,
There are two papers by Snider about symptoms while on prophylaxis antibiotics. The one in 1999 had all sorts of compliance problems. The followup study in 2005 ( http://intramural.nimh.nih.gov/pdn/pubs/pub-9.pdf ) showed equal effectiveness in suppression of PANDAS exacerbations by both azithromycin and penicillin. Strangely, that wasn't the original intent of the study, but was an interesting result.
I have dearly wanted to check with the authors about whether they've had any PANDAS kids who would have been classified as 'carriers' and whether these kids did better on zith or penicillin, but haven't done so.
There is no paper I believe showing how kids react to strep, etc. WHILE on antibiotics.Regards,
Buster
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On BioFilms ... here's a recent study...
Hi Peglem,
Here's a recent paper on biofilms that folks might find useful.
http://www.pubmedcentral.nih.gov/articlere...i?artid=1594624
"Therapeutic Failures of Antibiotics Used To Treat Macrolide-Susceptible Streptococcus pyogenes Infections May Be Due to Biofilm Formation"
Regards,
Keith
So far, there is no approved test for biofilms, but researchers at Northern Arizona University have invented a way to test for the chemicals that the biofilm critters use to communicate. (or is it the stuff that the "cloaking device" is made from?) Anyway, the test hasn't made it to market yet. -
Carrier State and what is known ... warning -- this is a bit long
I debated about starting a whole new post about carrier state and might as this is starting to get somewhat far afield of the original post. However, peglam's comment about cloaked mother ships was a good launching point.
From the literature there seem to be four major phases:
- adhesion
- colonization
- invasion
- infection
Adhesion is about how the bacteria attaches itself to the skin or to a mucosal lining -- i.e., why isn't the strep wiped away. There was lots of study on this between 1970 and 2000 with the result that they think it is a combination of protein M, lipoteichoic acid and protein F.
Colonization has to do with growth. It is not at all clear what causes the limiting of colonization in carriers. Certainly some have shown that other bacteria/flora in the throat compete for various building block material so one bacteria can interfere with another bacteria's growth. On p.68 of Dr. Kaplan's book "Streptococcal Pharyngitis" http://books.google.com/books?id=YiYY86j9A...F0ih6D5yurBrejg Dr. Kaplan makes some very interesting observations that the streptococcal progenes cells seem to stop producing M protein in those with carriage. Kaplan observed that the mecahnisms that produced the "symbiotic relationship with the human host have not been identified."
Invasion has to do with penetration of the epithilial cells. There are two types of invasion: extra-cellular invasion and intra-cellular invasion. In extra-cellular invasion, the streptococcal pyogenes release a spreading factor (e.g., hyaluronidase) that destroys connective tissue and streptokinase (which indirectly destroys fibrin and prevents blood clotting). In addition, the strep produces stretolysin O which acts to kill phagocytes. The cloaking items (per peglam's comment) are things like the hyaluronic acid capsule that prevent easy detection by phagocytes (i.e, those cells that detect antigens). On intracellular strep, Kurlan notes in the above reference that strep that produces M1 proteins have the ability to penetrate cells. Again the exact mechanism isn't known.
So the theory about carriers was that they had "adhesion and colonization without invasion" -- meaning that if you did a throat culture you'd certainly get streptococcal pyogenes, but that for reasons not known, the strep hadn't penetrated/invaded. This state has been declared to be benign, but actually no one knows this. The strep is most certainly producing streptolysin O, streptolysin S, hyaluronidase, streptokinase, ... however, these seem either to not penetrate past the epithilial layer or to not overwhelm the immune system such that any "leak" is blocked.
Infection, on the other hand, is what happens when the invasion overwhelms the immune system's ability to keep up the wall of defense. During infection, the growth continues unchecked and antibiotics help by either stopping reproduction of the strep or by weakening the actual cell wall of the strep (penicillin). In addition many of the macrolides are immunomodulating and shift the production of Th1 versus Th2 cells. The Th2 get the stuff extracellular and Th1 gets the stuff that is intracellular (if it can find it). So essentially, antibiotics stem the flow, the immune system builds up a response and then overwhelms the bacteria (if it can find it all).
Breaks in skin, tooth extractions, dental work, ... all enable rapid invasion and infection since the protection of the epithilial cells is broken and the bacteria can get right into the blood stream and reproduce rapidly. In addition, the subsequent exposures to strep (or its exotoxins) seem to be much more severe and so the recommendation is for prophilaxis antibiotics for ARF and SC individuals.
So, why are carriers resistant to antibiotics?
Well, it isn't clear that they are. It seems that there is a class of carriers who are only colonized (i.e., have no other symptoms of strep -- no ASO titers, no Anti-DNAse rise, no sore throat, ...). For this class of carriers, its really, really hard for the antibiotic to reach the strep since it is really on the surface of the skin and not invasive. For the one who has some invasion (i.e., had some rise of ASO titers), it appears that the surface colonization is not killed by the antibiotic or the antibiotic can't get the intracellular versions until they burst. This is where the macrolides come in if this intracellular form is the cause of recolonization. This is certainly not proven but is hinted at in Kaplan's 2006 papers. Penicillin can take out the extracellular stuff so perhaps penicillin is enough if it stops the cycle of intracellular infection. Similarly, the macrolides holding the intracellular infection in check allows the immune system to take out the extracellular stuff. At this point, please know that this is all theories and as far as I know there are no papers on this topic.
Just to throw an entirely weird wrinkle on this, the recent Kurlan paper shows that ASO titers drop after long exposure to strep (even if the strep is untreated) -- indicating either the strep is changing in what it produces or that the body gets used to the Streptolycin O (sort of getting used to bee stings) and stops mounting such a defense. This sure raises questions about the effectiveness of ASO as a strep selection tool.
Regard,
Buster
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Hi PANDAS_denmark,
Your post was really interesting. I wanted to check whether your child was evaluated for Acute Rheumatic Fever (ARF) and what the differential was. I'd also be very interested in what is the dosage of your child's azithromycin and your child's weight.
As such I am very interested in finding a scientific paper (or more) proving (or to some extent proving), that PANDASkids DO have a reaction when exposed to streptococcus (and/or other bacterias/virusses).Have you ever come across such a paper ???
Regarding proof, this is in essense the controversy between Kurlan/Kaplan and Swedo/Snider. The NIH has multiple studies that are showing a significant correlation between Streptococcal Pyogene and initial onset OCD/tics. http://intramural.nimh.nih.gov/pdn/recent_publications.htm
Probably the strongest of the papers showing correlation are Swedo's 1998 original work: http://intramural.nimh.nih.gov/pdn/pubs/pub-3.pdf and the literature review in 2003: http://intramural.nimh.nih.gov/pdn/pubs/pub-1.pdf.
Kurlan/Kaplan responded in their 2003 commentary that correlation doesn't imply causality and that the PANDAS diagnostic criteria was too broad and did not include sufficient differentiation to other diseases (namely Tourettes Syndrome which is Kurlan's specialty). Swedo replied to this in Pediatrics http://pediatrics.aappublications.org/cgi/reprint/113/4/907 that there was sufficient differentiation and that the suddenness of onset was a telltale sign. However, this was still correlation, not causality.
Please note that even with the huge amount of study (> 20 years) on acute rheumatic fever (ARF), ARF isn't shown to becausedby streptococcal infection just highly, highly correlated. This very high correlation is what causes propholaxis antibiotic but it isn't "proof". Proof is really hard since you have to show that the disease can't happen without the streptococcal infection.In 2005, Kurlan/Kaplan then did a 2 year study that was published very recently in Pediatrics (June 2008) http://pediatrics.aappublications.org/cgi/...ract/121/6/1188 where they took kids with chronic tics (i.e., > 3 years of tics) and tried to see if there was any correlation with proven streptococcal pyogenes (i.e., positive throat culture and rising ASO titer). They found there was a correlation that was greater than chance, but that there seemed to be many other causes of exacerbations (i.e., that most exacerbations weren't only caused by streptococcal infection).
It's important to note that Kurlan was studying kids with severe tics whereas Swedo was studying kids with severe OCD begging the question whether tic-only kids should be included in a PANDAS subgroup. In addition, Kurlan and Kaplan were looking at kids with chronic conditions rather than sudden onset kids.There were numerous problems with the conclusions from the study that I've posted here Problems with the Singer/Kurlan studies. However, the short summary is that causality is still not shown. To prove causality, you have to show that the result cannot occur without the "cause" (i.e., that the OCD or tics in these children couldn't come from some other cause). This is nearly impossible unless you are willing to infect children purposefully with strep -- Yikes! I can't imagine anyone funding that study.
So the best we get is the annecdotal data when kids come back into contact with strep. We don't have a study of exacerbation rates between kids on antibiotic propholaxis versus those not on antibiotic propholaxis.
What has been studied (Snider's work) is whether kids on one form of antibiotic have fewer exacerbations than on another form of antibiotics and this study showed that both azithromycin and penicillan were equally effective in prevention of strep reinfection.
Regards,
Buster
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How severe were exacerbations?
Hi Indigo,
I realized that I got so involved in trying to answer questions about recolonization and carrier state that I didn't check on the severity of your dd's symptoms.
Is her aggitation really severe (i.e., much worse that pre May?) Has this been largely going on since you first found out you had strep? Have you ever had a negative culture for strep?
Regards,
Buster
Recolonization seems reasonable given what you said. Hopefully your body fights off the strep and can eradicate it so hers can do the same.How long has she been on clarithromycin? Do you have any others in the house who are culture positive for strep but are asymptomatic? It actually sounds like you might be a carrier -- but you said you were symptomatic. Did you have a cough?
I'm really intrigued by your comment that you have had strep since May. What antibiotics have you been on and were you culture positive each time at 2 weeks after treatment?
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What might be happening...
Hi Indigo,
First off, if you are cultured positive and your dd has PANDAS then this can certainly cause exacerbations even if she is on antibiotics.
The reason is a bit complicated. Essentially, your daughter can get recolonized with strep before her immune system can take out the bacteria even if she's on antibiotics.
I know this sounds strange, but many antibiotics (certainly macrolides) don't directly kill the strep. Unlike penicillan (which kills strep by weakening the cell wall of strep). Macrolides work by preventing replication of strep. They hold strep in a biostatic state until your immune system can kill it off. The advantage of macrolides is that they go intracellular (if the strep is inside cells) and also prevents replication by extracellular strep. The advantage of penicillin is it directly takes out extracellular strep (i.e., the stuff outside cells).
So what could happen is that your dd gets recolonized (potentially from you) in the mucosal layer of the pharanx. Strep can then invade using one of its invasins (e.g., stretolysin-0) to invade through the mucosal layer and then the clarithromycin gets a chance and stops the strep from spreading (by inhibiting a protein the strep needs to replicate).
It's important to note that some strep will keep replicating but most won't be able to. So now the strep is held in check waiting for her body's immune system to come and wipe out the strep with a phagocyte/T-cell. Strep is unfortunately pretty clever at evading recognition by the immune system (e.g., encapsulation) and this is why some people do better on penicillan (which kills the strep) rather than macrolides (which relies on recognition by the immune system).
All this could be working just fine, and her body could be mounting all the right attack, but the strep is there and can generate small amounts of exotoxins. Now her body responds and who knows what happens...
We basically don't know yet why the strep causes the reaction it does in PANDAS subjects or how much strep is necessary to get an exacerbation. It could be the T-cells or IgG antibodies get confused and attack neuronal tissue (Swedo and Snider's theory). It could be the exotoxins actually cross the blood-brain barrier and cause inflammation near the basal ganglia. We just don't know.
But what is likely happening is she's getting some of the strep in her system, her immune system is recognizing it and responding, and she gets exacerbations in behavior/tics.
Having now said all that -- it could be something else. Recolonization seems reasonable given what you said. Hopefully your body fights off the strep and can eradicate it so hers can do the same.
How long has she been on clarithromycin? Do you have any others in the house who are culture positive for strep but are asymptomatic? It actually sounds like you might be a carrier -- but you said you were symptomatic. Did you have a cough?
I'm really intrigued by your comment that you have had strep since May. What antibiotics have you been on and were you culture positive each time at 2 weeks after treatment?
Regard,
Buster
Hello,I have had strep throat since May. I am now on my fifth antibiotic. Meanwhile, my dd has been on Clarithromycin for 3 weeks now to treat the PANDAS. This past weekend she was very agitated...I even called her doctor to see if maybe we should try something else or up the nystatin or something. Well, he did give her Diflucan, but this was before I presented with strep starting yesterday.
Sooo...would strep have been in my system this past weekend with my symptoms starting yesterday....causing dd's increased agitation? Then today I started antibiotic and she had her worst day in awhile. Her throat is hoarse but she says it doesn't hurt...it could be from crying and screaming. But she is still on clarithromycin.
I'm confused if she would have PANDAS symptoms come up even though she is still on antibiotic. AND I'm confused of how I can possibly rid myself of this strep.
I've been on oregano for several weeks now and am on another Zpack now. It's been such a horrible summer because of this, I'm just so exhausted. -
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Problems with the Singer Study
Hi Kim,
You asked a bunch of interesting questions in your post.
Moreover, researchers found no evidence of strep antibodies – the antibodies produced by the immune system against the streptococcus bacterium – binding to or interacting with brain tissue, a finding that makes an immune origin of PANDAS unlikely, investigators say.I haven't been abe to get my mind around the fact that they found nothing in these 12 children, but IF it's only a certain strep for a certain child that causes a problem, would they catch it using only 12 kids over 2 years? I wonder how many confirmed strep infections each child had during the 2 year period.Your point is really good. The underlying paper is a paper by Singer et al. in the June issue of Pediatrics:
http://pediatrics.aappublications.org/cgi/...ract/121/6/1198
I think the paper is fundamentally flawed and I have 5 major issues with this paper.
- This study is about long-term tic disorders in older kids (11-12) and not about sudden onset PANDAS (mean age 7.5).This is study about children with long term chronic tics who had onset over 3 years prior. 75% of the subjects in the proported PANDAS group were diagnosed with TS (i.e., had symptoms for > 1 year and no remission for > 3 months). The sample is pulled from the longitudinal study by Kurlan reported in the same issue of Pediatrics.
- The diagnostic criteria used by Kurlan for his proported PANDAS group is not the same as used by Swedo or Snider. Kurlan used a "clinical course characterized by the abrupt onset of symptomsorby a pattern of dramatic recurrent symptom exacerbations and remission". Swedo used an "Episodic course characterized by acute, severe onsetanddramatic symptom exacerbations." (emphasis added) While these sound similar, they are not. Indeed the episodic nature is the key distinguishing element in Swedo's studies as is the severity of the symptoms. Swedo wrote in her May 2003 response to Kurlan, "The episodic, relapasing-remitting course of the PANDAS subgroup is distinctly different from the undulating, waxing-waning course seen in other patients with OCD or tic disorders." In addition, Singer discloses that the average onset was over 4 years prior to his study. Kurlan discloses that the onset was not from documentation, but rather obtained through interviews thus being very prone to recall bias. So it is unclear whether the proported PANDAS subjects met the Episodic course, the severe onset, and the dramatic symptom exacerbations of the Swedo critieria.
- The subjects exhibited no OCD behavioral changes and are different from Swedo's/Snider's subjectsThe subjects attributed to be PANDAS subgroup in the Kurlan and Singer studies had a CY-BOCS score that changed only 1.6 [-0.4 to 3.6] (i.e., no change) with controls changing 1.0 [-1.1 to 3.1] (i.e., no change). This is hardly episodic given the baseline CY-BOCS scores and certainly does not indicate remission within the 2 year period but rather the small waxing and waning of OCD symptoms and the limited objective accuracy of the CY-BOCS measure. Swedo subjects often exhibited > 15 points of change in CY-BOCS score. Granted, I have some issues with these studies as well, but this 10 fold difference in CY-BOCS measured exacerbations definitely makes one wonder if these are the same subgroups.
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The subjects have high tic exacerbations but not OCD exacerbations.It is true that the subjects in the Kurlan/Singer studies had YGTSS-tic exacerbations of 11 pts [4.2-17.9] and certainly this is significant, but most of the other papers on PANDAS focus on the OCD element and less on the tics. So this begs the question about whether the study was more about Tourette's and association with streptococcal pyogenes rather than PANDAS. It also begs the question whether Swedo's criteria should include tic-only exacerbations. It also begs the question whether chronic tics are fundamentally different than onset.
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The subjects were all on numerous anti-psychotic, alpha-agonists, and mood stabilizers. it is totally unclear what these effects had on the subjects and how these variables were controlled
So the key question is how many of the kids in Kurlan's and Singer's studies actually had PANDAS as opposed to being kids with severe Tourettes with the unfortunate waxing/waning of tics associated with Tourette symptoms.
This is a long way of saying that I don't see how they can reach any conclusion regarding PANDAS given that their kids don't seem to be PANDAS subjects but rather Tourette's subjects.
in re-reading this post, I realize I should soften my criticism by saying how very impressed I was to see the size of the Kurlan study and Singer study and that the data set they collected is undoubtedly very helpful. Think of it, 40 kids being bleed every 4 weeks for 2 years with no immediate benefit. The study is impressive in scope, the data undoubtedly valuable, but the claims are definitely questionable.
Okay, now onto the second part of the study -- about antibody interaction with nuronal tissue.
Let me paraphrase, they took blood from this group of kids who I don't think have any PANDAS kids. They then injected this into cadaver brains (i.e., dead tissue) to see if the anti-bodies in the blood or the T-cells in the blood would attack the dead brain's of non-PANDAS kids, and they didn't find anything. Okay, so what conclusion can you draw from that. Most certainly not the conclusion that seems to be drawn from folks not reading the actual paper. This stuff gets me soooo irritated.
Finally, onto your last question about M-proteins. This is also very interesting.
Dr. Ed Kaplan has been studying this for the past 20 years. There's a citation in a recent book, "Streptococcal Pharangytis: Optimal Management", http://books.google.com/books?id=YiYY86j9A...a+streptococcal
Where Kaplan indicates that M-protein production was surpressed in children with carrier state streptococcal infections. That is a really interesting result and something that has me wondering. I'll post more about this separately as this post is already pretty long.
Best regards,
Buster
- This study is about long-term tic disorders in older kids (11-12) and not about sudden onset PANDAS (mean age 7.5).
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Hi Peglem,
I really appreciate you bringing up this very interesting set of questions and the paper.
I suppose, though, something could be "marking" body tissues with non self antigens- triggering NK cells to attack. I guess I need to find out how the strep neurotoxins work. Or maybe I don't- what good would it do me, really? I mean, the azith is keeping the strep at bay, and I don't know how that info would help as far as treatment.On carrier state- I suspect that biofilms are involved in this.
Thanks again, for doing my research for me- I agree that this does indicate a Th1 reaction to strep causing tissue damage.
I ran across the following link:
Encephalomyelitis-associated antimyelin autoreactivity induced by streptococcal exotoxins
According to http://www.neurology.org/cgi/content/abstract/54/7/1433
CONCLUSION: In vivo exposure to S. pyogenes may have induced activation of pathogenic myelin reactive T cells, contributing to the dramatic inflammatory demyelination.This certainly seems to support the hypothesis that the super antigens interaction with the Th0 cells is having a significant affect on the creation of the T-cells/Th2 cells and that these created Th2 cells are attacking things other than what the dendrites or macrophages would have signaled.
On your other topic of the carrier state, I've been wondering whether the situation is that the colony isn't growing fast (i.e., isn't sensitive to penicillan's attack mechanism). Perhaps in the carrier state, the bacteria is just slow growing -- and thus the amount of Streptolyicin O/Dnase-B is low or controlled.
Kaplan provided an alternate explanation (and a bunch of questions) in his 2006 paper "Reduced Ability of Penicillin to Eradicate Ingested Group A Streptococci from Epithelial Cells: Clinical and Pathogenetic Implications"
http://www.journals.uchicago.edu/doi/abs/10.1086/508773
Here he notes that GABHS is going intracellular.
Perhaps what is happening in the carrier state is that the GABHS is recolonizing after cell breach, invading other cells similar to a virus, and then the extracellular bacteria is getting destroyed again by anti-biotics during rapid growth.
Perhaps what azithromycin is doing in this case is :
1) as an antibiotic, it is going intracellular and preventing the protein growth and thus preventing the cell from "bursting" -- biostatic
2) as an immunomodulator is re-biasing the activated Th2's back to Th1's -- i.e., creating more antibodies to go after the intracellular strep.
I sure wish I knew more here but think this whole line of thought is promising and would be interested in anything others find here.
Regards,
Buster
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Oh, and where do the cytokines come from that trigger the Th0 cells to "pick sides"?
Hi Peglem,
Fascinating article!
In answer to your question, it seems that the cytokines are generated by B cells, Macrophages, and Dendrite cells. My understanding is that B cells and Macrophages can only activate Memory T-cells (i.e., ones that have already seen the presented antigen signature). Dendrites can activate memory T-cells and naive T-cells (i.e., those that could go either to Th1 or to Th2). So the dendrites seem to be the deciders of whether to send IL-10 or IL-12 to cause the naive T-cell to go to Th1 or Th2.
You might want to look at http://en.wikipedia.org/wiki/T-helper_cell .
What I found particularly interesting (with respect to PANDAS) was that multiple articles indicate that GABHS produces super-antigens that bind directly with the naive T-cells and thus cut the Dentrite and Macrophages out of the whole process. In one of the studies I was reading it indicated that Th2 (the inflammatory response) was being created even though there wasn't any IL-10 (i.e., that the super antigen was itself causing the production of Th2).
So this got me thinking -- yeah, I know I'm out on a limb here, but see what you think. Suppose that the super-antigens are converting naive Th0-cells into Th2 but miscoding them --> causing inflamation, but also creating cells that aren't looking for things the macrophanges want them to find. Instead this super-antigen is causing the creation of Th2 cells that will destroy any Th1 or Th2 cells that would have attacked the actual strep. I know this sounds odd, but why else would the SuperAntigen attach directly to the naive Th0 cells?
So now we bring azithromycin into the mix (or progesterone or NSAIDs or aktos or ...) and we get something that is slowing up the production of Th2 cells and rebiasing toward Th1 production. So if the strep were intracellular than the Th1 cells can now get it and not be killed off by these mis-programmed Th2.
Anyway, just a theory, but wow! great paper.
Regards,
Buster
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Hi Peglem,
Our daughter also did not exhibit high titers despite positive cultures (throat and perianal) for strep. We are pretty sure she got the strep infection 2 months earlier when 5 children from her class were out with high fevers and 2 were cultured positive for strep (we learned afterwards). She had an initial fever and sore throat (which we thought was viral). She appeared physically healthy the following week.
However, she had a tooth extraction later in the month and bam! she started shouting and having very pronounced defiant behavior and stopped eating breakfast and had signficant irrational separation anxiety. She had another tooth extraction two weeks later and bam! she stopped eating almost all meals. She then exhibited huge OCD issues with ritualistic questions around food, fear of being > 50 lbs, concerns about body image (this is a 7 year old)! Then we noticed a verbal tic and an odd movement disorder -- a strange jerkiness in motion and clumsiness. Her handwritting had deteriorated into a scrawl. From this, she progressed to suicidal statements. It was horrible. She lost 15% of her weight and we were able to get her into the hospital for malnutrition and they took numerous tests and I insisted on a strep culture, ASO, AntiDNAse B, and B-12 depletion (I had read somewhere about B-12 depletion with nitrous oxide) The strep tests came back positive (both throat and perianal) but the ASO was not considered elevated (31) as was the Anti-DNAse B (149).
We then had her sister tested and it turned out she was positive for strep. She was asymptomatic, but dx was willing to work on theory of PANDAS and we tried to clear both with Augmentin while also trying on dd refeeding therapy, CBT, and SSRIs. We had some issues getting sibling cleared of strep. At the 3 week culture, sibling came back positive for strep again (dd was on amoxicillan while we were trying to clear sister). Our dd was having all sorts of symptoms and checking with strep experts they indicated that dd could be recolonizing from the sibling even if on anti-biotics. We put sibling on azithromycin and 3 weeks later the strep test came back negative.
We took new titers on dd and titers were down even lower ASO (29) and AntiDNAse(<60). We started searching everywhere for whether strep can exist while there is declining titers. There just wasn't any study showing the rate/circumstances of ASO decline. We reached streptococcal experts at WHO and they indicated that there really wasn't any study of titer behavior with long term strep infections. They indicated a recent study by Kurlan where there was a subject with strep for 23 of 25 months who had continuously declining titers. While we were researching this, we switched our dd to azithromycin since her sister's strep was eradicated with azith. We wondered if the strep was intercellular. On the 9th day of azith, we saw dramatic improvement in all symptoms -- and I mean dramatic (she went from not eating to eating, panic to calm, OCD questions to none, ...). I can fill in lots of other detail here, but the short summary is that we think this whole carrier state is less benign that dxs are making it out to be. Perhaps it was this particular strain/emm-type, but bottom line is dd's symptoms (all of them) that we had been fighting for 5 months were noticably down on day 9 and mostly gone by 30 days. Motion disorder was last symptom to disappear (took 40 days).
Now there could be all sorts of reasons for what we saw. We had upped her SSRI during this window -- it could have been the SSRI. She was having headaches and we tried Advil during this time -- this seemed to have a positive effect. Lots of things going on, but definitely the strongest temporal correlation was the azithro.
I posted a note at top level about what I've learned thus far about titers. It sure would be interesting to find out how many folks seem to be in this low titers state and potentially have had multi-month/year strep infections that haven't been caught (what is usually called carriage -- but maybe it's not so benign).
Best regards,
Buster
Carrier means they harbor the bacteria but do not get sick from it. They can infect others. I don't think my daughter is a carrier, though, because 1) She does gets symptoms, they are just atypical, all behavioral, and 2) There have been many negative swabs-which should not happen for a carrier.My daughter's titers vary from extremely below normal range to slightly above normal range. I think this has more to do with a poorly functioning immune system than anything else, since "typical" symptoms are the signs that the immune system is fighting the disease. My daughter NEVER gets a fever. She used to, years ago...but not for a very long time.
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In reading through multiple posts, it seems there is a lot of confusion about titers and carriage of streptococcal infection. As a parent struggling to understand the medical information, I wanted to post what I've learned thus far and I hope it will be of use to you.
1) Titers need to be compared to a baseline. Direction is much more important than absolute value.
Some people produce very significant antibody responses, some don't. Some have high baselines, some don't. Since most often there isn't a test result from the prior month to compare against, most doctors (and labs) use a measure known as the "upper limit of normal" [uLN] as defining the baseline for ASO tests. Then if your single sample is > 130%-150% (depends on lab) of this baseline, they consider the test positive.
2) So this begs the question of what is the ULN for ASO? There are lots of studies here but what is important is that the studies have a very large range. For example in one study, kids not suspected of GABHS strep in the 5-10 year range, had
- 48% had titers below 100
- 6.8% had titers of 100
- 10.6% between 101-125
- 7.6% between 126-156,
- 22.1% between 157-195
- and 4.5% in 196-244
Unfortunately, even in this study, there didn't seem to be a second measurement taken within 1-2 weeks to look for rise/decline.
3) This begs the question of "what level of response consistitutes a positive?." Could a result of <100 still be an indication of a recent strep infection?
The answer appears to be yes, but only if you have a prior value done by the same lab, using the same technique. Most studies show that subjects will have a response 2-4x their baseline, this statistically could still fall within this "normal" range depending on the individual. So again, the importance is to look at trends and not absolute values.
4) What about falling titers? Does a high number indicate a current strep infection?
The answer seems to be no. There is just no good study about how fast ASO titers fall and what drives the rate of fall. Thus a single sample really gives no good indication of direction. Most studies agree that the rise is within a week of infection with a peak at 4 weeks, but there isn't a study of whether this peak remains if the initial infection goes untreated. So could someone with an untreated strep infection have a declining ASO titer? -- the answer appears to be yes.
For example, the most recent study by Kurlan [June 2008 - Pediatrics] has one subject that has positive throat cultures for 23 of 25 months but the ASO titers are falling within this entire time. What does this mean? No one knows.
5) Do all strains of strep produce an ASO reponse?
The best study I've found on this is Kaplan's 2003 paper "Immune Response to Group A streptococcal C5a Peptidase in Children: Implications for Vaccine Development." What this paper shows is that despite positive strep cultures on day 1, at a subsequent visit 4 weeks later,
- 46% of subjects presented no ASO rise,
- 55% presented no Anti-DNAseB rise,
- and 37% presented no rise of either ASO nor Anti-DNAseB
There also seems to be good research indicating that skin GABHS infections does not produce ASO response despite producing Streptolysin O.
What does this mean?
Does this mean that the test was bad? That some strains don't produce the streptolysin O protein? That some people don't mount a high immune response? That the individual is a strep carrier? That the strep was going on for some time and the ASO titers have already fallen? That skin GABHS infection differs from pharangytis GABHS? The answer is that the scientific community doesn't know. There has been no careful study of the decline rate of ASO titers and the entire field of "strep carriers" is not at all clear.
So summarizing,
- a rising ASO titer (regardless of absolute value) is an indication of GABHS strep; however, you need a baseline to be sure it is rising.
- A falling ASO titer indicates that there was strep, but no one knows when.
- A high ASO titer could be anything including that the titer is falling, rising, or just a high baseline. Statistically it is likely to be a falling titer.
- Most will treat a titer of > 400 IU's as a falling titer (i.e., that there was once a strep infection sometime in the past). But the exact time of the infection is not known.
- The interpretation of a low ASO titer is unclear. There could have been an infection and the titer has already fallen, the baseline for the person could be low, the individual may not respond with a strong immune response, the strain may not produce significant amounts of streptolysin O.
One final comment, Swedo does not require high ASO titers or even rising ASO titers to diagnose PANDAS. The titers are checked only when a positive strep culture is not available and you are retroactively looking for an indication of past infection. The flaw with using titers as an indication of prior strep infection is (as I stated above) that "low" values can still be associated with prior strep infections since the rate of ASO titer decline is not known, most people only have a single sample, and the ASO response is variable across individual and strep type.
Regards,
Buster
- 48% had titers below 100
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Dear thnksmom:
A couple of quick comments regarding Dr. Singer's paper in the June issue of Pediatrics. It appears that Dr. Singer is using (or provided) a subset of the sample data from the 2 year study summarized in the Kurlan paper appearing in the same issue.
I have a long list of issues with both studies, but let me list the 5 big ones here.
1) This is not a study of sudden onset, but rather one of studying children who have chronic conditions. 75% of the subjects in the proported PANDAS group were diagnosed with TS (a condition requiring symptoms for > 1 year and requiring no remission for > 3 months), 87.5% of those in the control group were diagnosed with TS. Thus the critical item is what separates the PANDAS group from the TS group.
2) The separation critieria used by Kurlan for selecting the PANDAS patients was different from the diagnostic criteria proposed by Swedo. Kurlan used a "clinical course characterized by the abrupt onset of symptoms or by a pattern of dramatic recurrent symptom exacerbations and remission". Swedo used an "Episodic course characterized by acute, severe onset and dramatic symptom exacerbations." (emphasis added) While these sound similar, they are not. Indeed the episodic nature is the key distinguishing element in Swedo's studies as is the severity of the symptoms. Swedo wrote in her May 2003 response to Kurlan, "The episodic, relapasing-remitting course of the PANDAS subgroup is distinctly different from the undulating, waxing-waning course seen in other patients with OCD or tic disorders." In addition, Singer discloses that the average onset was over 4 years prior to his study. Kurlan discloses that the onset was not from documentation, but rather obtained through interviews thus being very prone to recall bias. So it is unclear whether the proported PANDAS subjects met the Episodic course, the severe onset, and the dramatic symptom exacerbations of the Swedo critieria.
3) The subjects attributed to be PANDAS subgroup in the Kurlan study had a CY-BOCS score that changed only 1.6 [-0.4 to 3.6] with controls changing 1.0 [-1.1 to 3.1]. This is hardly episodic given the baseline CY-BOCS scores and certainly does not indicate remission within the 2 year period but rather the small waxing and waning of OCD symptoms and the limited objective accuracy of the CY-BOCS measure. Swedo subjects often exhibited > 15 points of change in CY-BOCS score. Granted, I have some issues with these studies as well, but this 10 fold difference in CY-BOCS measured exacerbations definitely makes one wonder if these are the same subgroups.
It is true that the subjects in the Kurlan study had YGTSS-tic exacerbations of 11 pts [4.2-17.9] and certainly this is significant, but most of the other papers on PANDAS focus on the OCD element and less on the tics. This begs the question whether tic-only exacerbations should be treated as the "episodic course" or "dramatic symptom exacerbation" when OCD scores did not move.
4) Many of the subjects in Kurlan's and Singer's studies were on numerous anti-psychotics, alpha-agonists, mood stabilizers, ... and it was very unclear how these variables were controlled.
5) The subjects in the Kurlan study were 11.0 +- 1.7 (i.e., older than almost all Swedo/Snider patients). In the Singer study, the children were listed as being 10.9+-2.5 with a full year difference in the controls 11.8 +-2.3. Almost all Swedo/Snider patients had a mean age of 7.5.
So the key question is how many of the kids in Kurlan's and Singer's studies actually had PANDAS as opposed to being kids with severe Tourettes with the unfortunate waxing/waning of tics associated with Tourette symptoms.
Please note, that despite my criticism of the studies, I am impressed with the Kulan's study and think the data collected from such a study will be extremely valuable to all sorts of post-study analysis. My difficulty is rather with the critieria of subject selection. No OCD episodic behavior, no documented sudden onset (recall bias only), chronic conditions existing in most cases for > 4 years, older children less prone to strep, ...). Hence the study is a great study of streptococcal relationships in Tourettes, but the lack of episodic OCD behavior makes me doubt that their net caught PANDAS cases.
Regards,
Buster
I was reduced to tears today at the peds. neuro appointment. Just when I thought we were getting somewhere with our son's primary physicians understanding and believing what we were saying, we go to this new dr. (appt set up months ago when tics started by our ped). He said that if I would follow the work of Harvey Singer who is "the foremost expert on PANDAS" I would know that his studies prove that tics are not caused by strep. So, I researched Dr. Singer to find that he cannot PROVE the connection, although he continues to ask for further studies (to me that means he cannot disprove the theories). He admits that tics can be exacerbated by strep (although not caused by strep), stress, fatigue, etc. but does not approve of using prophylactic antibiotics (which we are not on, but I would not be against). His most recent findings were published on June 8th. (http://www.hopkinschildrens.org/newsDetail.aspx?id=4914)The peds neuro we went to is very well respected in this area. He went on to say that Azith is of no use as an immunomodulator and seemed to belittle me when I respectfully) questioned that. I also researched that when I got home and found a 2004 report that was released about the immunomodulator qualities of Azith. He did say that some children take Haldol and other drugs for tics, but that he didn't see the need for my son because he is perfectly normal. It didn't matter that he has had major tic outbreaks three times and all three times he responded well to antibiotics, in this doctor's mind there is no such thing as a relationship between strep and tics.
I am hoping that this physician's viewpoint does not sway my primary physician, as I really need him on my team for this. We are fighting a huge uphill battle, and will continue, and next it will be with insurance coverage of this disorder that my son shows all the signs of but that really doesn't exist. . .
Just needed to vent-- hopefully we will hear from Dr. Murphy this week, because I am ready to fly to Florida for someone who doesn't have to question logic left and right, but that will just help us navigate through this very complex maze!
I've been on oregano for several weeks now and am on another Zpack now. It's been such a horrible summer because of this, I'm just so exhausted.
N-acetylglucosamine (GlcNAc)
in Tourette Syndrome and Tics
Posted
Hi Kim,
I was really delighted to see your post. I think there is something very significant here with the GlcNAc. Dr. Kirvan in her paper with Dr. Swedo isolated the antibody idiotype to one targeting the GlcNAc (i.e., the streptococcal carbohydrate). The problem was that this antibody seemed to react with neuronal tissue. This was Kirvan's paper in 2006 "Antibody-mediated neuronal cell signaling in behavior and movement disorders"
http://www.csus.edu/bios/faculty/Kirvan/Ki...JNI_article.pdf
She later went on to isolate reactions to Tubulin in her 2007 paper, "Tubulin Is a Neuronal Target of Autoantibodies in Sydenham’s Chorea."
http://www.csus.edu/bios/faculty/Kirvan/JI_paper_2007.pdf
What is so fascinating here is whether there are anti-idiotype antibodies that supress the GlcNAc antibody and that for some reason these anti-antibodies aren't doing the supressing they are supposed to.
To me, this explains why IVIG might work... it is adding in this anti-anti-body that supresses the immune response.
Regards,
Buster