Dr_Rosario_Trifiletti

I think it's a complex neuroimmune response. I just mention CaMK2 only because there seems to be the most known about this. Obviously Dr. Cunningham would like to try to try to correlate the 4 antibodies she measures to clinical phenotype. All 4 (and I'll bet quite a few more) are important, but we're just having difficulty making sense of the anti-CaMk2 info. I think this will end up being like the chicken soup of autoantibodies that rheumatologists that treat patients with lupus-like illnesses think about all the time. Dr. T

Dr. T., Have you ever tested your patients who are band 41 positive with the Igenex test to see if they have bands 31 and 34 also? No, I literally began finding this over the past few weeks. If you just ask for "Lyme titers", you will come up empty as Western blot done only as a reflex if titer exceeds a pre-defined threshold (<0.91 in my geographic area). Now I routinely ask for LYME WITH WESTERN BLOT, and we find the p41 IgG and IgM bands in almost all "PANDAS" patioents (LabCorp testing in most patients). There is so much BS about lime out there I have to follow my gut instincts (no pun intended) You bet these patients need thorough Igenex testing for p31 and p34 at least. Would you also recommend the Igenex co-infection panel? Also, can you send me any contact information on Dr. Charles Ray Jones? (you can reach me best at trifmd@gmail.com) I'm going to start to screen for common flagellated enterics as well. Dr. T

I call the patients who ONLY show p41 IgG/M positivity "Lyme-like illness" just to keep an open mind. I'm aware this could be Borrelia burgerdorfi (Bb) Lyme disease. In fact, with this finding it's our obligation to do the best we can (and it's very hard, I know) to rule Bb infection in our out. However, p41 is a very interesting protein. It is called FLAGELLIN, so these patients have anti-flagellin antibodies. The p41 is a major component of the bacterial tail found in those bacterial that are flagellated, i.e. have a motile tail, similar in function to that on a sperm cell. Now p41 is found on many bacteria that (seemingly) have nothing to do with what generally think about. It is NOT found in streptococci or mycoplasma, so infection with those can't be confounding this result. Spirochetes, in general, are flagellated, so there are many possible non-Bb candidates. BUT THE PLOT THICKENS ... p41 is found on many enteric (pathogens such as Campylobacter, Giardia, etc.) The interesting thing is that the immune response to p41 is HIGHLY specific. p41 activates Toll-like receptor #5 (TLR5), and another (minor) pathway. Furthermore, p41 is the only known activator of TLR5. Recently, it has been shown that TLR5 knockout mice develop severe colitis. It is now widely believed that the physiological function of TLR5, which is highly expressed in gut endothelial lining, is to protect us from nasty food-borne bacteria. http://www.ncbi.nlm.nih.gov/pubmed/18066550 Now, is there any example of a flagellated enteric pathogens leading to a NEUROimmune response - absolutely! Camyplobacter is the major cause of Guillain-Barre syndrome (don't worry if you don't know what that is) http://www.ncbi.nlm.nih.gov/pubmed/20157729 But pathogenic Campylobacter, while flagellated, plays a trick on the immune system to avoid TLR5. So this could be the link to stomach pain experienced by many of our patients before the onset of PANDAS. See Dr.K's discussion on "adolescent variant" of PANDAS! http://www.webpediatrics.com/pandas.html

anti-CaMK2 must be marking a common final pathway NEUROimmune reaction - after all these are mostly brain symptoms that we are talking about here. It is very likely NOT infectious etiology specific A positive Cunningham test likely means a neuroimmune etiology, need not be bacterial, need not even be infectious (for example lupus-like illnesses). This is what I find it most useful for: 1. Distinguishing non-immunological TS and/or OCD from PANDAS-like illnesses. If this can be verified, we may be able to answer questions like "How many kids with tics and/or OCD really have PANDAS-like illness" - just sample 1000 kids with tics or OCD (all comers) and find out what percentage have positive Cunningham tests. (it can't be that easy ....). 2. Get a sense (along with response to steroid burst) if costly immunological interventions like IVIG and/or PEX are likely to work 3. Distinguish between PANDAS and SC when there is clinical confusion. I realize there are kids out there (I know of three) that have anti-CaMK2 in the SC range (200's) but do not appear to have SC. I don't routinely do echocardiograms on patients with clear-cut PANDAS any more; but I think if anti-CaMK2 >200 maybe it should be done, as it can be missed. THIS DISTINCTION IS IMPORTANT AS IT CHANGES LONG TERM MANAGEMENT. 4. Separate out non-immunological TS and/or OCD from "pure OCD" and "pure TS group" and focus genetic studies on large pedigree "pure OCD" and "pure TS groups". Essentially, try to filter out a major epigenetic factor which confounds linkage analysis. This may be the way to looking at underlying genetics of these disorders, which leads to proteins, which leads to disease pathways, which leads to rational treatment. At the end of the day, in PANDAS patients, there is still the trigger. It is very very important to try to find the trigger(s) as early as possible and try to treat them. Immune treatments will put the disease into remission, but root cause treatments are the only way to a cure. Dr. T

Yes, if this is true -- about the CamK being indicative of autoimmune caused neuro-psych symptoms. Not just strep, but ANY bacterial infection. I wonder what Dr. Cunningham's thoughts are on this. A concern is certainly that a person gets "confirmation" though these CamK numbers and assumes it is solely strep related, when indeed it could be other bacterial infections are there instead of, or in addition to, strep. I wonder if people understand this? The key is obviously getting the right type of treatment for the underlying infection(s). Thanks for your thoughts. Mary ABSOLUTELY CORRECT! anti-CaMK2 must be marking a common final pathway NEUROimmune reaction - after all these are mostly brain symptoms that we are talking about here. It is very likely NOT infectious etiology specific A positive Cunningham test likely means a neuroimmune etiology, need not be bacterial, need not even be infectious (for example lupus-like illnesses). This is what I find it most useful for: 1. Distinguishing non-immunological TS and/or OCD from PANDAS-like illnesses. If this can be verified, we may be able to answer questions like "How many kids with tics and/or OCD really have PANDAS-like illness" - just sample 1000 kids with tics or OCD (all comers) and find out what percentage have positive Cunningham tests. (it can't be that easy ....). 2. Get a sense (along with response to steroid burst) if costly immunological interventions like IVIG and/or PEX are likely to work 3. Distinguish between PANDAS and SC when there is clinical confusion. I realize there are kids out there (I know of three) that have anti-CaMK2 in the SC range (200's) but do not appear to have SC. I don't routinely do echocardiograms on patients with clear-cut PANDAS any more; but I think if anti-CaMK2 >200 maybe it should be done, as it can be missed. THIS DISTINCTION IS IMPORTANT AS IT CHANGES LONG TERM MANAGEMENT. 4. Separate out non-immunological TS and/or OCD from "pure OCD" and "pure TS group" and focus genetic studies on large pedigree "pure OCD" and "pure TS groups". Essentially, try to filter out a major epigenetic factor which confounds linkage analysis. This may be the way to looking at underlying genetics of these disorders, which leads to proteins, which leads to disease pathways, which leads to rational treatment. At the end of the day, in PANDAS patients, there is still the trigger. It is very very important to try to find the trigger(s) as early as possible and try to treat them. Immune treatments will put the disease into remission, but root cause treatments are the only way to a cure. Dr. T

Buster, if you're reading I thought you might be interested in the "protein tyrosine phosphatase receptor-N," part in particular. This fits with a general theory which I favor Multiple infections triggers (strep, MP, Lyme-like, others) >> multiple Toll-Like receptor activation >> multiple signaling pathways >> increased NF-kB >> increased gene expression of pro-inflammatories Slowly but surely the pieces of this PANDAS puzzle are coming together. Dr. T

I found this information on a "Lyme Doctor's" website http://www.drcharlescrist.com/testing.htm He states: For this reason I believe the screening tests are practically worthless, and is why I use the Western blot to “screen” for borreliosis, even though it is a “confirmatory” test. Antibodies are very specific as to what they bind; consequently, in over 700 borreliosis patients false positive blot results occurred in only three percent of them, based upon research I presented at the 2000 International Lyme Borreliosis conference. Data from those same 700 patients showed that if their Western blots had even one antibody significantly associated with the bacteria, there was a 97 percent chance they would feel better with antibiotics. Consequently, I tell my patients not to worry if the laboratory interpretation is “negative” or “equivocal,” if they have antibodies that are significantly associated with Borrelia burgdorferi. As you know, many PANDAS patients, with "normal" Lyme titers are showing p41 IgG and IgM on Western blot. Could this have something to do with antibiotic-responsive strep-negative illnesses? Dr. T

From your lips to God's ears! Dr. T Actually, I meant in the GENERAL POPULATION, i.e. someone you meet randomly at the mall or something, those are the numbers. That person would have a 20% chance of having a positive strep titer, 10-40% chance of having a positive mycoplasma titer and a 10-20% chance of having positive p41 IgG and IgM on Lyme Western blot. Assuming these to be independent factors (and they may not be) the chance of having all three would be about ) 0.2 x 0.2 x 0.1 or 4-8%. I think at least 50% of PANDAS patients have >2 of these positive and 20% all 3, much higher than the general population. So the key to PANDAS in many cases is co-infection .... Dr. T

From your lips to God's ears! Dr. T

As you may know, I have been interested in positive Mycoplasma IgG titers and have been treating a number of patients here for mycoplasma. What is the chance of seeing a positive Mycoplasma IgG in the general population? Answer: it depends on age See Fig 1B in this paper http://www.ncbi.nlm.nih.gov/pmc/articles/P...df/cd000734.pdf You find elevated mycoplasma titers in 40% of adolescents in a healthy Finnish population. I'm not sure what the USA numbers are, but they're likely to be similar. Of course, very few of these people have tics and/or OCD; so it is going to be hard to find an association between elevated mycoplasma IgG and anything. However, what I'm finding is that patients with PANDAS often have: 1. Peristently elevated ASO, ADB or streptozyme (about 20% chance) 2. Persistently elevated Mycoplasma IgG (about 40% chance) 3. Persistent anti-flagellin (p41 IgG and IgM) - probably no more than 20% chance The chance of having all three together - probably no more than 5%. So, the proper study would be to look at multiple co-infections, not just one, to prove association. You would need an enormously large population to prove association with any one alone. MY GUESS: So what is the common thread here? : strep, mycoplasma and Lyme all have tendencies to be persistent illnesses, i.e. in some people there is difficulty clearing them from the body. There is a progressive accumulation of peristent bacterial illness, individually subclinical but together, problematic. All signaling through a common TLR (toll-like receptor) mechanism producing abnormal cytokines and ultimately PANDAS like symptoms. P.S. These are just my ideas, not reality. But you gotta have hypotheses or there are no answers - that just how science works. Dr. T

Dear Parents, I know that some of you have opted for tonsillectomy. Although removed tonsils are routinely sent to pathology for examination, they are not routinely cultured. What organism are left behind in children with PANDAS who have their tonsils removed? So far 3/3 kids - Haemophilus influenzae, non-Type B (NTHI). No strep in a single case. This is NOT the organism that HiBVax protects against, not the Type B organism that causes neonatal meningitis. Does anyone else have culture results on tonsils? Perhaps NTHI is a benign squatter, merely occupying territory formerly occupied by strep. Or it may be of pathogenic significance. Or perhaps yet another potential co-infection? Dr. T

If we define a "PANDAS-like illness" as the acute onset of tics, OCD, or marked behavioral changes, that are antibiotic-responsive, then I can now say that the vast majority of these children are positive for Group A strep, some other type of strep, mycoplasma, or a putative Lyme-like illness (the p41 IgG/M phenomenon). In some cases, the infection is acute, in other cases chronic with a secondary trigger (like a vaccine). I would stop the workup with looking for those agents ... if not found - I would pursue a minimal immune workup, and consider immunosuppression. Let me emphasize again - Fungi do not appear associated with PANDAS-like illness, but it would be hypocritical for me to not keep an open mind, especially in highly unusual cases In medicine, you can always do more tests. If I do 1,000 tests on every person reading this, it is virtually guaranteed that 10 of those tests will be abnormal. Which leads to more tests. This fishing expedition approach to medicine is not a good idea, for two reasons: 1) almost all the fish you will catch will be red herring (i.e. false positives); 2) the fishing boat is a yacht (i.e. very expensive). I'm trying to come up with an answer to the question: what is a reasonable workup for all children who have a PANDAS-like illness? I think we're getting there ..... Dr. T

Never suggested that at all. But readers beware that antibiotics can cause a whole host of additional problems if they are used repeatedly and long term. If the body isn't a good host for infection then the infections will no longer be reoccurring and/or rampant. Each individual case has differing causes and we all need to do many kinds of tests to figure out each case. Abx in isolation can cause a lot of problems in an immuno-compromised individual long term. They suppress the immune system, they don't cure it. They do nothing to aid the body's weakness, the underlying causes of the reoccurring infections. Just read about Beauchamp versus Pasteur. If that is all people look for, is the next ailment and the next course of antibiotics then it is nothing more than a vicious cycle. Yes, antibiotics kill bacteria; but they are a mold and if the body is not in balance they will proliferate in that already sick body over time, especially if the diet is full of mycotoxins, sugars, and starch and has been repeatedly stripped of beneficial bacteria over a long period of time. I never suggested not to use abx for strep. You misunderstood my concern. I only warn that repeated and long term abx will cause other health problems down the road if that is the main course of treatment and dietary restrictions are not involved. PERSONAL EXPERIENCE guides me, drives me to make this point. Repeatedly if I have to. You suggest that only mild yeast overgrowth can be present in these kids. In MANY cases an antifungal diet has put children with symptoms of OCD and chronic multifocal ticcing into remission. There is much documented evidence suggesting that fungal infections can affect the brain and behavior. In a case where Pandas isn't 100% proven clinically why wouldn't a parent have their child tested for fungi? Dr. Bruce Semon has a program dedicated to working with T.S. patients using an anti-fungal approach. Doug Kaufman has a show dedicated to educating folks with auto immune disorders on the benefits of an anti-fungal diet. Sheila Rogers also discusses it in her book. Great Plains Labs in Kansas runs a series of diagnostic tests for children with Neurological issues. An ASO titer panel is one. Mycotoxins and Fungi are another....... The microbe is nothing. The terrain is everything. We all have potentially dangerous pathogens in and on our bodies. In a healthy individual they are in balance. In a sick person they wreak havoc. I agree with what you say. I am not a fan of antibiotics long term. I really wish there were some way we could pick out, by the appropriate immune testing, those that absolutely need it. There could well be patients with PANDAS who would benefit from immune strengthening protocols just as much, if not more, than chronic antibiotics. But I do believe that in most people even chronic antibiotics, especially when given prophylactically, are preferable to chronic SSRI's or chronic risperdal. One of the big arguments of the PANDAS naysayers is that by treating an illness that they feel is unproven to exist, we will be filling the world with antibiotics. Simply not true. Even if all tics and OCD turned out to be antibiotic-responsive (and it certainly is not) that would amount to treating no more than 2-3% of children. The likelihood of spreading a hypothetical resistant organism would be very low. It's also why MRSA exists in the world, but unless you are in a MRSA-haven (aka hospital) you are unlikely to encounter. The answer then is to analyze the patient as carefully as possible. Not just say, you have PANDAS - here is my protocol. I think once a diagnosis of a PANDAS-like illness is strongly suspected, the questions should then be: 1) what are the infectious triggers in this patient? 2) what is wrong with this patient's immune system? I think some of what you are saying is that fungi or their mycotoxins should be on the list of infectious/toxic triggers. It makes total sense. I think its very prudent to begin to look for these in patients in whom the "usual suspects" cannot be found, and especially in whom there are multiple affected family members to suggest an environmental exposure. As time goes on, and we become more refined in our ability to classify patients with PANDAS-like illnesses, we may be able to pick out those patients who need the full-blown fungal workup. The low-down is you are right and I need to learn more about fungi and mycotoxins. You should know that most MD's knowledge of this amounts to no more than a half-dozen lectures in medical school! Pity us fools! Dr. T

This is a very common but sorely under-recognized finding post-strep - in NJ we had an epidemic of acute post-streptocoocal enthesopathy over the past two years. Almost invariably involving bilateral knee and ankle joints with sufficient pain that many of these children refused to walk (and so neurology was called a lot). Everyone went from mild-severe-mild pain over the course of 1-3 days. Although this can possibly be viewed as a minor version of rheumatic fever (no fever, no rash, no heart involvement, just the rheumatic), it's different as that is usually over joints, and this is over tendons. There is almost nothing about this in the literature - so there's another paper to write Sigh. If others can confirm, this might be considered to be another strep warning sign to look out for .... Dr. T [/quot When this happened to him last year, it started in one achilles tendon and they booted him. After about 2 weeks in the boot (with no improvement) his other achilles went. That's when they started talking auto immune disorders, and ordering bloodwork. Nothing really showed up except that he had obvious inflammation. Ibuprofen around the clock didn't help either. He was booted on the other leg too, but eventually had to have a wheelchair because he felt pain even in the boots. After about a month total, it went away. Only to reappear right before we went to UCLA in the underside of his elbow (which lasted less than 24 hours) and then the next day in the tendon on his wrist, which also lasted less than a day. The only thing that troubled the UCLA pediatric rheumatologist with her "diagnosis" was that it lasted so long, because she said this type of reactive arthritis usually goes through fairly quickly. Well, here we are a year later, he just spent the last month fighting a sinus infection, strep and staph in the throat, and another sinus infection (4 different antibiotics). He finally feels better (last Tuesday), plays a couple of hours at the park with his buddies, and then his achilles starts bugging him. By the next day he can't walk on it at all, and now even in the boot (from last year) he has pain. Today the 2nd achilles goes down. I am not sure what to do for him. We are going to pediatrician tomorrow, so I guess we'll see what she says. Have you seen this type of tendonitis last so long in a post strep situation? Every one of the patients I dealt with were better in 2-4 days, it was like a script .... Because strep can be persistent, it's not inconcievable that it could last much longer, but what happened to your son may well be something different. Was he checked for HLA-B27? Dr. T

I don't think fungus has anything to do with the symptoms of enthesopathy. Please be careful. Caveat legator, let the reader beware. Fungal infections can profoundly affect the immune system and may be behind some cases of SEVERE immunocompromise. BUT to suggest that we avoid using antibiotics to treat PANDAS due to concerns regarding fungal infection is simply spreading wrong information. There can be mild yeast overgrowth, not the deep seeded fungemia seen in mycotoxic patients. This is not to say that mycotoxins are not an important and perhaps even under-recognized problem in medicine, but this is not what we are talking about here. I'm actually involved in the treatment of two women who have OCD symptoms and are heavily infected with black mold, as well as strep and mycoplasma. But these were women who worked in an extremely infested environment. Dr. T

Mel, please contact me via phone or e-mail ... Dr. T

My son does this too. Like the rest of his behaviors, it seems to cycle in and out. He also has described it as getting stuck. Here is a recent review by Swedo's group that mentions staring type compulsions http://www.ncbi.nlm.nih.gov/pmc/articles/P...df/JCI37563.pdf I think neurologists need to be more aware of this condition as these children may be confused with children with absence seizures Dr. T

This is a very common but sorely under-recognized finding post-strep - in NJ we had an epidemic of acute post-streptocoocal enthesopathy over the past two years. Almost invariably involving bilateral knee and ankle joints with sufficient pain that many of these children refused to walk (and so neurology was called a lot). Everyone went from mild-severe-mild pain over the course of 1-3 days. Although this can possibly be viewed as a minor version of rheumatic fever (no fever, no rash, no heart involvement, just the rheumatic), it's different as that is usually over joints, and this is over tendons. There is almost nothing about this in the literature - so there's another paper to write Sigh. If others can confirm, this might be considered to be another strep warning sign to look out for .... Dr. T

PM me and we will set up a time to talk. No charge. There may be a few tests to do if strep tests are negative, like Lyme with Western Blot and some basic immune testing. Save the $400 you would spend on travel costs to come see me and spend it on the Cunningham test. Then we will be able to use state-of-the-art testing to determine if this is infectious or not. Dr. T Then we can determine if it might be infectious or not

Galileo said, on recanting, when the Catholic Church threatened to excommunicate him for his discoveries of four moons moving around the planet Jupiter, which clearly debunked the Church's position of an earth-centered universe "Eppur, si muove" (and yet, it moves) And Gamaliel: And now I say unto you, refrain from these men, and let them alone, for if this counsel or this work be of men, it will come to nought: but if it be of God, ye cannot overthrow it, lest haply ye be found even to fight against God. (Acts 5:34) in other words, ignore the naysayers, eventually the truth will out ... Dr. T

I like the pediatrician's position .... what's the big deal with just checking it out http://www.thealternativepress.com/article...l-Professionals Dr. T

I agree that most of the parents on this forum are of higher than average IQ, whatever their ethnicity. However, we also know that in general untreated streptococcal infections generally follows poverty. While I could see how milder cases of tics/ocd/behavioral changes could be under-reported, it's hard to believe that the severe quasi-psychotic cases could be missed. I think this may be the case as the few African-Americans I have seen with this have been very severe cases. The passing off of milder tics/ocd/behavioral changes as just things that "kids normally do" could have as much to do with cultural as with socio-economic factors. This means that an important place to focus initial efforts of a "Got Strep" campaign could well be the inner city. I am by no means a sociologist, I just raised this issue as it may be an important scientific clue in the etiology of PANDAS-like illness. Definitely something to consider discussing at the Autism One "think tank" session in May. Dr. T

My initial review of the literature suggests this is largely unknown. What a great PhD thesis project (projects) for the interested individual ...I would also think there is ready funding for this type of research. An even bigger question: how big is this PANDAS problem, in general? Since this appears to be a common, and in some cases chronically disabling condition in many cases, the health/cost burden must be substantial. Just think of all the lost work hours and additional expenses parents incur in taking care of these children. Dr. T

I have seen very very few African-Americans or native Africans with PANDAS. I don't think this is merely a sampling or access issues, as I have spent a number of years in Newark, NJ, which is about 70% African American and saw only one case. I'm wondering if there are any African-Americans on this board or if this might be a bonafide observation. I'm thinking perhaps a tropical ancestry selects for an immune system particularly geared toward efficiently eliminating certain pathogens. I think most of you may be aware of the malaria-resistance conferred by SS-Sickle Cell disease. Dr. T

I love the air filter analogy! I'm curious, does anyone ever culture tonsils after they've been removed? It seems that everyone assumes there is no infection (hence no abs, or low dose amoxcillin) pre and post surgery. It seems that the excised tonsils could give you a better culture/indication as to whether the infeciton is really gone, better than the typical swab at least. I just saw a patient a few hours ago who had a tonsillectomy for PANDAS on 2/12. The child was on appropriate antibiotics pre-operatively. Both tonsils were cultured and from both: Haemophilus Influenzae ! I can't tell from the prelim path report if it is Type B (the kind that causes meningitis and why your child gets HIBVAX) or so called non-typable H.Flu. So I treated for the worst possible scenario as a precaution (Augmentin and Rifampin). Could H.Flu be another on our list of PANDAS-like illness culprits? Or does this simply tell us that the tonsillectomy is unlikely to affect PANDAS symptoms (there's been no appreciable benefit thus far). Has anyone else's child had cultures of removed tonsils? I'm beginning to think that we should request ENT physicians request cultures on their tonsils. This is almost never done in routine practice. Another reason for that paper ... Dr. T