PANDAS research for your doubting doctor

[Buster]

Best summary papers on PANDAS

• Swedo's 1998 landmark paper: http://ajp.psychiatryonline.org/cgi/reprint/155/2/264.pdf
  
• Feitosa de Olvieira did a nice job summarizing research in 2007: http://www.scielo.br/scielo.php?script=sci...=en&nrm=iso
  
• Mell's 2007 summary: http://pediatrics.aappublications.org/cgi/...t/full/116/1/56 (although I couldn't find a free version of this)
  

Exellent summary of GABHS

• Cunningham wrote an outstanding paper summarizing the literature http://cmr.asm.org/cgi/reprint/13/3/470
  
• Kaplan wrote a very good paper on intracellular strep: http://www.journals.uchicago.edu/doi/pdf/10.1086/508773
  

Best summary papers on IVIG and Plasma Exhange

 

The best study that I've found about IVIG was Perlmutter's 1999 Lancet report: http://intramural.nimh.nih.gov/pdn/pubs/pub-5.pdf where there was a demonstrated improvement of both IVIG and Plasma Exchange over Placebo in the decline of OCD symptoms. The followup actually offered IVIG to those who had placebo and again these had good results. There was a followup study on IVIG for OCD for non-PANDAS kids by Orvidas and Slattery (2001) that showed no improvement for non-PANDAS kids. I sure wish they had just repeated Perlmutter's test.

 

Incredibly, despite this begging for a followup experiment, there has been no followup study to test efficacy of IVIG on PANDAS vs non-PANDAS cases. Indeed the current NIMH site warns that IVIG should only be considered for severe cases and if anything recommends against it till there is more research (but hasn't funded any) -- grr.

 

There is a very good paper on "Evidence for the presence of streptococcal-superantigen-neutralizing antibodies in normal polyspecific immunoglobulin G" http://iai.asm.org/cgi/content/abstract/64/12/5395 where the author notes that IVIG seems to neutralize two of the superantigens of streptococcal infections. The exact mechanism of neutralization is not known.

 

Best summary papers on Azithromycin vs Penicillin as treatment

 

There also hasn't been a followup to Swedo's azith vs pen study -- which seems incredible given the efficacy of both pen and azith. Swedo even comments that they had expected azithromycin to be a control in her study and hadn't expected it to work as well as the penicillin. There are several studies on certain strains of strep being able to go intracellular (i.e, where penicillin can't reach). Kaplan wrote an excellent paper on the efficacy of macrolides on getting intracellular strep in 2005 http://www.journals.uchicago.edu/doi/pdf/10.1086/508773.

 

At the same time there are numerous papers on resistance by strep (GABHS) to macrolides. For example,

http://www.journals.uchicago.edu/doi/pdf/10.1086/432480

and

http://www.journals.uchicago.edu/doi/abs/10.1086/320745

 

So it is a bit of a hit/miss. If penicillin can reach the strep, then it remains the preferred bactericidal option; however, many doctors prefer Augmentin or Cephalosporins (e.g. Keflex) as these have higher clinical efficacy.

 

Theory of why IVIG, Plasmapheresis, Prednisone, Azithromycin and Penicillin all seem to work

 

The best research I've found comes from Kirvan and Cunningham (see http://www.pandasnetwork.org/CunninghamJNICaMKinase.pdf). Kirvan and Cunningham have isolated several anti-nerual antibodies that seem to be produced PANDAS children that interfere with neural tissue and cause faulty neuronal signalling. Note: these are NOT anti-streptolycin-O (ASO) or Anti-DNAse-B antibodies.

 

Kirvan and Cunningham isolated three anti-host antibodies that target a carbohydrate on the streptococcus cell wall. Unfortunately, this carbohydrate sequence is very similar to receptors on neural cells and so the antibody can bind with neural tissue and interfere with neuronal signalling.

 

The antibody is produced during a strep infection and remembered by a B-cell. When a subsequent strep infection comes along, the B-cell recreates the antibody and replicates it to go after the strep. Unfortunately, the faulty antibody binds with other cells other than just the strep. In most people, a T-cell regulator notices the faulty antibody and stops the faulty antibody from replicating. In PANDAS and Sydeham Chorea, the regulation doesn't seem to happen.

 

So, in some ways, PANDAS and Sydeham Chorea are thought to be due to a deficiency in T-cell regulation.

 

As therapy, plasmapherisis is thought to work by removing the antibody. Penicillin works by killing off the bacteria that causes the body to massively replicate the antibody. Azithromycin does something similar and seems to have anti-inflammatory and immunomodulating effects (i.e., slows the bacteria, slows the creation of lots of antibodies and helps to keep the blood brain barrier closed).

 

In the case of IVIG, the belief is that the T-regulator cells get reset and begin to suppress the faulty antibody. The exact mechanism for this is not understood. In addition, IVIG tends to have excellent anti-inflammatory effects and this may also have significant effect by closing the blood-brain barrier (if open) and reducing inflammation of the basal ganglia.

 

The biggest complaint about the theory is "how did the antibody cross the blood-brain barrier?" There are lots of theories on this as well. One is that the exotoxins from the strep are affecting the blood-brain barrirer http://www.neurology.org/cgi/content/abstract/54/7/1433.

 

Another holds that perhaps inflammation (from the strep infection or some other source) is keeping the blood brain barrier open. Strong anti-inflammatories (such as prednisone) and IVIG have been found to close the blood brain barrier in other diseases. It is possible that the anti-inflammatory effect and closing the blood brain barrier is why IVIG works for PANDAS kids - whereas Plasmapherisis removes the faulty antibody so an open BBB wouldn't matter. Stress (epinephrine), infection, inflammation can all cause openings in the blood brain barrier, but the exact mecahnism is not known for PANDAS.

 

 

Best regards,

 

Buster

[Buster]

What about Kurlan's June 2008 Pediatrics article?

 

I've gotten a bunch of questions regarding Kurlan's June 2008 article in Pediatrics that is titled: "Streptococcal Infection and Exacerbations of Childhood Tics and Obsessive-Compulsive Symptoms: A Prospective Blinded Cohort Study" and Singer's article in the same journal titled "Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections." http://pediatrics.aappublications.org/cgi/...ract/121/6/1198

 

These papers are very recent and even our pediatrician sent us links about them saying that "New research shows PANDAS doesn't exist." This is not what these papers show. I've probably never been so annoyed in my life.

 

First and foremost, I should compliment the authors on a very careful study. However, they basically blew it on their sample of children and seem to have selected Tourette's children with > 3 years of continuous tics with no exacerbations in OCD as their proported PANDAS group. So the science was probably good, but they weren't testing the hypothesis they intended to test.

 

Problems with the Kurlan and the Singer Studies

 

I think the paper is fundamentally flawed with 6 major issues.

1. 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.

   
    
   

2. The study did not indicate how many of the children had already hit puberty with the massive hormonal and immune changes that occur.

   
   

   Multiple studies indicate that progestrone and other hormones affect the T helper cell regulatory response. Kirvan and Swedo looked at sudden onset in pre-pubescent children and thus if this was not controlled, this brings even more question into whether the sample is valid.

   
    
   

3. 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 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.

   
   

4. The subjects exhibited no OCD behavioral changes and are different from Swedo's/Snider's subjects
   
   The 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.

   
   

5. 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.

   
    
   

6. 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. Did this suppress the OCD response?

   
   

I have numerous other issues including sampling theory problems, but 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 Singer's conclusions (or non-conclusions)-- about antibody interaction with neuronal tissue

 

So the good news is they tried to repeat Kirvan's 2006 work on cross-reactivity of an antibody with idiotype of GlcNAc. However, their sample set again, didn't have PANDAS kids (at least no episodic courses of OCD exacerbations), so they found that there wasn't cross-reactivity difference between their controls and their sample of proported PANDAS kids. 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.

 

 

Best regards,

 

Buster

[colleenrn]

I was wondering if anyone knows if the longer a person has strep, the more likely the strep is to be intracellular, therefore responding better to macrolides like Azithromycin.

[EAMom]

Colleen,

 

I believe the answer is "yes," those that carry strep long term ("strep carriers") tend to have intracellular strep. (Perhaps Buster can provide more details when he has a chance.)

 

Our younger (non-pandas) dd is (was?) an assymptomatic strep carrier. We also believe our PANDAS dd is (was?) a strep carrier (even though she had initial FEVER). Children that are strep carriers once year tend to be strep carriers in subsequent years, even if infection is cleared in between. It is also possible for someone to "carry strep" for many many months. One child in the Kaplan/Kurlan June 2008 pediatrics study had strep the entire 24 mo. of the study (no antibiotics were administered, perhaps on the faulty assumption that the carrier state is benign.)

 

Our dd (non-pandas) was cleared on 5 days of Azithromycin so that goes along with the theory that the strep was intracellular, thus responding to Azithormycin. She was not cleared on Augmentin, the first antibiotic she was on. My older dd's PANDAS finally went into remission on Azithromycin (4th antibiotic we were on) so that goes along with our intracellular/strep carrier theory as well.

 

Also, per Buster, there are certain strains of strep that are more likely to go intracellular (and be carried)...M3, M18. So, some of this depends on the person, and some of it depends on the strain of strep.

[EAMom]

edit--double post

[P_Mom]

EAMom,

Did your daughter continue to culture positive through the first 3 antibiotics before starting Zith?

Can you have intracellular strep and culture negative?

 

Thanks!!!!

 

Kelly

[EAMom]

Hi Kelly,

 

Good question. We did have PANDAS dd re-cultured in early May when her PANDAS symptoms were flaring up again. She on was amoxicillin at the time and the culture was NEGATIVE. (This was after Augmentin and during Amoxicillin, we hadn't tried the Cephalosporin yet.)

 

Our non-PANDAS dd also cultured NEGATIVE the day after she stopped Augmentin. (Normally I would not have re-cultured her so soon but we were at the pediatricians anyway.) However, when we re-cultured her again 2 weeks later, she was once again POSITIVE.

 

What I think happened is that the antibiotics suppressed the strep enough so that it was not culture-able...but it was still there. My M.D. sister-in-law confirmed that that was likely. A culture taken too soon after stopping antibiotics (or during antibiotics) is likely to result in a false negative.

 

I'm not sure if intracellular strep, not on antibiotics, is more likely to culture neg. however. ????

[P_Mom]

Thanks, EA Mom!

 

 

What I was trying to figure out is if by chance my son could have/had intracellular strep. (we have never done Zith.....so, the posts and intracellular strep make me a bit nervous....I really don't know why 'cause he is doing great. However, with this second episode my younger son has never quite reached 100%..... so close, but...

That is why I am wondering about intrecellular strep.)

 

The last time my sons were cultured was before prophylactic antibiotics...and it was negative. So, I guess the chances of intracellular strep are low..??

Also, wouldn't it be unlikely for my sons PANDAS to go into remission if intrecellular strep were present?

Could intracellular strep result in smoldering, very mild symptoms?

Were your daughters symptoms full blown until the Zith?

 

yikes...sorry so many questions!!

 

Makes sense about the antibiotics supressing the strep...I have heard of that, too.

 

Hope all stays well!!

 

Thanks for you help!

 

kelly

[Buster]

The last time my sons were cultured was before prophylactic antibiotics...and it was negative. So, I guess the chances of intracellular strep are low..??

 

Well, this is not really well understood. Kaplan did a great study on "failure rates" http://www.journals.uchicago.edu/doi/pdf/10.1086/320745 when he was comparing efficacy of different antibiotics.

 

What is extremely interesting in his study was on page 3 where there is a graph of the followup. Here he shows that the subjects were treated with azithromycin and clarithromycin. 10% had positive throat cultures at 13-19 days after treatment, 18% had positive throat culture at 28-39 days. His purpose in Figure 1 was to show that clarithromycin was effective at clearing strep -- but this also indicates that 5-10% of folks will have false negatives and will re-colonize with strep even if "negative" at 2 weeks.

 

I thought this was a good experiment and write up.

 

Buster

[pmoreno]

Hello Kelly,

I heard that amoxicillin is not really very effective. It may be that the Augmentin kept the culture negative, but when she switched to Amoxicillin, it was not able to keep the strep in check. Pat

 

 

 

Hi Kelly,

 

Good question. We did have PANDAS dd re-cultured in early May when her PANDAS symptoms were flaring up again. She on was amoxicillin at the time and the culture was NEGATIVE. (This was after Augmentin and during Amoxicillin, we hadn't tried the Cephalosporin yet.)

 

Our non-PANDAS dd also cultured NEGATIVE the day after she stopped Augmentin. (Normally I would not have re-cultured her so soon but we were at the pediatricians anyway.) However, when we re-cultured her again 2 weeks later, she was once again POSITIVE.

 

What I think happened is that the antibiotics suppressed the strep enough so that it was not culture-able...but it was still there. My M.D. sister-in-law confirmed that that was likely. A culture taken too soon after stopping antibiotics (or during antibiotics) is likely to result in a false negative.

 

I'm not sure if intracellular strep, not on antibiotics, is more likely to culture neg. however. ????

[Buster]

edit

[EAMom]

Pat,

 

PANDAS dd throat culture was NEGATIVE 4/28/08 (25 days after stopping Augmentin, still on Amoxicillin). I believe the (false) NEGATIVE 4/28/08 culture (PANDAS symptoms worsening) was b/c of the Amoxicillin since...

 

non-pandas (strep carrier) younger dd was already strep POSITIVE only 14 days after stopping Augmentin.

 

In other words, if the Amoxicillin wasn't affecting the culture results, and we were only looking at the effect of the Augmentin, then why would younger dd culture POSITIVE after only 14 days, yet PANDAS dd was still NEGATIVE after 25 days (with PANDAS symptoms worsening).

 

Does this make sense?

 

Dh calls younger non-pandas dd our "canary in a coal mine" since we can't trust cultures of PANDAS dd's cultures while she's on ongoing antibiotics.

 

Both girls had strep on Amoxicillin/Augmentin, just not enough to culture while on the meds (or too shortly thereafter). When younger dd cleared her strep (NEGATIVE 3 weeks after stopping 5 day course of Azithromycin) that was our clue that it would work on PANDAS dd. (It did.)

 

Younger dd tested cultured NEGATIVE again in August (just to be sure she stayed that way!)

 

EAmom

[pmoreno]

I wonder, though, if the negative culture 3 weeks following azithro couldn't have been coincidental - in other words - no exposure to strep at that time. And with the Augmentin - once they went off it and were no longer protected - they happened to be exposed to strep again and got it.

 

 

Pat,

 

PANDAS dd throat culture was NEGATIVE 4/28/08 (25 days after stopping Augmentin, still on Amoxicillin). I believe the (false) NEGATIVE 4/28/08 culture (PANDAS symptoms worsening) was b/c of the Amoxicillin since...

 

non-pandas (strep carrier) younger dd was already strep POSITIVE only 14 days after stopping Augmentin.

 

In other words, if the Amoxicillin wasn't affecting the culture results, and we were only looking at the effect of the Augmentin, then why would younger dd culture POSITIVE after only 14 days, yet PANDAS dd was still NEGATIVE after 25 days (with PANDAS symptoms worsening).

 

Does this make sense?

 

Dh calls younger non-pandas dd our "canary in a coal mine" since we can't trust cultures of PANDAS dd's cultures while she's on ongoing antibiotics.

 

Both girls had strep on Amoxicillin/Augmentin, just not enough to culture while on the meds (or too shortly thereafter). When younger dd cleared her strep (NEGATIVE 3 weeks after stopping 5 day course of Azithromycin) that was our clue that it would work on PANDAS dd. (It did.)

 

Younger dd tested cultured NEGATIVE again in August (just to be sure she stayed that way!)

 

EAmom

[P_Mom]

EA Mom,

I just had a thought while reading your last post.....

 

I noticed your younger daughter was culturing postive, while older daughter was culturing negative yet still having symptoms....until younger daughter was cleared of her carrier state after Zith.

 

Could it be at all possible, or am I misunderstanding this...but, could it be possible that older daughter was reacting (increasing symptoms) to mere exposure from younger daughters carrier strep? Could that possibly be why there was no improvement on the other antibiotics..because younger daughter still had strep and older daughter was continually exposed to it, hence the continued symptoms? I know that mere exposure to strep, even without contracting the actual illness and not being able to find any evidence of the exposure through any tests....this can cause dramatic PANDAS symptoms.

 

I guess this is what I am trying to ask:

 

Could the fact that your older daughter finally recovered while on Zith be due to the fact that it was then that younger daughter was cleared of her carrier state, thus ending older daughters exposure, which in turn would lead to a gradual remission of symptoms........ And not necessarily because of the Zith itself?

 

(just still trying to determine if we should try Zith)

[EAMom]

Could intracellular strep result in smoldering, very mild symptoms? --IMO yes.

 

dd got strep 1/23: symptoms *relatively* mild/moderate...tantrums, very subtle tics, stopped eating breakfast/snacks, increased anxiety, emotional lability;

1st tooth extraction 2/21 all symptoms worsened;

2nd tooth extraction 3/7 things got a lot worse, full blown Anorexia Nervosa and OCD, psychotic/suicidal, tics worsened. Parents terrified, frantically searching for qualified psychiatrist, long wait list to be seen at eating disorder clinic; dd drops from more than 15% of body weight in 2 week period (down to 42 pounds).

3rd week in March symptoms improved after hospitalization/Augmentin/lexapro/klonopin/re-feeding..."smoldering" PANDAS (still lots of ocd questions re weight/food, tics, overall behavior improved) for most of April. Gaining some weight.

end of April/May things getting bad again (serotonin syndrome w/lexapro further confuse matters!) Anorexia Nervosa returns in full-force when lexapro stopped (therefore prozac started at low dose). Losing a pound a week...Eating Disorder Clinic wants to re-hospitalize.

 

June 1 onward...improvement, then remission on Azithromycin. Eating now very normal. Weight and mood great. No tics. (Still on 10mg prozac, 250mg Az. daily.)

 

Were your daughters symptoms full blown until the Zith? ups and down...worse after tooth extractions (before we knew about strep/pandas)...suspect more strep was released into bloodstream with dental procedure. Bettter after Augmentin, worse again in May (although not quite as bad as 3rd week in 2nd/3rd week in March before hosp.).