PANDAS research for your doubting doctor

[EAMom]

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?

....we wondered if PANDAS dd got re-infected from younger dd in early or mid April (before younger dd was cleared with Azithromycin).

 

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?

 

younger dd was on Azithromycin April 19-23 (so I assume clear after these dates, but we waited 3 weeks to do culture)

PANDAS dd had worsening symptoms end of April and all of May (when younger dd was clear). PANDAS dd was on Amoxicillin during this time (except for 10 days on Cefuroxime, mid-May)

 

Also, note that PANDAS dd wasn't completely better after hosp. in March, improved but still lots of OCD, tics, disordered eating...of course part of this incomplete may be b/c of "strep exposure" from younger dd.

After Azithromycin she was completely better.

[pmoreno]

You really know how to find answers - I'm impressed! My daughter just had IVIG with Dr. K last weekend and I'm still pretty nervous about what to expect. She did have the typical nausea/vomiting/fever/headache for about 5 hours. The night after the 2nd dose of IVIG. But what concerned me more was her worsening behavior. She had really strange behavior during her first episode of PANDAS last Nov./Dec/Jan/Feb/March. Then she got better in April, symptoms gone May, June, & July, Got it again in August, but not as bad - she had tics & some staring into space, unable to concentrate in school or to do ADL's, but not aggressive, overly emotional, no crying jags, no anger, very placid. After the IVIG - the first & second day so far she has had many outburts of anger, extreme sadness, crying, etc. It's hard to watch. I've been told this happens initially and then things change sometimes over a few weeks. We'll see. I don't know exactly what causes all the negative behavior all of a sudden - it would be nice to know - its a little scary right now because we don't know exactly what to expect - every child is different - our worst fear is that she might stay like this. What have you heard about this? Do you have any publications to refer to? Pat

 

 

 

 

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

 

Now as to why is any of this working at all... well, that's really what's been on my mind for the last 2 months. Plasma Exchange removes antibodies. IVIG puts in antibodies. Penicillin is bactericidal to fast growing bacteria. Azithromycin is bacteriostatic to slow growing bacteria. Why should all of these show some efficacy (anecdotally or in clinical trials)?

 

There was an excellent paper by Norrby-Teglund in 1996 entitled "Evidence for the presence of streptococcal-superantigen-neutralizing antibodies in normal polyspecific immunoglobulin G" http://iai.asm.org/cgi/reprint/64/12/5395 in which it is argued that IVIG works by neutralizing the super antigens SPeB and SPeC (at least) of streptococcal infection. However, it was noted that SPeA was not affected. So perhaps, the IVIG works by suppressing some of the super-antigens and preventing the cascading immune response and inflammatory response while the other residues get removed from the blood. Perhaps plasmapheresis is also removing most of these super-antigens.

 

I also thought that Kirvan's 2006 paper was extremely interesting in which she indicates that PANDAS kids create an antibody with an idiotype for GlcNAc (see http://www.csus.edu/bios/faculty/Kirvan/Ki...NI_article.pdf). This antibody is noted as cross-reacting with neuronal tissue. How it gets across the blood brian barrier is not known. Howeer, there was an excellent article about epinephrine affecting the blood-brain barrier, and a fascinating paper on exotoxins potentially affecting the blood barrier http://www.neurology.org/cgi/content/abstract/54/7/1433 . This seems consistent with the article above on super-antigens and perhaps the blood brian barrier closes with IVIG.

 

Another author puts forward the theory that IVIG adds an IgG antibody that attacks the residuals of strep http://iai.asm.org/cgi/content/full/66/5/2279 . However, if so, why would also plasmapheresis work? I have a theory on that...

 

Yet another theory (not proven)

 

I've been following up on a theory that most non-PANDAS kids suppress the antibody highlighted in Kirvan's paper.

 

This theory is that IgG is bringing in an anti-antibody (call it Fred) that attacks the GlcNAc idiotype antibody and prevents it from replicating. http://content.jci.org/articles/view/37099. Thus IVIG works because it adds the good regulatory antibody (Fred, the anti-antibody). Plasmapheresis works because it removes a bunch of the bad antibody. The exacerbations happen in PANDAS kids because the strep is active, the antibody replicates, attacks the strep (and neuronal tissue) and then declines in the blood stream as the strep is wiped out. I think azithromycin works by attacking any intracellular strep http://www.journals.uchicago.edu/doi/pdf/10.1086/508773 and also shifting the immune response (Th2 to Th1) thereby suppressing the replication of the antibody to the GlcNAc. I think this is also why prednisone seems to work (a strong immunosuppresant). Of course this is all just a theory.

 

As to why amoxicillin works, I think it just gets rid of the strep. After a period of time, the body stops replicating the antibody and the immune system settles down (we hope). In my dd case, I think we needed additional help to supress the immune response and reduce inflammation so azith worked better -- but without a clincial trial it is just anecdotal evidence.

 

 

Best regards,

 

Buster

[Buster]

After the IVIG - the first & second day so far she has had many outburts of anger, extreme sadness, crying, etc. It's hard to watch. I've been told this happens initially and then things change sometimes over a few weeks. We'll see. I don't know exactly what causes all the negative behavior all of a sudden - it would be nice to know - its a little scary right now because we don't know exactly what to expect - every child is different - our worst fear is that she might stay like this. What have you heard about this? Do you have any publications to refer to?

 

Hi Pat,

 

I haven't studied this area of IVIG symptoms and their progression. The best I've found so far is section 9 of http://www.emedicine.com/med/topic3546.htm where they outline all the really awful stuff that can follow with IVIG.

 

Hearing your dd's symptoms, you definitely should talk with your doctor/neurologist about what you are seeing. There is a rare form of aseptic meningitis that has been associated with IVIG http://www.annals.org/cgi/content/full/121/4/259 that can drive such extreme behavioral changes. It wasn't clear from your post whether the emotional lability was there before IVIG or seemed to be result.

 

Are you treating the headache and nausea with anything? I'll keep looking, ...

 

Best wishes and thoughts,

 

Buster

[P_Mom]

Pat,

Did dr.K go over "flipping of the pages?" Sounds like it could be that.

[pmoreno]

Hello Buster

 

Thanks for the very informative links. Actually the severe headache, vomiting, fever were short-lived. They lasted from midnight after the 2nd day of infusion until about 7 AM. After that she had a slight headache intermittently throughout that day, but no more nausea or fever. She was able to eat without a problem that day.

 

The emotional lability was quite severe that day. She did have some emotional lability with the first episode, particularly around Dec-Jan (worst months) during which time she had a lot of angry or extremely sad outbursts. I had not seen this repeated until this day after the IVIG, which was Sunday, Oct 5. On Monday morning she had some odd paranoid/suspicious behavior against her twin so I decided to keep her home from school. She spent most of the day rather quietly, drawing and making various art projects independently. She wanted to go to school in the afternoon so I did let her go for the last 2 hours. Unfortunately I had to work last night (I work the afternoon shift in the hospital on a part-time basis) so I missed seeing her behavior last night. My husband is not much help because if you ask him how she is (even on her worst and most bizarre days) he will say "fine - she's wonderful - perfect" - not sure if its denial or his inability to really assess her, or just not spending enough time watching her behavior. Although he did go along with me on this IVIG, he now tells me that he thinks I'm over the top with this, and wants me to send her back to a psychologist - he thinks maybe she just has a little low self-esteem & needs therapy. She never had low self-esteem in the first place, was just a little shy - not as outgoing in new situations like her twin. The therapy (after the PANDAS first appeared last Nov. was useless - she made no progress with it and it was sporadic -depending on when the therapist had time in her schedule - occasionally weekly or bi-weekly. All meds they put her on such as prozac, trazadone, and they even tried ativan (the worst! brought out all kinds of aggression & anxiety, hyperactivity within 30 minutes of taking it) nothing worked so I took her off all of it & tapered off with the therapy. She eventually improved over about 5 months. - was OK for 4 months - then back with a milder case which started in August. (No aggression or crying seen with this until the day after IVIG)

 

Her behavior this morning (Tuesday) was fairly subdued. She went through her morning ritual kind of zombie-like and would ask me with a flat affect for approval about how she dressed herself "Is this OK?" She did not seem emotional in any way and she went off to school - I'll have to find out how things went from the teacher. I know that yesterday when I pushed her a little to do some math when she was home from school, she got quite frustrated if things were difficult for her - she would rip up the paper and pound on the table and have a very angry expression. The thing that was a little different about her sleeping last night is that usually she always wakes up around 2AM and complains about being scared or wants me to sleep in the bed with her (since all this started I do sleep in the room, but usually in a separate bed) last night she got up to say that she was hot and when I asked her to just take off her pajama bottoms she responded that she was too tired and she laid back down. She seemed to go back to sleep fairly quickly which is unusual because she would frequently stay awake for at least an hour or more complaining that she couldn't sleep even when she was tired. So this is a good sign actually.

 

The hardest part about this is not knowing what is going to come next. Even though I've been told by the doctor and others what will probably happen, every child is an individual so you never really know. Since she had all the strange lability after the IVIG, I was almost afraid that we may have caused some damage to her brain and I wondered if she could think normally again. She had made comments about death & dying, end of the world, brain hurts, not working, can't think. It was pretty scary.

We haven't had more of that since Sunday so I'm hoping we're done with that, but again, you never know. It's a daily wait and see game.

 

I'm curious - have you considered IVIG with your child? I don't know if you've addressed that subject in earlier posts.

 

thanks again for your help, Pat

After the IVIG - the first & second day so far she has had many outburts of anger, extreme sadness, crying, etc. It's hard to watch. I've been told this happens initially and then things change sometimes over a few weeks. We'll see. I don't know exactly what causes all the negative behavior all of a sudden - it would be nice to know - its a little scary right now because we don't know exactly what to expect - every child is different - our worst fear is that she might stay like this. What have you heard about this? Do you have any publications to refer to?

 

Hi Pat,

 

I haven't studied this area of IVIG symptoms and their progression. The best I've found so far is section 9 of http://www.emedicine.com/med/topic3546.htm where they outline all the really awful stuff that can follow with IVIG.

 

Hearing your dd's symptoms, you definitely should talk with your doctor/neurologist about what you are seeing. There is a rare form of aseptic meningitis that has been associated with IVIG http://www.annals.org/cgi/content/full/121/4/259 that can drive such extreme behavioral changes. It wasn't clear from your post whether the emotional lability was there before IVIG or seemed to be result.

 

Are you treating the headache and nausea with anything? I'll keep looking, ...

 

Best wishes and thoughts,

 

Buster

[EAMom]

Hi Kelly,

What's that? (flipping the pages)

[P_Mom]

Hi!

 

 

As explained to me by dr. K, it is very common for PANDAS kids to go through "flipping of the pages" after IVIG. This is when they kind of rewind. (like flipping back pages of a book) You will see bursts of old PANDAS behaviors out of nowhere, this can last weeks.

 

Does that make sense? It is kinda hard to explain.

 

kelly

[Buster]

I'm curious - have you considered IVIG with your child? I don't know if you've addressed that subject in earlier posts.

 

Hi Pat,

 

No, our dd hasn't been through IVIG. We had a horrible feb-june and are now in a holding pattern and a bit concerned about changing any meds. It is such a relief from the storm that the past 3 months of calm is very healing for all of us. We're not thrilled with staying on antibiotics, but as long as her symptoms stay in remission, we'll keep on this routine..

 

I noticed that you mentioned that your dd has a twin. Are they identical twins?

 

Regards,

 

Buster

[pmoreno]

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.).

 

Now that she's stable on zith, have you thought about taking her off prozac to see if that isn't needed anymore? Seems like a shame to keep her on those kinds of meds if unnecessary. However, I can imagine that it would be a scary thing to do - just in case it would bring on the symptoms again. Pat

[pmoreno]

Buster,

you had asked me about Gaby's twin - they are not identical, although both had speech/language delays (Gaby's is more severe than Stefi's) Stefi can blend in pretty well - doesn't affect her school work - she excels and has no social issues. Gaby's delay though is more severe - affects her learning somewhat and makes it hard for her to seek out friends or be sought out - she's lucky that she has her sister to latch on to which broadens her own social circle. Since she sounds very immature when she is talking and says things in kind of an odd way, it makes it that much harder to sort out sometimes whether its panda silliness or just her developmental delay. Certainly the PANDAS has made an already difficult situation much worse - since its that much harder for her to make progress. Pat