Below is a list of excellent summaries and simply articulated medical analysis of how PANDAS came to be and the treatment of PANDAS. These postings and others can also be found on the on-line forum.
Best summary papers on PANDAS
- Swedo’s 1998 landmark paper.
- Feitosa de Olvieira summarizing research in 2007.
- Mell’s 2007 summary. (No free version available.)
Excellent summary of GABHS
- Cunningham wrote an outstanding paper summarizing the literature.
- Kaplan wrote a very good paper on intracellular strep.
Best summary papers on IVIG and Plasma Exhange
The best study that I’ve found about IVIG was Perlmutter’s 1999 Lancet report 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“ 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.
At the same time there are numerous papers on resistance by strep (GABHS) to macrolides. For example, “Persistent Macrolide Resistance among Group A Streptococci: The Lack of Accomplishment after 4 Decades” and “Macrolide Therapy of Group A Streptococcal Pharyngitis: 10 Days of Macrolide Therapy (Clarithromycin) Is More Effective in Streptococcal Eradication than 5 Days (Azithromycin).”
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.
HOW MACROLIDES Work
Principles of Pharmacology By Susan E. Farrell, M.D.
The short summary is that macrolides (such as azithromycin) affects the RNA’s ability to copy a protein. So this doesn’t technically kill the step, but rather stops it from replicating. Essentially macrolides rely on your immune system to find the tagged cells and wipe out those cells. Azithromycin and other macrolides hold the replication in check.
Now a thing to note is that it looks like azithromycin is stopping other rapidly replicating proteins too. So it is possible it isn’t the strep, but some other inhibited copy procedure. I’m still looking into whether azithromycin supresses the copying of certain antibodies. If anyone runs across something here, I’d sure be interested.
There are a lot of theories about what causes macrolide resistance, but the short summary is that the copying happens in resistant strains whereas it isn’t copied in non-resistant strains. They aren’t sure whether something keeps the macrolide from binding/interfering or whether the interference only works on certain protein strains.
Theory of why IVIG, Plasmapheresis, Prednisone, Azithromycin and Penicillin all seem to work
The best research I’ve found comes from Kirvan and Cunningham. 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.
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.
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.