My thoughts on PANDAS and related conditions

[Dr_Rosario_Trifiletti]

Dear parents,

 

Below please find a summary of my current thinking on the subject of PANDAS and related illness.

 

This is an outline of a paper I hope to submit for publication soon which summarizes our understanding at of the dawn of the '10 decade

 

This is somewhat dense. Any comments appreciated (especially any from Buster!)

 

 

 

 

Post-infectious Neuropsychopathy of Childhood

 

Basic problem:

Selective immunopathy to streptococcus (or less commonly other infectious agents) that incite an dysimmune process leading to a functional catecholaminergic neurotransmitter imbalance in basal ganglia circuits and perhaps other part of the brain, Resulting in some combination tics, OCD and affective symptoms

 

Classic (Swedo) presentation:

1. Age 3-11

2. Acute onset OCD and/or Tics, often remitting/recurring

3. Temporally associated with infection (if GABHS = PANDAS)

 

 

Variants (see my Pavone 2006 paper):

1. < 3yrs old at onset

2. > 11 yrs old at onset

3. Subacute or chronic temporal features

4. Atypical symptoms

5. Severe symptoms

a. Exorcist syndrome

6. PANDAS in children with other conditions

a. PDD-PANDAS

 

Immune subgroups:

 

Type 1 PANDAS – Overactive immune system

1. Markedly elevated ASLO, Anti-DNAase B and/or streptozyme

2. Intermittent culture positive for GABHS

3. (?) Immunocompetent on pneumococcal serotype testing

4. Anti-CaM2K positive in PANDAS range – possibly higher end

5. Immunoglobulin levels fall with effective strep treatment (?)

6. ASLO, Anti-DNAase B and streptozyme fall with effective strep treatment

 

 

Type 2 PANDAS – Underactive immune system

1. Non- or minimally elevated ASLO, Anti-DNAase B and/or streptozyme. May show serial changes (though feeble) with streptococcal infection

2. Can be culture positive for strep, don’t develop expected titer rise afterward

3. (?) Immunodeficient on pneumococcal serotype testing

4. Anti-CaM2K positive in PANDAS range – possibly lower end

5. Immunoglobulin levels don’t change much with effective treatment

6. ASLO, Anti-DNAase B and streptozyme fall with effective strep treatment

 

 

Type 1 PANDAS is easier for the medical community to digest since there is evidence of streptococcal infection, similar to Sydenham Chorea, etc.

 

Type 2 PANDAS is harder for the medical community to understand since there is little evidence of streptococcal infection, similar to Sydenham Chorea, etc.

 

Non-PANDAS

 

1. Not GABHS (i.e. non-GABHS PANDAS) GABHS=group A beta-hemolytic streptococcus

A. Alpha-hemolytic

B. Non- group A Beta-hemolytic

C. Gamma-hemolytic

 

2. Not strep at all (i.e. non-PANDAS PITANDS)

 

A. Lyme and related illnesses

1. Borrelia

2. Babesia

3. Erlichia

4. Other tick-bornes

B. Viruses

a. EBV

b. Others

 

3. Idiopathic antibiotic-responsive neuropsychiatric disorder (no cause identified but amazingly good response to antibiotics)

 

4. Not infectious at all

A. Medication-related

a. Tics with stimulant medication use

b. Others

B. Metabolic disease

a. Wilson’s disease

b. Others

C. Other known causes (very rare)

a. Structural brain lesions

 

5. Idiopathic

According to medical thinking circa 1985, this is the ONLY group.

For PANDAS non-believers, this is STILL the only group

 

 

INITIAL WORKUP

 

 

Basic workup in everybody with clinically suggestive picture should be:

 

Initial screen:

 

1. ASLO, Anti-DNAase B, streptozyme (GABHS marker enzymes = GABHS-ME)

2. Lyme titers (especially if from endemic region, suggestive symptoms, others infected)

 

If GABHS-ME panel positive, then diagnosis of probable Type 1 PANDAS made. This diagnosis is strengthened by longitudinal temporal correlation of clinical symptoms with repeated infection. If 3 or more such episodes (rarely fully documented) – definite Type 1 PANDAS

 

If GABHS-ME panel negative, then diagnosis is likely Type 2 PANDAS or non-PANDAS

To further workup in these patients:

1. Repeat GABHS-ME when convalescent ( to compare acute vs. convalescent titers)

2. Throat culture – helpful if positive; supports Type 2 PANDAS. Not helpful if negative.

3. If Prevnar has been received, anti-pneumococcal panel (14 serotypes). If panel abnormal, supports Type 2 PANDAS. Probably not helpful if Prevnar not received. If Prevnar received and normal, probably non-PANDAS.

4. Further investigation of immune status if anti-Prevnar deficient.

 

 

FURTHER PATIENT CLASSIFICATION

 

At this point, one should be able to classify patient with a working diagnosis:

A. PANDAS TYPE 1

B. PANDAS TYPE 2

C. NON-PANDAS

 

Treatment of all but most severe Type 1 or all Type 2 PANDAS , ANTIBIOTIC TREATMENT PHASE can begin at this point.

 

For NON-PANDAS patients, further “trigger search” should be attempted, but not too exhaustively, in most cases.

 

In SEVERE (i.e. Exorcist-syndrome) Type 1 PANDAS, consider proceeding directly to STRONG IMMUNOSUPPRESSION PROTOCOL. This will almost always be done in the hospital setting.

 

In Type 2 PANDAS patients, a PANDAS IMMUNOPATHY WORKUP should be done before considering STRONG IMMUNOSUPPRESSION PROTOCOL

 

 

All NON-PANDAS patients should be further investigated with the NON-PANDAS WORKUP . While this workup is in progress, and if there are no contraindications, treatment with ANTIBIOTIC PHASE should be considered.

 

If patient initially felt to have NON-PANDAS does in fact respond very well to antibiotics, patient should be labeled IDIOPATHIC ANTIBIOTIC-RESPONSIVE NEUROPSYCHIATRIC DISORDER.

 

 

 

So we now have 5 categories:

 

A. PANDAS TYPE 1 (HYPERIMMUNE TYPE)

B. PANDAS TYPE 2 (IMMUNODEFICIENT TYPE)

C. NEUROPSYCHIATRIC DISORDER WITH NON-STREPTOCOCCAL TRIGGER

D. IDIOPATHIC ANTIBIOTIC-RESPONSIVE NEUROPSYCHIATRIC DISORDER

E. IDIOPATHIC ANTIBIOTIC-RESISTANT NEUROPSYCHIATRIC DISORDER (AKA PLAIN OLD OCD AND/OR TICS)

 

 

 

 

BASICS OF TREATMENT - DIFFERENT, DEPENDING ON GROUP

 

PANDAS TYPE 1 (HYPER-IMMUNE)

 

Not very severe:

1. ACUTE ANTIBIOTIC PHASE (consider adjunctive steroids or Advil)

2. ANTIBIOTIC PROPHYLAXIS

3. Consider tonsillectomy

4. Adjunctive psychotherapy ( if indicated)

5. Consider adjunctive psychotropics

6. IF NECESSARY, IMMUNOSUPPRESSION

Steroid burst

IVIG

PLASMA EXCHANGE

 

Severe: 1. Antibiotics and psychotropics can be tried, but are usually ineffective at this stage, so consider proceeding quickly

A. IV CORTICOSTEROIDS

B. IVIG

C. PLASMA EXCHANGE

 

Strep STILL HAS TO BE AGGRESSSIVELY ELIMINATED once immune cool-down completed

 

PANDAS TYPE 2 (IMMUNODEFICIENT)

1. ACUTE ANTIBIOTIC PHASE (consider adjunctive Advil)

2. ANTIBIOTIC PROPHYLAXIS (with good probiotic regimen)

3. Consider tonsillectomy

4. Adjunctive psychotherapy (if indicated)

5. Consider adjunctive psychotropics

6. ATTEMPT TO BOOST IMMUNE SYSTEM –

a. CONSIDER IVIG CAUTIOUSLY.

b. KEFIR

c. AVOID CORTICOSTEROIDS, PEX

d. IF EVER AVAILABLE, STREP HYPER-IMMUNE GLOBULIN ideal here – A GOOD SOURCE WOULD BE PANDAS TYPE 1 KIDS!

 

 

 

 

 

 

IDIOPATHIC ANTIBIOTIC-RESPONSIVE NEUROPSYCHIATRIC SYNDROME

1. ACUTE ANTIBIOTIC PHASE (consider adjunctive Advil)

2. ANTIBIOTIC PROPHYLAXIS (with good probiotic regimen)

3. Consider tonsillectomy

4. Adjunctive psychotherapy (if indicated)

5. Consider adjunctive psychotropics

 

NON-PANDAS

1. WAIT AND WATCH – RE-EVAL IN 6-12 MOS

2. Adjunctive psychotherapy (if indicated)

3. Consider adjunctive psychotropics

 

SPECIAL SITUATIONS

1. SYDENHAM CHOREA CONCERNS

a. CaM2 kinase essential (needed to distinguish SC vs. PANDAS groups)

b. PEDIATRIC CARDIOLOGY EVALUATION

 

2. UNUSUALLY STRONG FAMILY HISTORY

a. CONSIDER CGH MICROARRAY

 

Hopefully this framework can guide workup and treatment protocols. I think the Cunningham and ant-pneumococcal tests may be the most specific we have, and the most helpful. Obviously, there is a lot to verify here.

 

Happy new year to all with a wish of hope and recovery in 2010,

 

Dr. Rosario Trifiletti ( Dr. T)

[P_Mom]

Wow...ThANKS! I had contacted you a week or so ago regarding my two sons about PANDAS. I am going to call to schedule an appointment soon. That is the fully the best write up I have seen by far. It is SO aparant to me all these kids DO NOT have the same issues, cause, deficiencies, etc. So nice to see the different types....it makes so much sense. I feel that is why these kids present differently, different immune systems and responses...hence...different reactions to therapies. It is NOT a catch all for these kids. Thank you for realizing and posting on that!!!!

 

You have no idea how much this is appreciated by all.

 

Like I said when I spoke to you......you are going to become A VERY busy man. Thankfully so!

 

Kelly

[dcmom]

Wow- you are an angel Dr T, and a true doctor!

 

Trying to figure out what subtype dd would be... If a child is very responsive to steroids, then I guess pandas type 1 would be it?

 

Must make appt

[momofgirls]

Dr T

Thank you so much for all your dedication to this illness and helping our kids! You really are a wonderful doctor and also very generous with your time. This write up is a first and addresses some of the many factors in pandas.

 

I wanted to throw something into the mix because I think our personal situation is pretty common in pandas.

 

Let's say a child's first episode is missed completely. A child gets strep throat, is taken into the pediatrician, rapid test is positive so abx are prescribed. However, the pandas symptoms in the young child is completely missed and written off as behavioral. Perhaps a mild eye blinking tic is seen for a few weeks and some mood issues. Parents and pediatrician write it off as a "phase" and the child naturally recovers on their own from the first episode. Then a year later the child is hit hard with the flu and has their first major pandas attack. By now throat culture is negative and titers have normalized.

I also wanted to mention the articles SFmom has posted a few times regarding kawasakis and its link to strep pyogenes. Kawasakis kids do not have raised titers yet have the strep toxins. The articles sfmom posted explained how these toxins can actually deplete the immune system so to speak and I wonder if that is why some of these kids have low iggs and are failing the pneum strep serotypes. Perhaps the kids in your pandas category 1 are easily diagnosed before this happens to their immune system and it is actually a phase in the disease as opposed to a category. Maybe the kids in category 1, if left untreated would ultimately fit in to the second group.

 

Difficult for me to articulate these thoughts so to put it simply, a lot of us parents are wondering how do we really know when the strep has been eradicated. If it has the ability to go intercellular, deplete the immune system which maybe inhibit the body's ability to mount a response to the titer...

I just think it is real hard to really know which category of pandas a child fits.

I hope this post makes sense to someone other than myself!

Thanks again Dr T

Kim (claire's mom)

[momofgirls]

Dr T

I also often wonder about the prevnar vaccine. The original manufacturer (I believe is wyeth) must have done efficacy studies on healthy vaccinated children right? Do we know how long it is effective?

Kim

Dr T

Thank you so much for all your dedication to this illness and helping our kids! You really are a wonderful doctor and also very generous with your time. This write up is a first and addresses some of the many factors in pandas.

 

I wanted to throw something into the mix because I think our personal situation is pretty common in pandas.

 

Let's say a child's first episode is missed completely. A child gets strep throat, is taken into the pediatrician, rapid test is positive so abx are prescribed. However, the pandas symptoms in the young child is completely missed and written off as behavioral. Perhaps a mild eye blinking tic is seen for a few weeks and some mood issues. Parents and pediatrician write it off as a "phase" and the child naturally recovers on their own from the first episode. Then a year later the child is hit hard with the flu and has their first major pandas attack. By now throat culture is negative and titers have normalized.

I also wanted to mention the articles SFmom has posted a few times regarding kawasakis and its link to strep pyogenes. Kawasakis kids do not have raised titers yet have the strep toxins. The articles sfmom posted explained how these toxins can actually deplete the immune system so to speak and I wonder if that is why some of these kids have low iggs and are failing the pneum strep serotypes. Perhaps the kids in your pandas category 1 are easily diagnosed before this happens to their immune system and it is actually a phase in the disease as opposed to a category. Maybe the kids in category 1, if left untreated would ultimately fit in to the second group.

 

Difficult for me to articulate these thoughts so to put it simply, a lot of us parents are wondering how do we really know when the strep has been eradicated. If it has the ability to go intercellular, deplete the immune system which maybe inhibit the body's ability to mount a response to the titer...

I just think it is real hard to really know which category of pandas a child fits.

I hope this post makes sense to someone other than myself!

Thanks again Dr T

Kim (claire's mom)

[Suzan]

Totally awesome Dr. T! This is super great!

 

Of course I am concentrating on Type 2 since that is where my girls seem to fall, but I see other types that will be helpful for people I know in my area currenlty.

 

I do have 2 questions though about the treatment plan

 

PANDAS TYPE 2 (IMMUNODEFICIENT)

 

3. Consider tonsillectomy - I am assuming this only be necessary if strep throat is the culprit. If strep is in other areas of the body or intracellular, this would not be helpful, correct? (is that a dumb question?)

 

5. Consider adjunctive psychotropics - this means like prozac or adhd meds? I have noticed that most parents have indicated that these meds make their kids worse so it has made me nervous to consider. Are these the meds you mean?

 

6. ATTEMPT TO BOOST IMMUNE SYSTEM – would supplements that boost the immune system be safe? Or do you have suggestions what you mean regarding boosting the immune system?

 

Thanks Dr. T!

 

Susan

[matis_mom]

Thank you for posting this! Our ds12 definitely fits into type 1... Have you noticed any connection with the way the initial strep presents? Our son had stomach/GI issues, and joint swelling/pain off and on, never the typical "strep throat" symptoms, and now my dd7 is starting with the same kinds of symptoms (she did test + and was treated twice in the last two months, but currently cultures are negative, however, she has stomach aches and hip pain, plus a rash on her face that looks like impetigo)

[melanie]

Thanks Dr T

 

Happy New Year

 

Melanie and Danny

[peglem]

Variant 5. a) Exorcist Syndrome

I know exactly what you mean!

 

My daughter is, I guess, a mixture- onset before age 3,

 

Would fit neatly into type2 PANDAS, except her CamK score was upper SC range. Where would a strep A carrier with neg ASO/AntiDnase titers fit?

[nevergiveup]

Dr. T,

 

I would also consider is there is a serotype that would be more prone to present with autoantibodies, like an off the charts ANA plus autoantibodies like highly elevate antidopamine one antibodies from Cunningham. Which category would produce high anti brain antibodies? Plus in terms of medical histories, which of these categories would be more likely to have autoimmune disease in immediate family members? Several of the kids on this forum have high ana's , and others do not. Some have mothers with ms or chrons, or hashimotos.

Also could age of child, and length of illness change the markers from an under active immune system at early age to later a more aggressive disease with autoimmune markers and highly elevated cam kinase? Or maybe this is clues to the tic borne ilness?

 

Thanks for posting it has been very helpful.

[thereishope]

Thank you for posting this! I may be reading this too early and I did not finish my second cup of coffee yet, so I will be rereading it later.

 

Unless, someone wants to be a doll and point out to me something about other triggers post the original strep trigger occurring.

 

Also, with the catagory over-reactive immune system, would those kids get classic strep symptoms? Can a child be asymptomatic with strep in both catagories?

 

Dr T, my question would be what your suggestion is to a parent who lives in a state where doctors are told to be "followers" of an anti-PANDAS neurologist. And how one can convince these docs to give long term abx and something stronger than amox. Besides the answer to go to another state. Even though that's the ideal, it is not possible for all and we need to nip this ongoing problem in the bud and get through to these peds. Realistically, there are parents who will continue to take their peds' word as THE word and not do their own research. It's easy to say go somewhere else, but that doesn't solve the existing problem in the local med community.

 

I'm also curious how many times do you think a child can improve with abx alone?My son has had 3 bad strep triggered exacerbations, but they all eventually ran their course with abx and time. I am left worried that next time, it won't be good enough. I'm just curious if there seems to be a cut off where abx respondent kids will reach their limit and need IVIG. He's been strep free since March 2009, but has had viruses since then.

[forjpj]

I think this applies to us too, not sure. I need to absorb this more, printed it out on paper so I can really study it. Thanks again Dr. T for all your hard work!!

 

 

 

 

Dr T

Thank you so much for all your dedication to this illness and helping our kids! You really are a wonderful doctor and also very generous with your time. This write up is a first and addresses some of the many factors in pandas.

 

I wanted to throw something into the mix because I think our personal situation is pretty common in pandas.

 

Let's say a child's first episode is missed completely. A child gets strep throat, is taken into the pediatrician, rapid test is positive so abx are prescribed. However, the pandas symptoms in the young child is completely missed and written off as behavioral. Perhaps a mild eye blinking tic is seen for a few weeks and some mood issues. Parents and pediatrician write it off as a "phase" and the child naturally recovers on their own from the first episode. Then a year later the child is hit hard with the flu and has their first major pandas attack. By now throat culture is negative and titers have normalized.

I also wanted to mention the articles SFmom has posted a few times regarding kawasakis and its link to strep pyogenes. Kawasakis kids do not have raised titers yet have the strep toxins. The articles sfmom posted explained how these toxins can actually deplete the immune system so to speak and I wonder if that is why some of these kids have low iggs and are failing the pneum strep serotypes. Perhaps the kids in your pandas category 1 are easily diagnosed before this happens to their immune system and it is actually a phase in the disease as opposed to a category. Maybe the kids in category 1, if left untreated would ultimately fit in to the second group.

 

Difficult for me to articulate these thoughts so to put it simply, a lot of us parents are wondering how do we really know when the strep has been eradicated. If it has the ability to go intercellular, deplete the immune system which maybe inhibit the body's ability to mount a response to the titer...

I just think it is real hard to really know which category of pandas a child fits.

I hope this post makes sense to someone other than myself!

Thanks again Dr T

Kim (claire's mom)

[Buster]

Happy New Year. What a great writeup and outline. I can't wait to read your new paper. Your paper with Pavone from 2006 was excellent and I love the reference to the Exorcist variant since I think many parents on this forum can relate to what seems like demonic possession.

 

The classification seems good and it might be worth a poll to see where we'd each put our kids. The treatments are really consistent with what many of us have tried.

 

What's been a bit unusual on the forum is that we've seen:

• kids who have ASO/Anti-DNAse B associated with exacerbation (i.e. Swedo classic - ASO/AntiDNAse-B )
  
• kids who seem to react to others in house who have culturable strep (i.e., seems like more an allergic reaction - elevated IgE or Eosinophils)
  
• kids who have non-pharyngeal strep A (e.g., vaginal or skin strep -- no ASO but elevated Anti-DNAse B )
  
• kids who seem to react to non-strep triggers (e.g., viruses, other bacterial infections, ...)
  

In addition, we seem to have two camps of those with primarily tics and those with primarily OCD.

 

All seem to respond to antibiotics or short term prednisone bursts. The exacerbations seem to last 4-6 weeks (i.e., an episode) but if another trigger comes in, they last longer...

 

My wife and I wonder if perhaps this is really a blood-brain barrier problem and all the variants are really just different manifestations of how the BBB gets inflammed -- or how antibodies cross the BBB.

 

It sure seems like the antibodies that are causing CaM Kinase II activation are in the blood stream for some time. Some trigger then opens the BBB and symptoms emerge. I appreciate this is still not proven, but it sure seems to explain things.

 

One of the other symptoms we've seen (don't know if you've seen it) was elevated monocyte counts and elevated CD4/CD8 ratios. This made us wonder if perhaps the immune system is just confused about whether the bacteria is extracellular or intracellular and choosing the wrong type to attack. This would have the same effect of not being able to clear an infection. This seems to us to explain the carrier state, the folks with low IgG, and those with CD4/CD8 imbalance with no ASO rise. Those with carriage aren't clearing the colonization leaving what is essentially a low-grade infection. Those with low IgG aren't clearing the infection leaving a low-grade infection. Those with elevated CD4/CD8 ratios but have an intracellular strain of strep wouldn't clear the infection and wouldn't have the elevated ASO/AntiDNAse B. We wonder if this is the common theme. None of this, of course, changes your recommendations, but it's something we've been wondering if others have seen.

 

I love the "Idiopathic antibiotic-responsive neuropsychiatric disorder" -- and even if that was a "separate syndrome" it sure seems a ridiculously good risk/benefit argument. If it cures kids, try it. If it doesn't, then move on to other stuff. It sure seems less risky that these anti-psych drugs that seem easier to get than a 30 day supply of antibiotics.

 

Anyway, I share the enthusiasm of others on the forum about your outline, post and advice.

 

Best regards and thank you for the post,

 

Buster

[memom]

Nice outline. What I most appreciate is the idea of a somewhat standardized approach to diagnosis and a somewhat standardized treatment strategy. Since I happened upon our journey, it has been somewhat a hit or miss strategy. Algorithms are helpful for both parents and care providers who though want to help, have no clue on how to proceed. Since the few of you who have dealt with Pandas treatment in any significant amount are often far distances from the children suffering, the beginning work up and early treatment strategies could be begun by non experts (Pediatricians for example). If not full recovery by end of steriod burst, abx, CBT and or psych meds, then go to an expert about need for IVIG/PEX. Keep up the good work. So many families are struggling and are despirate to get their kids back.

 

Ellie

[dut]

Hello

 

I also feel that, certainly for our dd, exacerbations follow opening of/lowering of integrity of the BBB. Strep triggers the inappropriate immune response and then other pro-inflammatory events open up the BBB. That's how, I believe, she could have a high middle range CaMK when out of exacerbation. Then, along comes a flu-like illness, BBB integrity lowers and the nasties get through.