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Friday, 27 November 2015

Inflammatory Response to GAS (Group A Strep) and Dysmaturational Syndrome (Tourette’s Syndrome with Autism “Recovery” by 6 Years Old)



Michele Zappella was Head of the Department of Child Neuropsychiatry
 at Siena Hospital from 1973 to 2006


Today’s post is the one I mentioned some time ago about odd behavioral reactions to Group A Streptococcus.  It does veer off to Italy and Tourette’s Syndrome and the interesting sounding Dysmaturational Syndrome, which probably accounts for many of those autism “recovery” stories that are used to support some pretty odd therapies.

Several readers of this blog have noticed that exposure to Group A Streptococcus causes their child’s autism to worsen.  Quotes range from facial grimacing, to raving like a lunatic.

Much has been written about the conditions PANDAS and PANS.  The proposed mechanism behind PANDAS/PANS is highly disputed, with some strong evidence showing it not to be valid.

What is clear is that in some people, following a strep infection, they change overnight from completely normal to something quite different.  This is the PANDAS/PANS phenomenon.

In people with autism, it is possible that a different mechanism is in play, rather similar to the allergy induced behavioral change that has been discussed in depth in this blog and that is triggered by mast cell degranulation.

Parents naturally assume that if their child has autism and strep infections make it worse, that they must have PANDAS/PANS.  Maybe they do, but there is another completely different explanation.


TICS, OCD and Stereotypy

There are only a limited number of behavioral responses a human can make, whereas there seem to be an endless list of possible biological or genetic dysfunctions.  The end result is that entirely different dysfunctions can lead to apparently similar behaviours and a lot of confusion and misdiagnoses.

In autism, Obsessive Compulsive Disorder (OCD) and Tourette’s Syndrome common features are repetitive behaviors, physical tics and stereotypy. These three disorders are diagnosed solely based on observation, rather than any biological testing.

The underlying biological causes for these behaviors are not understood and there are likely many different causes, some overlapping, between the three observational diagnoses.

We can also work backwards from a therapeutic perspective and see what therapies work in each condition.  One well documented compulsive behavior is trichotillomania, which is when people compulsively pull out their own hair.

Many people with this type of OCD find near complete relief from the same therapy that benefits people with autism and stereotypy.  Both groups respond to the antioxidant NAC and their compulsive behaviors abate.

I recently noted that some people with trichotillomania find Inositol also makes these compulsive behaviors abate.  A very small trial showed that Inositol did not help autism.

I think it is fair to say that there is some overlap between what is causing stereotypy and what is causing some OCD.

When it comes to tics, there seems to be an endless list of causes.  Numerous conditions are known to cause foot flapping and restless leg syndrome.

Breath holding is a common problem in Rett Syndrome, it occurs in classic autism, but it is also seen as a tic disorder.

Most people with OCD, Tourette’s and tic disorders do not have autism.  However, some very young children with Tourette’s and apparent autism, actually may have something termed “Dysmaturational Syndrome”.

Dysmaturational syndrome was identified and documented by Michele Zappella, an Italian doctor interested in autism and Tourette’s syndrome.

He identified a sizable subgroup of autism in very young children that was comorbid with the Tourette’s Syndrome tic disorder.  The unusual thing is that by the age of six, these children had “grown out” of their autism entirely.

Zappella’s study in 2010 suggests that his Dysmaturational syndrome applies to about 6% of early childhood autism.  In effect, he is saying that 6% of the children diagnosed before 5 years old with autism, fit this Dysmaturational syndrome and “recover” to have normal IQ, no seizures, and no signs of autism.  The tics though do not go away.


Early-onset Tourette syndrome with reversible autistic behaviour: A dysmaturational syndrome. European Child and Adolescent Psychiatry



ABSTRACT
Early-onset Tourette syndrome comorbid with reversible autistic behaviour is described in twelve young males. After a normal gestation, delivery and first-year development, regression set in between the age of one and two with loss of various abilities and the emergence of autistic behaviour. At this time, or slightly later, they showed multiple motor and vocal tics, simple and complex: the latter could also be traced to most of their parents. Following an intervention based on intense cuddling, motor activation and paedagogic guidance, these children's abilities rapidly improved, reaching at follow-up a normal or borderline intellectual functioning and with the disappearance of their initial autistic behaviour. At follow-up tics were present in all, usually with the features of a full-blown Tourette syndrome, often comorbid with ADHD, and in some cases with OCD.


Autistic regression with and without EEG abnormalities followed by favourable outcome.


Abstract


OBJECTIVES:

To explore the relationship between autistic regression (AR) with and without EEG abnormalities and favourable outcome.

METHODS:

Follow up data on children with favourable outcome in a series of 534 cases aged below 5 years and diagnosed as ASD.

RESULTS:

Cases with regression were 167 (31.8%), usually with persistent ASD, intellectual disabilities and EEG abnormalities. Thirty nine children (7.3%) went off autism and recovered entirely their intellectual and social abilities. Few of them included examples of pharmacologically treated Landau and Kleffner syndrome and other similar complex cases with abnormal EEG. The majority was represented by 36 (6.7%) children, mostly males, with a dysmaturational syndrome: their development was initially normal up to 18 months when an autistic regression occurred accompanied by the appearance of motor and vocal tics. Relational therapies were followed by rapid improvement. By 6 years all children had lost features of ASD and their I.Q. was in most cases between 90 and 110. Convulsions were absent and EEG was normal in all cases except one. In a few of them recovery was spontaneous. Seventeen children were followed after 5 years 6 months: 12 (70%) had ADHD, 10 (56%) persistent tics. Tics were often present in parents and relatives, ASD absent, suggesting a genetic background different from cases with persistent ASD. With one exception all "off autism" children had a previous autistic regression.


Back to Group A Strep

For those of you not familiar with PANDAS/PANS.  The term ‘PANDAS’ is short for ‘Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus’.  A child can be diagnosed with PANDAS when Obsessive Compulsive Disorder (OCD) or tic symptoms suddenly appear for the first time, or the symptoms suddenly get much worse, and the symptoms occur during or after a strep infection in the child.








Faced with a pediatric patient demonstrating the abrupt onset or exacerbation of psychiatric and physical symptoms, clinicians should consider PANS in their differential diagnosis.



Even though Dr Swedo, the leading researcher in the field, says that PANDAS/PANS is not autism, many parents of children with autism think they do have PANDAS/PANS.  This is likely because they have noticed that a strep infection makes their kind of autism worse.

All I can say is that there are very good reasons why strep infections can make autism worse and this has nothing to do with the autoantibodies that are the disputed cause of PANDAS/PANS.



Response to Group A Strep

Your immune system has two levels of defense:-

·        The innate immune system

·        The adaptive immune system


When you have a strep infection both systems respond.  Both of these responses could cause problems for people with autism.  The response from the innate immune system should continue only as long as the bacteria is present, while the response from the adaptive immune system may in some cases continue long after the bacteria is gone.


Innate Immune Response

It is well known that GAS is followed by a robust inflammatory response.

As you can see from the figure below, the inflammatory response results in a wave of pro-inflammatory cytokines including the “arch enemy” of autism, IL-6.

This surge in IL-6 will likely cause a sub-set of those with autism and an over activated immune system (activated microglia and so the “immunostat” is set to high) to go crazy.  This is the same IL-6 surge triggered by mast cell degranulation and the Il-6 surge used to signal milk teeth roots to dissolve.




Infections caused by group A Streptococcus (GAS) are characterized by robust inflammatory responses and can rapidly lead to life-threatening disease manifestations. However, host mechanisms that respond to GAS, which may influence disease pathology, are understudied.










Figure 1. Cellular receptors and signalling pathways involved in GAS recognition and inflammatory mediator release.

Inflammatory mediators are released from multiple leukocyte types during GAS infection; including PMNs, monocytes, macrophages, and dendritic cells . GAS and GAS-derived LTA, SLO, and soluble M1 protein (sM1), activate cellular responses to infection . Receptors involved in recognition of GAS include TLRs, TREM-1, complement receptors (CR), immunoglobulin receptors (FcR), Mac-1, and NLRP3 . Ligand binding to these receptors leads to downstream signalling via MyD88, HIF-1α, STING, IFR3, IRF5, and TBK1 . Recognition of GAS triggers release of interleukins, TNF-α, IFN-β, HBP, resistin, and LL-37 .




The Adaptive Immune Response:

Streptococcal Infection Causing Rheumatic Fever


Acute rheumatic fever (ARF) may occur following an infection of the throat by the bacteria Streptococcus pyogenes. If it is untreated ARF occurs in up to three percent of people.

Acute rheumatic fever (ARF) is not caused by the strep bacteria, but to aberrant immunological reactions to Group A streptococcal antigens.  The underlying mechanism is believed to involve the production of antibodies against a person's own tissues.

ARF, is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a throat infection. Signs and symptoms include fever, multiple painful joints, and involuntary muscle movements.
It would appear that in some children, following a strep infection, they develop tics.  These involuntary muscle movements are a symptom of acute rheumatic fever (ARF).  So rather than calling it by a new name PANDAS, perhaps better just to use the old name?



Strep infections PANDAS, OCD and Tourette’s

There is quite a lot of research on this subject, but much is contradictory. The idea put forward by researchers like Swedo is that elevated streptococcal antibodies causes PANDAS, but other researchers appear to have disproved this.

So you can make what you will of the research.

What is undisputed is that a strep throat can lead to acute rheumatic fever, which can affect the brain and cause involuntary muscle movements (tics) amongst other things.



Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A β-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and α-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood–brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.




ABSTRACT

Background: An autoimmune-mediated mechanism has been proposed for both pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and Tourette syndrome (TS). Confirmatory evidence has, in part, been based on controversial findings of autoantibodies in the sera of children with these disorders.

Objective: To compare antineuronal antibody profiles in subjects with TS and PANDAS to age-matched controls.

Methods: Sera were obtained from 48 children with PANDAS, 46 with TS, and 43 age-matched controls. Serum autoantibodies were measured by use of ELISA and Western immunoblotting against a variety of epitopes, including human postmortem caudate, putamen, and prefrontal cortex (Brodmann area 10). Immunoreactivity was also measured against commercially available α- and γ-enolase, aldolase C, and pyruvate kinase M1. Several assays were repeated after preabsorption of sera with M6 strain streptococci.

Results: Median ELISA optical density readings were similar among the groups. Western blot analyses showed complex staining patterns with no differences in any tissue region based on the number of bands, reactivity peaks at molecular weights 98, 60, 45, and 40 kDa, or total area under ScanPack (Biometra, Gottingen, Germany)–derived peaks. Immunoreactivity against four putative pathologic antigens did not differentiate the clinical groups. Repeat immunoblotting after serum preabsorption with streptococci showed no loss of reactivity. ELISA values exceeding a specified cutoff did not predict changes in binding to either brain epitopes or commercial antigens.

Conclusions: Results do not support the hypothesis that PANDAS and Tourette syndrome are secondary to antineuronal antibodies. Longitudinal studies are required to determine whether autoantibodies correlate with fluctuations in clinical activity







CONCLUSIONS. The failure of immune markers to correlate with clinical exacerbations in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections raises serious concerns about the viability of autoimmunity as a pathophysiological mechanism in this disorder.




Conclusions: The present study does not support a strong relationship between streptococcal infections and neuropsychiatric syndromes such as obsessive-compulsive disorder and Tourette syndrome. However, it is possible that a weak association (or a stronger association in a small susceptible subpopulation) was not detected due to nondifferential misclassification of exposure and limited statistical power. The data are consistent with previous reports of greater rates of diagnosis of Tourette syndrome or tics in white populations.






Our results demonstrate the potential pathogenic role of autoantibodies produced following exposure to GAS in the induction of behavioral and motor alterations, and support a causal role for autoantibodies in GAS-related neuropsychiatric disorders.





Background: Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder.
Methods: Twenty-one patients, ages 4–17 years (average 10.63±2.34 years, 13 males), with a clinical diagnosis of Tourette's syndrome (TS) or chronic tic disorder (CTD), were selected based on having clinic visits that coincided with a tic symptom exacerbation and a remission. Ratings of tic severity were assessed using the Yale Global Tic Severity Scale (YGTSS) and serum cytokine levels (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and granulocyte macrophage-colony stimulating factor [GM-CSF]) were measured using Luminex xMAP technology.
Results: During tic symptom exacerbation, patients had higher median serum TNF-α levels (z=−1.962, p=0.05), particularly those on antipsychotics (U=9.00, p=0.033). Increased IL-13 was also associated with antipsychotic use during exacerbation (U=4.00, p=0.043) despite being negatively correlated to tic severity scores (ρ=−0.599, p=018), whereas increased IL-5 was associated with antibiotic use (U=6.5, p=0.035). During tic symptom remission, increased serum IL-4 levels were associated with antipsychotic (U=6.00, p=0.047) and antibiotic (U=1.00, p=0.016) use, whereas increased IL-12p70 (U=4.00, p=0.037) was associated with antibiotic use.
Conclusions: These findings suggest a role for cytokine dysregulation in the pathogenesis of tic disorders. It also points toward the mechanistic involvement and potential diagnostic utility of cytokine monitoring, particularly TNF-α levels. Larger, systematic studies are necessary to further delineate the role of cytokines and medication influences on immunological profiling in tic disorders.






Objective: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a subtype of obsessive compulsive disorder (OCD) marked by an abrupt onset or exacerbation of neuropsychiatric symptoms. We aim to characterize the phenotypic presentation of youth with PANS.
Methods: Forty-three youth (ages 4–14 years) meeting criteria for PANS were assessed using self-report and clinician-administered measures, medical record reviews, comprehensive clinical evaluation, and laboratory measures.
Results: Youth with PANS presented with an early age of OCD onset (mean=7.84 years) and exhibited moderate to severe obsessive compulsive symptoms upon evaluation. All had comorbid anxiety and emotional lability, and scored well below normative means on all quality of life subscales. Youth with elevated streptococcal antibody titers trended toward having higher OCD severity, and presented more frequently with dilated pupils relative to youth without elevated titers. A cluster analysis of core PANS symptoms revealed three distinct symptom clusters that included core characteristic PANS symptoms, streptococcal-related symptoms, and cytokine-driven/physiological symptoms. Youth with PANS who had comorbid tics were more likely to exhibit a decline in school performance, visuomotor impairment, food restriction symptoms, and handwriting deterioration, and they reported lower quality of life relative to youth without tics.
Conclusions: The sudden, acute onset of neuropsychiatric symptoms, high frequency of comorbidities (i.e., anxiety, behavioral regression, depression, and suicidality), and poor quality of life capture the PANS subgroup as suddenly and severely impaired youth. Identifying clinical characteristics of youth with PANS will allow clinicians to diagnose and treat this subtype of OCD with a more strategized and effective approach.


Conclusion

If exposure to strep causes your child to “go crazy” I think this is a case of IL-6 triggering an autism flare-up.  Once the strep is treated, IL-6 levels will fall and the crazy behavior and raging will subside.  This should be a short term problem.  This is unrelated to PANDAS/PANS.  IL-6 autism flare-ups caused by an inflammatory response, as opposed to an allergic response, do respond remarkably well to a small dose of ibuprofen. Ibuprofen can even be used to prevent this type of flare-up.  If the IL-6 surge was triggered by mast cell degranulation, ibuprofen will not help.

If exposure to strep causes facial grimacing and other tics then the short term increase in IL-6 and TNF-α is exacerbating a, likely already existing, tic disorder.  If the tics do not go away after the strep has been treated, then it may be that strep autoantibodies are indeed the problem and you may have a variant of rheumatic fever, in which case you could look at the suggested PANDAS/PANS therapies.










14 comments:

  1. Thanks Peter. My limited understanding from the PANDAS community is that a lot of the studies have shown conflicting results for precisely the same types of reasons you mention -- i.e. wrong samples with conflicting diagnoses, etc.). I think many did believe that they should have had kept the rheumatic fever diagnosis. My child did not have tics except in kindergarten and 14 years of age along at 14 with other classic Sydenham's chorea -- some that resolved with traditional PANDAS therapies and is in both of your buckets. However, there is residual piano playing chorea (that is beyond the 2 years and lots of PANDAS therapies) and any recommendations would be welcome (he is on long term anti-inflammatories and is on antibiotics when flares), He was not diagnosed correctly for a long time and I think that affected his ability to heal faster given his age. Interesting that on both sides, grand-parents and great grandparents were bed-ridden with rheumatic fever for almost a year.

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    1. What anti-inflammatories do you use?

      I think sometimes tics may become "learned behaviors" meaning that at the start there was a biological cause, but later it just got added to his repertoire of behaviors. This is true with agression and self injury, once you start doing it, it is hard to stop. So the piano hands may be continuing for no good reason. It also good have become a comforting "stim", in which case you could try therapies like NAC and Inositol, both cheap and safe. Nac would be 600mg say three times a day and Inositol powder is 6g a day. If no effect after a few days then it is not going to help.

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    2. Thanks for your reply. My son is on naproxen (Aleve) and now on low dose aspirin on occasion. Have used Sytrinol but not given it a committed try. At one point, I would have said stim for the hands (he had many tics during his acute rheumatic feve/pandas phase, and part may be a stim -- but clearly when he closes his eyes and puts hands out for the chorea test, the fingers still move when trying not to). There is still some basal ganglia (or some part) dysfunction going with the hands.

      We were fortunate to go on a few rounds of high dose iv steroids and ivig which is the treatment for autoimmune encephalitis and for some sydenham's chorea and on the path to healing (but with residual and possibly lasting effects). We have tried nac and inositol but should give them a renewed try as other issues have been stripped away (inositol def didn't work early on). Btw, Sydenham's Chorea significant symptoms showed up 4-6 months later == so the big chorea movements don't necessarily come right after exposure.

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  2. Thanks for this post! I dont know if the reaction, tics, ocd, facial grimacing, is due to the increase of TNFalpha levels and IL6 triggering an autism flare-up , or are the strep autoantibodies. His sore throat always return, is like it never goes away,even if the strep test is negative.So the reaction i described is almost always there. I will try ibuprofen, Do you think that it helps? what dose is good? regards! Valentina

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    1. If it is IL-6, then ibuprofen should help. The regular dosage based on age/weight for pain relief is a good place to start.

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    2. and when should i notice the effect? 200 mg a day is correct? he is 9 with normal weight.valentina

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    3. Any effect should apparent within half an hour and last for about 4 hours. The ibuprofen will lower the inflammatory cytokines for a short period, There are longer acting NSAIDs.. All these drugs are really for short term use, due to side effects. But some people with autism in the US appear to be on these kinds of drugs for long periods.

      http://stopcallingitautism.org/content/pdf/SCIAMedicalTreatmentProtocolGeneralEdition.pdf

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    4. Thanks for the links, i think that sytrinol would be a better choice than ibuprofen, do you know other substitute of tangeretin? because i can´t find it.

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    5. Sytrinol is the only one I know. Ibuprofen is more potent, so if you try ibuprofen and it has no effect then you can forget about sytrinol. One researcher even suggests giving ibuprofen to one year olds showing signs of autism to halt the progression of the condition and avoid synaptic pruning "mistakes".

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    6. ok, i understand, if it works, which dose would you try for your son if he was 9, not just for ocasional use, there is a protocol 10 days on 20 days off but i dont know what dose and if it is effective. what would be better?thanks

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    7. I would try 200mg twice a day for a few days and see if it has an effect.

      People seem to use other NSAIDs that have a much longer half-life, like the reader above who is using Naproxen.

      All these drugs have some possible side effects, which is why they are not used long term, or they are combined with drugs to treat the side effects. The side effects relate to GI problems and often H2 anti-histamines are proton pump inhibitors are given.

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  3. Peter thanks for your blogs - thank you for sharing your findings - one more step in the right direction

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  4. Hi Peter, My 7 yrs old daughter with ASD has very high Total B cells (1406/cumm) and Total T cells(3531/cumm).CD19, CD4,CD3 all are very high in count while CD8, CD16, CD56 are low. Her cholesterol level is very high and calcium level is high though still within range ( she is dairy free)..... I'm really worried...does this mean leukemia? . I know its correlated with autism. ...Thanks for your reply

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    1. Hi Bee M, you need to go and talk with your doctor. You have serious concerns and they need to be addressed by a doctor.

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