“Autism treatments proposed by clinical studies and human genetics are complementary” & the NSAID Ponstan as a Novel Autism Therapy

Today’s post was not my idea at all, it was the author of one of the papers who has drawn my attention to the subject.

Genetic studies are complicated and are not the sort of thing I would have chosen to read, let alone write about, before starting this blog. 

The optimal time to initiate pharmacological 

intervention in Autism?

However, much of the complex subject matter has now already been covered, step by step, in earlier posts. Regular readers should not feel put off.

It is perhaps easier to think about ion channel dysfunctions, or channelopathies.  Some of the key genetic dysfunctions produce these channelopathies.  There are many posts in this blog about channelopathies, partly because many therapies already exist to treat them.

Then we have the complex signaling pathways which are often the subject of cancer research, but we have seen that certain ones like RAS and PTEN are key to conditions like some autism and some MR/ID.

So it is not a big leap therefore to consider the findings of a statistical reassessment of the existing genome-wide association studies (GWAS).  As is often the case in medical science, it is the acronyms/abbreviations, like GWAS, that make it look more complex than it really is.

If you only ever read one paper about the genetics of autism, I suggest you make it this one.

Fortunately, the conclusion from the genetic study really fits nicely with the clinical studies reviewed on this blog and even my own first-hand experience of investigating and treating my n=1 case of autism.

Knut, the Biometrician

It was Knut who left a brief comment on this blog and, after a little digging, I was very surprised how much a statistician/biometrician could figure out about autism, from re-analyzing the existing genome-wide association studies (GWAS).

I think the Simons Foundation could save themselves a decade or two by giving him a call.

The Research

For those wanting the science-lite version, there is a short article reviewing the research in lay terms:-

Biostatistics provides clues to understanding autism: an interview with Dr Knut M. Wittkowski

“Hence, modulation of ion channels in children at the age of about 12 months, when the first symptoms of autism can be detected, may prevent progression to the more severe end of the spectrum.” .

The actual research paper is here:-

You may find it heavy going and I have highlighted some key parts.

A novel computational biostatistics approach implies impaired dephosphorylationof growth factor receptors as associated with severity of autism

  

“Despite evidence for a likely involvement of de novo and environmental or epigenetic risk factors, including maternal antibodies or stress during pregnancy  and paternal age, we contend that coding variations contribute substantially to the heritability of ASD and can be successfully detected and assembled into connected pathways with GWAS—if the experimental design, the primary outcome, the statistical methods used, and the decision rules applied were better targeted toward the particulars of non-randomized studies of common diseases.”

The data comes from the Autism Genome Project (AGP), and there are two sets of data AGPI and AGPPII.

The third data set is for Childhood Absence Epilepsy (CAE)

What I would call Classic Autism, others call severe autism or autistic disorder; Knut calls it Strict Definition Autism (SDA).  HFA is high functioning autism, much of which is Asperger’s Syndrome.

“Study design We aimed at risk factors specific to strict definition autism (SDA) by comparing case subpopulations meeting the definition of SDA and milder cases with ASD (excluding SDA), for which we here use the term ‘highfunctioning autism’ (HFA). To reduce variance, we included only subjects of European ancestry genotyped on the more frequently used platform in either stage. In AGP II, we also excluded female cases because of confounding between chip platform and disease severity. The total number of subjects included (m: male/f: female) was 547/98 (SDA) and 358/68 (HFA) in AGP I and 375 (SDA) and 201 (HFA) in AGP II.

Overall, the results (see Supplementary Figure 1 for a Manhattan plot) are highly consistent with previously proposed aspects of the etiology of ASD. The clusters of genes implicated in both of the independent stages (Figure 2a/b) consistently overlap with our published CAE results (Figure 2c), confirming the involvement of ion channels (top right) and signaling downstream of RAS (bottom left), with two noticeable additional gene clusters in ASD. Both stages implicate several genes involved in deactivation of growth factor (GF) receptors (Figure 2a/b, top left) as ASD-specific risk factors and chloride (Cl − ) signaling, either through Ca2+ activated Cl− channels

Click to enlarge the figure 

A new term is PTPR (protein tyrosine phosphatases receptor), just to confuse us it is also called RPTP.

Receptor Protein Tyrosine Phosphatases in Nervous System Development

 

For example, the receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ) are expressed primarily in the nervous system and mediate cell adhesion and signaling events during development.

In an earlier post I highlighted the numerous dysfunctions in growth factors (GF) in autism.  Knut is highlighting here the effect of PTPR on growth factors.  Later it is suggested that this cascade of GF dysfunctions could be halted, pharmacologically if it was identified very early.  But, as Courchesne from UC San Diego noted, by the time people have been identified as having autism, around three years old, the accelerated brain growth has already run its course.

You would need to intervene around one year old.

Broad evidence for involvement of PTPRs One of the most striking observations is the involvement of at least five PTPRs in ASD (Figure 2, 10 o’clock position). PTPRs (Table 1e) regulate GF signaling through reversible protein tyrosine dephosphorylation.72 PTPRT (90th/20th, 8.57) was implicated in ASD by a deletion73 (Table S2 AU018704) and a somatic mutation

It was my post pondering the reasons for the positive effect of potassium supplementation that drew Knut’s attention to this blog.  Now we move on to Knut’s ideas on potassium and chloride channels.

K+ and Cl− ion channels as drug targets

Aside from PTPRs (Figure 2, 10 o’clock) as a risk factor for protracted GF signaling, our results suggest a second functional cluster of genes, involved in Cl− transport and signaling, as specific to ASD (Table 1f). In AGP I, the CaCCs ANO4 and ANO7 scored 1st and 70th, respectively. In AGP II, the lysosome membrane H+ /Cl- exchange transporter CLCN7 scored 21st, followed by CAMK2A, which regulates ion channels, including anoctamins82 (55th), and LRRC7 (densin-180), which regulates CAMK2A83 (Figure 2a/b, 2 o’clock). The role of the anoctamins in pathophysiology is not well understood, except that CaCC activity in some neurons is predicted to be excitatory84 and to have a role in neuropathic pain or nerve regeneration. More recently, CaCCs have also been suggested as involved in ‘neurite (re)growth’. Finally, we compared the HFA and SDA cases as separate groups against all parental controls in the larger AGP I population. Overall, the level of significance is lower and the enrichment is less pronounced, especially for the SDA cases (Supplementary Figure 9), as expected when cases and some controls are related. For the HFA cases (Figure 4, and Supplementary Figure 8), however, a second anoctamin, ANO2, located on the other arm of chromosome 12, competes with ANO4 (Figure 1, left), for the most significant gene among the result. Hence, drugs targeting anoctamins might have broader benefits for the treatment of ASD than in preventing progression to more severe forms of autism. ANO2 and ANO6 are associated with panic disorder and major depressive disorder, respectively. ANO3, ANO4, ANO8 and ANO10, but not ANO1, are also expressed in neuronal tissue.86 As ‘druggable channels’, anoctamins ‘may be ideal pharmacological targets to control physiological function or to correct defects in diseases’.  Few drugs, however, target individual anoctamins or even exclusively CaCCs. Cl− channel blockers such as fenamates, for instance, may decrease neuronal excitability primarily by activating Ca2+-dependent outward rectifying K+ channels.

Here is a follow-up paper with consideration of the possible next steps.

Early Pharmacological Intervention in Autism: Wide-Locus GWAS Leading to Novel Treatment Options

Gene gene environment behavior development interaction at the core of autism:

Here, we combine a recent wide-locus approach with novel decision strategies fine-tuned to GWAS. With these methodological advances, mechanistically related clusters of genes and novel treatment options, including prevention of more severe forms of ASD, can now be suggested from studies of a few hundred narrowly defined cases only.

(Nonsyndromic) autism starts with largely unknown prenatal events (♂: age, ♀: virus/stress ...)

• Mutations in growth factor regulators (PTPRs) lead to neuronal overgrowth (brain sizes).

• Mutations in K+/Cl− channels cause Ca2+ mediated over excitation of neurons (“intense world”).

• Stressful environments (urbanization) contribute to epistatic interaction (increasing prevalence).

• This GGE interaction causes “migraine-like” experiences during the “stranger anxiety” period where children learn verbal/social skills, leading to behavioral maladaptation (“tune-out”).

• The lack of verbal/social stimuli causes “patches of disorganization” (Stoner 2014, NEJM) as a form of developmental maladaptation when underutilized brain areas are permanently “pruned”. The PTPRs point to a short window of opportunity (WoO) for pharmacological intervention:

• Treatment has to begin as early as possible, while neurons are still growing (12 months of age. Broad support for the proposed unifying etiology and the 2nd year of life as the WoO:

• Regression (“loss of language”) seen in some children >12 mos of age.

• “Patches of disorganization” in >2 yr old brains.

• Romanian orphans developed “quasi-autism” when placed into foster care at >24 mos of age. 

• Hearing impairment leading to intellectual disability when diagnosed >24 mos of age.

 A rational drug target: treating either of two epistatic risk factors suffices:

• Blocking growth factors (Gleevac, ...) is unacceptable in children merely at risk of ASD.

• Ion channel modulators have been used in small children for arthritis and seizures.

Here is a response to Knut’s first paper from a professor at the UCLA medical school who suggests the combination of the specific NSAID and bumetanide. 

The professor would better understand the mechanism of action of bumetanide in autism if he read Ben Ari’s research more thoroughly, or even this blog.

  

Autism treatments proposed byclinical studies and human genetics are complementary

  

The article by Wittkowski et al.¹ reports results of human genetic studies that suggest that a nonsteroidal anti-inflammatory drug (NSAID) given for a few months from the time of the first symptoms might help some children who are at risk of developing more severe forms of atrial septal defect.

While the authors mention the recent article by Lemonnier et al.,² which reported that a clinical study of the diuretic Bumetanide was partially effective in children with milder forms of autism, they seem to have overlooked that these two treatments may well be complementary, leading to sequential interventions, each targeting specific risks related to well-defined stages in the development of brain and social interactions.

Since abnormal brain development in autistic disorder goes through different stages from infancy to childhood, targeting different developmental stages with different treatment interventions may well be necessary to foster continued normalization of brain growth.

Bumetanide is known to block inward chloride transporters, yet the relation of this mechanism to the etiology of autism is unknown. Wittkowski et al. identified mutations in calcium-activated (outward) chloride channels as associated with autistic disorder, suggesting loss-of-function mutations in anoctamins as one of the risk factors for autism. This provides a testable hypothesis for the mechanism by which Bumetanide alleviates symptoms of autism. For example, mouse models could test whether Bumetanide ameliorates a stress-induced phenotype caused by a knockout/down in ANO2 and/or ANO4.

A second cluster of genes identified receptor protein tyrosine phosphatases, which downregulate growth factors. These findings support the notion that successful treatment should start as early as possible,³ while neuronal development still takes place.

The rationale for combining these two treatments rests on the fact that Bumetanide is contraindicated in infancy because it is known to interfere with neuronal development when used long term. In contrast, the NSAID proposed in the second study has been given for decades to children with juvenile idiopathic arthritis from 6 months of age on, with no adverse effects on brain development. It is known to modulate chloride channels (see above) as well as potassium channels.⁴

In conclusion, I wish to extend their hypothesis based on the synergy of the two treatment approaches: (1) early treatment with NSAID can reduce early maladaptive behaviors that cause abnormal pruning of neurons in the cortical areas; (2) these children could subsequently benefit from Bumetanide, which would compensate for the primary ion channel defect, but could not reverse the secondary effect of abnormal pruning.

This hypothesis allows for a novel two-way interaction between behavior and molecular events. Traditionally, one assumes that molecular events determine behavior. The new hypothesis, based on human genetics, also allows for symptoms (such as the absence of social interactions, delayed speech onset and language development) during certain sensitive periods to change molecular events (pruning of neurons in areas required for normal development).

Therapeutic implications from the genetic analysis

Some of the therapies that Knut is proposing, based on the genetic analysis, have already been reviewed in this blog.  Some have not.  A few therapeutic ideas in this blog actually target genes Knut has identified, but not highlighted a therapy.

I will just review the drugs and genes that the above study highlights.

Benzodiazepines

Low dose clonazepam fits in this category.  We have the work of Professor Catterall to support its use.  At higher doses, benzodiazepines have different effects but use is associated with various troubling side effects.

Bumetanide

Bumetanide is at the core of my suggested therapy for classic autism or what Knut calls SDA (strict definition autism).  We have Ben-Ari to thank for this

Fenamates (ANO 2/4/7 & KCNMA1)

Here Knut is trying to target the ion channels expressed by the genes ANO 2/4/7 & KCNMA1. 

·        ANO 2/4/7 are calcium activated chloride channels. (CACCs)

·        KCNMA1 is a calcium activated potassium channel.  KCNMA1 encodes the ion channel K_Ca1.1, otherwise known as BK (big potassium).  This was the subject of post that I never got round to publishing.

  

Fenamates are an important group of clinically used non-steroidal anti-inflammatory drugs (NSAIDs), but they have other effects beyond being anti-inflammatory.  They act as CaCC inhibitors and also stimulate BKCa channel activity.

  

Fenamates stimulate BKCachannel osteoblast-like MG-63 cells activity in the human.

 “The fenamates can stimulate BKCa channel activity in a manner that seems to be independent of the action of these drugs on the prostaglandin pathway”

Molecular and functional significance of Ca2+-activated Cl− channels in pulmonary arterial smooth muscle

“Of this “first generation” of CaCC inhibitors, NFA (a fenamate called niflumic acid)  is the most potent blocker of these channels and the compound most frequently used to investigate the physiological role of CaCCs”

Choice of Fenamate

There are several fenamate-type NSAIDs, but one is a very well used generic drug, Mefenamic acid known as Ponstan, Ponalar, Ponstyl, Ponstel and other generic names.  It is even available as a syrup for children.

 It is not available in all countries.

Gabapentin

Gabapentin is used primarily to treat seizures and neuropathic pain. It is also commonly prescribed for many off-label uses, such as treatment of anxiety disorders, insomnia, and bipolar disorder.

Some people with autism are prescribed Gabapentin.  Some people suffer side effects and others do not.

If you have a dysfunction of voltage operated calcium channels, Gabapentin should help.

Memantine

This is all about modifying NMDA receptors.  Memantine is but one method.

http://epiphanyasd.blogspot.rs/2015/06/altered-homeostasis-in-autism-cl-k-ca2.html

Minocycline

Minocycline is an antibiotic with several little known extra properties.  In autism, we looked at its ability to reduce microglial activation and so improve autism.  A clinical trial showed that it did not help autism.

Minocycline also affects MMP-9.  MMP-9 is an enzyme found to be associated with numerous pathological processes, including cancer, immunologic and cardiovascular diseases.

High MMP-9 activity levels in fragile X syndrome are lowered by minocycline.

 “ The results of this study suggest that, in humans, activity levels of MMP-9 are lowered by minocycline and that, in some cases, changes in MMP-9 activity are positively associated with improvement based on clinical measures.”

So if you are treating a case of Fragile-X, or partial "Fragile-X-like" autism, better take note.

Rapamycin

Rapamycin and mTOR was the subject of the following post:

mTOR – Indirect inhibition, the Holy Grail for Life Extension and Perhaps Some Autism

Both too much and too little mTOR can occur in autism.

Conclusion

My conclusion is probably different to yours.

For me, it seems that all the pieces really are fitting together and so this blog on the cause and treatment of classic autism will eventually cover the current scientific knowledge, in its entirety.  No complex areas are off limits, because in the end they are not as complex as they seem, when you lift the veil of jargon and acronyms.

From the all-important therapeutic perspective, new insights from today’s post are:-

·        Those with a dysfunction of voltage operated calcium channels might want to give Gabapentin (Neurontin) a try.

·        The fenamate-type NSAID mefenamic acid,  widely known as Ponstan, really should be tested, either at home, or in a clinical trial.

This statistical analysis is based on “all autism”, so any one person would be highly unlikely to have all the mentioned dysfunctions.  These are the most common genetic dysfunctions and many can both hypo and hyper, as in the case of NMDA dysfunctions and indeed mTOR. 

In Knut’s chart, I would add a green line pointing to RAS and PTEN with the word Atorvastatin.  Baclofen would point to the growth factors.  Verapamil would point in multiple places.

The motto of University of Tübingen, where Knut originally comes from, is Attempto !  The Latin for "I dare".

This might be a useful motto for readers of this blog, and also a good tittle for a book on treating autism.

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.

PANDAS factsheet

Stanford PANS-PANDAS

Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies.

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.

Host Responses to Group A Streptococcus: Cell Death and Inflammation

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.

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection

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.

Serum auto antibodies do not differentiate PANDAS and Tourette syndrome from controls

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

Serial Immune Markers Do Not Correlate With Clinical Exacerbations in Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections

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.

Streptococcal infection, Tourette syndrome, and OCD

Is there a connection?

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.

Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats

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.

Cytokine Correlations in Youth with Tic 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.

Characterization of the Pediatric Acute-Onset Neuropsychiatric Syndrome Phenotype

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.