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Showing posts with label Cunningham panel. Show all posts
Showing posts with label Cunningham panel. Show all posts

Friday, 3 February 2017

Autism + PANDAS/PANS ? - Basal ganglia circuitry mechanism underlying some repetitive behaviour



Pu-erh, a fermented tea from Yunnan province, China.  An mGluR5 inhibitor to remedy basal ganglia circuit abnormalities?


PANDAS/PANS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections/Pediatric Acute-onset Neuropsychiatric Syndrome) are recognized disorders in North America, but nowhere else.  If you take your child to Boston Children’s Hospital and ask about PANDAS they will know what you are talking about, try this at a children’s hospital in Europe and you will be directed to the local zoo.

For those new to the subject PANDAS/PANS cause sudden onset of tics and Obsessive Compulsive Disorder (OCD) accompanied by sudden cognitive regression.

I have written about PANDAS/PANS in previous posts.



I was surprised how well documented these syndromes are and that they are treated by some mainstream physicians.

The leading researcher in the field, Susan Swedo, makes a point that PANDAS/PANS is not autism.  I think that given the ever broadening definition of what counts as autism, it should be considered as a treatable sub-type of regressive autism.

To what extent can people with classic early onset autism also have PANDAS/PANS is an open question.

Can you have both?  Well based on my n=1 experience, it looks like you can.

After a brief infection just before Christmas, Monty aged 13 with classic early onset autism, suddenly developed Tourette’s-like loud verbal tics.  This behaviour had never occurred before and erupted overnight.  Even his brother declared that Monty now has Tourette’s and when would it go away.  This is the kind of behavior that many siblings, and I suppose some parents, would find extremely embarrassing.

Having a blog jam-packed with information on autism and related issues, I thought this was another problem that I should solve myself.  


On one of Harvard’s blogs it says regarding PANDAS/PANS symptoms:-


If your child suddenly shows any of these symptoms, call your doctor as soon as you can. Then contact the International OCD Foundation to find an OCD specialist in your area. Early treatment may prevent life-long mental illness.


Well none of that advice was an option for me, but I do think that early treatment is key in neurological disorders.  This also applies to people with autism developing seizures, where I think pre-treatment can lead to never developing seizures.

So I decided I would treat Monty as if he was having PANDAS flare-up.  This entails antibiotics and a short course of steroids.  The alternative was to do nothing and hope it just all went away.

Monty very rarely has antibiotics; his immune system seems very effective and quite possibly overly effective.

Having had a severe asthma attack several years ago we have prednisone on hand.  Oral prednisone is a cheap generic steroid drug that can be used as therapy for an asthma attack that does not respond to the usual inhaler treatment.  Long term use of prednisone has significant side effects and therapy longer than a few days requires you to taper the dose.

Having started the therapy, the loud random verbal tics continued for a few days and then faded away to zero over a couple of weeks.

Would this have happened without Amoxicillin and Prednisone?  I have no means of knowing, but I agree with Monty's big brother, we do not want to have Tourette’s/PANDAS/PANS in addition to autism.

Therapy started within two days of the tics.




If your child suddenly shows any of these symptoms, call your doctor as soon as you can. Then contact the International OCD Foundation to find an OCD specialist in your area. Early treatment may prevent life-long mental illness.


and an interesting comment on that same Harvard blog:-


“PANDAS and autism is very common. My son has both. When we can get his PANDAS under control, his autism is almost nonexistent. He has been diagnosed with PDD-NOS, which is atypical autism. PANDAS antibodies can also attack other areas of the brain if the infection gets out of control. People need to be aware of this. Untreated strep would result in my son regressing further into autism. If you have looked into Saving Sammy, you’ll notice he stopped responding, like many autistics, and that some of his repetitive behaviors could be considered similar to stimming.

With my son, he also gets repetitive movements and OCD, but ADHD symptoms, major defiance and extreme outbursts, threats of violence, etc.

More doctors of autistic kids need to screen them for PANDAS.”




PANDAS and Tourette’s Syndrome

There is a debate over whether PANDAS/PANDAS is just Tourette’s syndrome.

This is where you need to know the difference between the tic type of compulsive behavior and the repetitive behavior that is stimming/stereotypy.  They are not the same and do not respond to the same therapies.

In this blog I do refer to Tourette’s-type autism.  This is one type of autism that research shows can just fade away.



 



Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes.



Basal Ganglia and SAPAP3 gene

It is suggested that PANDAS is caused by group A beta-hemolytic streptococcal (GABHS) infections. The proposed link between infection and these disorders is that an initial autoimmune reaction to a GABHS infection produces antibodies that interfere with basal ganglia function.

Many other disorders that are often comorbid with autism are also linked to the basal ganglia, such as tics, stuttering, Tourette’s and even tardive dyskinesia caused by inappropriate treatment of autism with antipsychotics.



The following is a list of disorders that have been linked to the basal ganglia




Repetitive behaviors are common in several neuropsychiatric disorders, including obsessive-compulsive disorders and autism spectrum disorders. Guoping Feng and his team are investigating the pathological mechanisms underlying repetitive behaviors, with the aim of understanding the neural mechanisms and genetic factors that cause or contribute to autism.

The team’s previous studies in mice show that deletion of the SAPAP3 gene, which is implicated in obsessive-compulsive disorders, leads to repetitive behaviors1. The gene’s deletion leads to defective neuronal communications in the basal ganglia, a brain region known to be involved in voluntary movement.

There are two circuits within the basal ganglia, known as the direct and indirect pathways. Feng’s group generated transgenic mice in which SAPAP3 expression can be selectively turned on or off in these two pathways. They found that selective re-expression of SAPAP3 in the direct pathway of the basal ganglia completely reverses the repetitive behavior seen in mice lacking SAPAP3. This effect is not seen in the indirect pathway, indicating that the two pathways play different roles in the pathogenesis of repetitive behavior.

Feng’s group also studied SHANK3, which interacts with SAPAP3 protein in the basal ganglia. SHANK3 mutations are strongly linked to an autism spectrum disorder called Phelan-McDermid syndrome2. The researchers found that deletion of the SHANK3 gene in mice leads to repetitive behaviors similar to those seen in mice lacking SAPAP33. Importantly, the researchers discovered similar neuronal communication defects in the basal ganglia of SHANK3 and SAPAP3 mutant mice. Together, these results provide strong evidence for a common basal ganglia circuitry mechanism underlying repetitive behavior4





In the new study, Calakos’s team found that overactivity of a single type of receptor for neurotransmitters -- mGluR5, found in a brain region involved in compulsive behaviors -- was the major driver for the abnormal behaviors. When researchers gave Sapap3-lacking mice a chemical that blocks mGluR5, the grooming and anxiety behaviors abated.

“The reversibility of the symptoms was immediate -- on a minute time frame,” Calakos said. In contrast, the original study describing Sapap3-lacking mice found that antidepressants could help treat symptoms but on the time scale of weeks, as is typical with these drugs in patients.

Intriguingly, by taking normal laboratory mice and giving them a drug that boosted mGluR5 activity, Calakos’s team could instantaneously recreate the same excessive grooming and anxiety behaviors they saw in the Sapap3-lacking mice.

The researchers found that without a functioning Sapap3 protein, the mGluR5 receptor is always on. That, in turn, makes the brain regions involved in compulsion overactive. In particular, a group of neurons that give the “green light” for an action, like face-washing, is working overtime. (These same neurons can promote a habit, such as eating sweets, according to a study published by Calakos’s team earlier this year.)

Calakos said that mGluR5 should be considered for the treatment of compulsive behaviors. “But which people and which compulsive behaviors? We don’t know yet,” she added. 




Conclusions

These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.


Diagnostic Tests for PANDAS/PANS

Madeleine Cunningham, who used to work at the NIMH researching PANDAS with Susan Swedo, went off to set up a company to promote her “Cunningham Panel” of tests.

The Panel consists of 5 tests which measure circulating levels of autoantibodies directed against specific neuronal antigens in the patient including: Dopamine D1 Receptor (DRD1), Dopamine D2L Receptor (DRD2L), Lysoganglioside – GM1 and Tubulin. The 5th assay targets CaM Kinase II, a key enzyme involved in the up regulation of many neurotransmitters (dopamine, epinephrine, norepinephrine).




In the United States, 6.4 million children have received an ADHD diagnosis; 50% of all children with the disorder are diagnosed by age 6. Meanwhile, one million children have been diagnosed with Autism Spectrum Disorder ¹ and 500,000 children are living in the U.S. with OCD.
Identifying the underlying cause of these symptoms is imperative and answering the following question could change the course of treatment: ‘Could an infection be causing my child’s symptoms?’ Children may be misdiagnosed with a primary psychiatric disorder and receive psychotropic medications to treat the symptoms. But if the symptoms are due to an infection-triggered autoimmune response, the root cause of the behaviors must be addressed. Treatment must include eradicating the infection (if possible) and addressing the immune dysfunction.

                                                                                       

Treatments for PANDAS

Treatments for PANDAS are not yet well-studied as this condition has only recently been identified. Conventional treatments may include oral antibiotics to eradicate a Streptococcal infection, and prophylactic antibiotics to prevent recurrence. Oral prednisone is also used as a potent anti-inflammatory to relieve inflammation of the brain and prevent damage. Another therapy known as intravenous immunoglobulin (IVIG) is being investigated.

Intravenous glutathione, a potent antioxidant, can be used to protect the brain from being damaged from inflammation.








Time for Tea?

If you read the SAPAP3 research above, a totally different type of therapy might also improve OCD disorders stemming from the basal ganglia; you would try inhibiting metabotropic glutamate receptor 5 (mGluR5).

Given many people’s aversion to drugs, they might want to brew up some Pu-erh tea.  This type of tea is widely used for weight loss.  It should also reduce your cholesterol.





Glutamate is one of the major excitatory neurotransmitters of the CNS and is essential for numerous key neuronal functions. However, excess glutamate causes massive neuronal death and brain damage owing to excitotoxicity via the glutamate receptors. Metabotropic glutamate receptor 5 (mGluR5) is one of the glutamate receptors and represents a promising target for studying neuroprotective agents of potential application in neurodegenerative diseases. Pu-erh tea, a fermented tea, mainly produced in Yunnan province, China, has beneficial effects, including the accommodation of the CNS. In this study, pu-erh tea markedly decreased the transcription and translation of mGluR5 compared to those by black and green teas. Pu-erh tea also inhibited the expression of Homer, one of the synaptic scaffolding proteins binding to mGluR5. Pu-erh tea protected neural cells from necrosis via blocked Ca2+ influx and inhibited protein kinase C (PKC) activation induced by excess glutamate. Pu-erh tea relieved rat epilepsy induced by LiCl-pilocarpine in behavioural and physiological assays. Pu-erh tea also decreased the expression of mGluR5 in the hippocampus. These results show that the inhibition of mGluR5 plays a role in protecting neural cells from glutamate. The results also indicate that pu-erh tea contains biological compounds binding transcription factors and inhibiting the expression of mGluR5 and identify pu-erh tea as a novel natural neuroprotective agent.



Scientific studies report that consumption of pu-erh tea leaves significantly suppressed the expression of fatty acid synthase (FAS) in the livers of rats; gains in body weight, levels of triacylglycerol, and total cholesterol were also suppressed. The compositions of chemical components found to have been responsible for these effects (catechins, caffeine, and theanine) varied dramatically between pu-erh, black, oolong, and green teas.


Pu-erh tea supplementation suppresses fatty acid synthase expression in the rat liver through downregulating Akt and JNK signalings as demonstrated in human hepatoma HepG2 cells.

Fatty acid synthase (FAS) is a key enzyme of lipogenesis. Overexpression of FAS is dominant in cancer cells and proliferative tissues. The expression of FAS in the livers of rats fed pu-erh tea leaves was significantly suppressed. The gains in body weight, levels of triacylglycerol, and total cholesterol were also suppressed in the tea-treated rats. FAS expression in hepatoma HepG2 cells was suppressed by the extracts of pu-erh tea at both the protein and mRNA levels. FAS expression in HepG2 cells was strongly inhibited by PI3K inhibitor LY294002 and JNK inhibitor II and slightly inhibited by p38 inhibitor SB203580 and MEK inhibitor PD98059, separately. Based on these findings, we suggest that the suppression of FAS in the livers of rats fed pu-erh tea leaves may occur through downregulation of the PI3K/AKt and JNK signaling pathways. The major components of tea that have been demonstrated to be responsible for the antiobesity and hypolipidemic effects are catechins, caffeine, and theanine. The compositions of catechins, caffeine, and theanine varied dramatically in pu-erh, black, oolong, and green teas. The active principles and molecular mechanisms that exerted these biological effects in pu-erh tea deserve future exploration.



Conclusion

Sudden onset tic disorder associated with loss of cognitive function does seem to be a distinct dysfunction. Fortunately it is being well researched.

Whether antibodies, due to an infection, crossing the blood brain barrier and causing chronic inflammation in the basal ganglia is the cause remains unproven, but seems plausible.

Exactly what kinds of infections can trigger this response is an open question.  The people selling the PANDAS/PANS diagnostic test, the Cunningham panel, suggest that a wide range of both viral and bacterial infections can trigger this reaction.  As is often the case, there may be a case of some over diagnosis and very expensive use of IVIG therapy.  No test will be perfect because the area is highly subjective.

A recent paper reconfirmed the view that both the blood brain barrier and the intestinal barrier can be compromised in autism.





This suggests that all kinds of things might be crossing the blood brain barrier.

As we have seen, autism seems to be usually caused by multiple hits, rather than a single gene dysfunction, but we have also seen that in cases of severe autism there can be a step-change regression from earlier moderate autism to severe autism.  I called this double-tap autism, so as not to confuse with multiple hits. 

In double-tap autism things usually start out quite well, with good response to behavioral therapy, in early years, and then take a nose dive and can spiral completely out of control leading to institutionalization.

We have seen cases where the second tap/event is immune related and others where it is the onset of seizures around puberty, but usually the trigger remains unidentified.

I would imagine that PANDAS/PANS could also be such a second tap/event.  The issue is not just the tics/OCD but the associated loss of cognitive function. Given that immediate intervention has been shown to be highly effective in PANDAS/PANS, before the condition has become chronic and much less responsive, it would be wise for more people to be aware of what can be done.

Will some Chinese tea affect mGluR5 in a good way?  It remains to be seen; these receptors are present in different parts of the brain where they have opposing functions.  mGluR5 is a target of autism research at MIT and was covered in earlier posts. Here is another link:-




It may be necessary to have a brain region specific mGluR5 inhibitor.

We can add Pu-erh tea to the growing list of things that reduce cholesterol - cinnamon, pantethine (active form of vitamin B5), sytrinol etc.  Interestingly 600mg of pantethine lowers cholesterol but increases coenzyme Q10 (statins reduce coenzyme Q10).  Pu-erh tea actually has some naturally lovastatin in it, but that may not be its main mode of lowering cholesterol .