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Showing posts with label 3-Indolepropionic acid. Show all posts
Showing posts with label 3-Indolepropionic acid. Show all posts

Wednesday 24 October 2018

Choose your Statin with Care in FXS, NF1 and idiopathic Autism


There are several old posts in this blog about the potential to treat some autism using statins; this has nothing to do with their ability to lower cholesterol. 

Statins are broadly anti-inflammatory but certain statins do some other particularly clever things. This led me to use Atorvastatin and Fragile-X researchers to use Lovastatin.


Fragile X is suggested by an elongated face and big/protruding ears; 
other features include MR/ID and autism.

I was recently forwarded a Scottish study showing why Simvastatin does not work in Fragile X syndrome, but Lovastatin does.
Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E (see chart below). In people with Fragile X, they lack the FMR1 protein. Boys are worse affected than girls, because females have a second X chromosome and so a "spare" copy of the gene.


         Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.

So  ? = Does NOT inhibit

The researchers in Scotland did not test Atorvastatin in their Fragile X study.
The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.

RASopathies have been covered in this blog. Too much of the Ras protein is a common feature of much ID/MR. Investigating RAS took me to PAK1 inhibitors and the experimental drug FRAX486. This drug was actually developed to treat Fragile X; it is now owned by Roche. At least one person is using FRAX486 to treat autism.
You might wonder why the researchers do not just try Lovastatin in humans with Fragile X.  Unfortunately, Lovastatin was never approved as a drug in Scotland, or indeed many other countries.  Some researchers just assumed they could substitute Simvastatin, which on paper looks a very similar drug and one that crosses the blood brain barrier better than Lovastatin.



The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability. The therapeutic efficacy of lovastatin is being tested in clinical trials for FX, however the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in the Fmr1-/y mouse model. We find that while lovastatin normalizes excessive hippocampal protein synthesis and reduces audiogenic seizures (AGS) in the Fmr1-/y mouse, simvastatin does not correct either phenotype. These results caution against the assumption that simvastatin is a valid alternative to lovastatin for the treatment of FX.  

Although we propose the beneficial effect of lovastatin stems from the inhibition of ERK1/2-driven protein synthesis, it is important to note that statins are capable of affecting several biochemical pathways. Beyond the canonical impact on cholesterol biosynthesis, statins also decrease isoprenoid intermediates including farnesyl and geranylgeranyl pyrophosphates that regulate membrane association for many proteins including the small GTPases Ras, Rho and Rac [18, 46, 48, 49]. The increase in protein synthesis seen with simvastatin could be linked to altered posttranslational modification of these or other proteins. Indeed, although we see no change in mTORC1-p70S6K signaling, other studies have shown an activation of the PI3 kinase pathway that could be contributing to this effect [32]. However, our comparison of lovastatin and simvastatin shows that there is a clear difference in the correction of pathology in the Fmr1-/y model, suggesting that the impact on ERK1/2 is an important factor in terms of pharmacological treatment for FX.  There are many reasons why statins would be an attractive option for treating neurodevelopmental disorders such as FX. They are widely prescribed worldwide for the treatment of hypercholesterolemia and coronary heart disease [50], and safely used for longterm treatment in children and adults [46]. However, our study suggests that care should be taken when considering which statin should be trialed for the treatment of FX and other disorders of excess Ras. Although the effect of different statins on cholesterol synthesis has been well documented, the differential impact on Ras-ERK1/2 signaling is not well established. We show here that, contrary to lovastatin, simvastatin fails to inhibit the RasERK1/2 pathway in the Fmr1-/y hippocampus, exacerbates the already elevated protein synthesis phenotype, and does not correct the AGS phenotype. These results are significant for considering future clinical trials with lovastatin or simvastatin for FX or other disorders of excess Ras. Indeed, clinical trials using simvastatin for the treatment of NF1 have shown little promise, while trials with lovastatin show an improvement in cognitive deficits [28-30]. We suggest that simvastatin could be similarly ineffective in FX and may not be a suitable substitute for lovastatin in further clinical trials.


Conclusion
If you are treating Fragile X, best to start with Lovastatin and see if it helps.  In theory it might also help NF1 (Neurofibromatosis Type 1).

It looks to me that Atorvastatin also inhibits the relevant pathway and does much more besides that (PTEN, BCL2 etc)

What is Roche doing with FRAX486?




Thursday 8 February 2018

DHED, delivering Estradiol only to the Brain, also Lupron and Spironolactone










The Hungarian flag, for clever Laszlo Prokai

  

Lupron – partially right, but for the wrong reason? 

In the US there undoubtedly are some quack therapies for autism, however on occasion we have seen that you can stumble upon an effective therapy for entirely the wrong reason. In the history of medicine there are drugs that were stumbled upon, or created by accident.
In the case of the “Lupron protocol” which was promoted by a father and son (Geier and Geier), an extremely expensive therapy was apparently applied to hundreds of children, before being shut down by the medical regulators.
Without going into all the details, Geier’s therapy combined chelation (antioxidants) and a drug called Lupron that causes a dramatic reduction in testosterone levels.  In the jargon, it causes hypogonadism - diminished functional activity of the gonads (the testes in males or the ovaries in females). Lupron is another of those drugs that costs ten times more in the US than in the normal world. So a single injection of Lupron, depending on the dose,  costs up to $1000 in the US. Lupron is approved for use in children, male and female, with early onset puberty.
The case attracted media attention because Geier was also heavily involved in the idea that vaccines could cause autism and because patients were reportedly paying up to $50,000 for the complete therapy.
Geier was naturally a target for the anti-quack movement and why treat autism at all movements. He features in their books and blogs. 

Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure  (no link provided on purpose)

Still making the news in 2018.

Regulators who targeted controversial autism doctor may pay millions for humiliating him 

In this case I think Geier stumbled upon a rather extreme, partially effective therapy but for the wrong reason. I doubt such an expensive  potent drug is needed to produce the same beneficial effect, in that sub-group that appear to respond.

The fact that Lupron is so expensive in the US, may indeed contribute to the desire parents had for it.  There is a term in economics called a “Giffen good”; it is for the type of good that the more it costs the more you want it, like those very expensive hand bags people buy.

Personally I like inexpensive autism therapies, available to all.

Having read so much about autism, I am much less critical of those putting forward alternative ideas and therapies. It is very easy to get something right for entirely the wrong reason in medicine, which is something that is highly unlikely in many areas of science.

What I do not like is the predatory nature of some people with unusual ideas and therapies who treat autism. This is almost exclusively a North American phenomenon. Some parents will pay nothing to treat autism, for example some in countries with socialized medicine, while others would sell their house for a hope of an improvement.

The name Geier comes from the German word for vulture, maybe not the ideal surname for a healthcare worker.

If you read the following article from the Baltimore Sun you will see that there likely were some responders to this therapy:-

Lupron therapy for autism at center of embattled doctor's case 

"Wessels, who lives in Rock Rapids, Iowa, took Sam to see Geier in his Indianapolis office two years ago. She said there were months of genetic and hormone tests, and then the diagnosis. She began injecting Sam with Lupron daily.
She said the diagnosis made sense to her. Sam was not only having trouble communicating and difficulty learning, but he was tall for his age, had hair on his legs and began constantly masturbating by the time he was 5.
She said there was no "wow" moment where Sam snapped out of his autism, a spectrum of disorders where sufferers lack an ability to communicate and interact properly. But in the course of the next year, Sam's reading improved from 35 words a minute to 85 and he focused in class. He stopped masturbating as much.
Wessels thought Sam was naturally advancing and planned to taper the Lupron at some point — at 9, he had reached the generally accepted age limit for a precocious puberty label.
The day came abruptly four months ago when a nationwide shortage cut off Sam's supply. Wessels said she saw Sam return to his old habits, from flapping his hands, to pacing, to forgetting how to get to his classes.
"I felt like I got a glimpse of the child my son was meant to be, not the one autism gave me," said Wessels, fighting back tears. "It's so sad to watch your child fade away again."


Lupron and RORalpha

Regular readers of this blog may have noticed an entirely different reason Lupron might be beneficial in a sub-group of people with autism. It has nothing to do with vaccines and mercury-containing thimerosal preservative.

Reducing testosterone in boys is going to have effects like increasing estradiol.
















The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER. 

androgen receptor = AR 
estrogen receptor = ER 

We have seen that RORA is suggested to act like a central point/nexus that affects dozens of biological processes disturbed in autism, making it a key target for therapy.



Other drugs that affect androgen receptors and are suggested in some autism?

Are there any other alternative autism therapies that affect testosterone and so androgen receptors? The answer is yes; this time a very cheap one called Spironolactone, that has been mentioned earlier in this blog.
The MAPS doctor known to some readers of this blog, Dr Rossignol, was one of the coauthors with the late Dr Bradstreet, in a hypothesis regarding Spironolactone.


Spironolactone is a potassium sparing diuretic, but also has the effect of shifting the balance between testosterone/estradiol towards estradiol, this makes it a useful therapy to treat acne for which it is sometimes prescribed. It seems to help some with autism.

I think any drug/supplement suggested to affect RORA in the right direction, will likely be reported to also improve acne, even if that sounds rather odd. If it does not improve acne, it lacks potency. Not all acne remedies will affect RORA.
In fact there are numerous ways to affect testosterone and estradiol and they are well documented on the internet because of all the males who are trying to become females (the transgender community).
Donald Trump and his personal physician declared they take a small daily dose of the drug finasteride, which is why both of them have such a full head of hair, and why Trump can brag about his low PSA result. This drug is used to treat an enlarged prostate and at a lower dosage, hair loss.  It works by decreasing the production of dihydrotestosterone (DHT), an androgen sex hormone, in certain parts of the body like the prostate gland and the scalp. 
Lupron might be too expensive in the US for males becoming females, but the other testosterone/estradiol modifying drugs seem to be very widely used/abused, depending on your views.

“Normal” levels of male/female hormones  
One criticism of Geier was that while he did many different tests to measure testosterone in his patients, he seemed over willing to prescribe his highly potent testosterone reducing drug. It was reportedly not the case that he only used Lupron on patients with extremely elevated levels of testosterone.
In fact what are normal levels of male/female hormones?
There does not seem to be a normal level, rather a very wide range. the charts below are in adults.


Serum total T (A) and bioavailable T (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).



Serum total estrogen (A) and bioavailable estrogen (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).



Affecting Testosterone/Estradiol Just in the Brain
I do sometimes receive comments asking about possible future autism drugs in the pipeline, I even once had a section called “Future Drugs”. Things move so slowly I now really only focus on repurposing what is already available.
However, a really interesting new drug, DHED, is being developed to increase the level of the hormone estradiol just in the brain. Now as regular readers will know, in autism there is a lack of estradiol and a reduction in the expression of estrogen receptor beta. We know that estradiol is highly neuroprotective and that estrogen receptors in the brain modulate RORa, which is one of those switches that control a large group of genes often disturbed in autism. So a new drug developed to help post-menopausal women has potential to be repurposed to treat neurological disorders like autism and indeed Alzheimer’s. 
Interestingly for me is that the lead researcher, a Hungarian called Laszlo Prokai, also researches another hormone, TRH, that I wrote about extensively a long ago in this blog. TRH is potentially another very useful therapy inside the brain.  
Thyrotropin-releasing hormone (TRH), is a releasing hormone, produced by the hypothalamus, that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary.  Thyroid-stimulating hormone (TSH) then goes on to stimulate the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body.
As I discovered a few years ago, TRH does much more within the brain, as a result it has antiepileptic properties and mood enhancing properties. The US Army is funding the development of a TRH nasal spray for ex-combatants with mood disorders and a risk of suicide. Antidepressants like Prozac have the odd side effect of increasing suicidal tendencies.
A TRH super-agonist (Ceredist) already exists in Japan, so I could never really understand why the US Army did not just get that drug approved by the FDA.  

More Laszlos please
The big gap in all neurological disorders is translational research, which means actually converting all the existing knowledge into usable therapies for humans.
So it looks like we need more people like Laszlo; in fact there is another - Katalin Prokai-Tatrai, I assume it is his wife.
So like we already have the very talented duo Chauhan & Chauhan, we have Prokai & Prokai. What we would ideally want is Prokai & Prokai to translate the knowledge of Chauhan & Chauhan into human therapies.
As described in one of their papers:
Our laboratory has been involved in medicinal chemistry-driven research with attention to facilitating drug delivery of central nervous system (CNS) agents via prodrug approaches.

This is important because there are clever drugs that would be useful to treat brain disorders but you cannot get them through the blood brain barrier (BBB). So making a new compound that can cross the BBB and then converts back to the original drug is a neat solution. 

Dr. Prokai's current research focuses on
(1) Novel therapies against neurodegenerative and ophthalmic diseases using site-selective prodrugs
(2) Development and use of proteomics in aging research, studying neurodegenerative diseases and cancer, with especial attention to quantitative expression profiling and oxidative stress-associated posttranslational modifications
(3) Discovering new therapeutic agents based on neuropeptides and peptidomimetics as lead molecules.

In particular:
·         Molecular mechanisms of estrogen neuroprotection

·         Molecular pharmacology of thyrotropin-releasing hormone




“10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) is an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol which was discovered by Laszlo Prokai and colleagues. Upon systemic administration, regardless of route of administration, DHED has been found to selectively and rapidly convert into estradiol in the brain, whereas no such conversion occurs in the rest of the body. Moreover, DHED itself possesses no estrogenic activity, requiring transformation into estradiol for its estrogenicity. As such, the drug shows selective estrogenic effects in the brain (e.g., alleviation of hot flashes, neuroprotection) that are said to be identical to those of estradiol, whereas it does not produce estrogenic effects elsewhere in the body.  DHED has been proposed as a possible novel estrogenic treatment for neurological and psychiatric conditions associated with hypoestrogenism (e.g., menopausal hot flashes, depression, cognitive decline, Alzheimer's disease, and stroke) which uniquely lacks potentially detrimental estrogenic side effects in the periphery


Highlights


·         Treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, for 8 weeks decreased amyloid precursor protein in APPswe/PS1dE9 double-transgenic mice
·         DHED treatment reduced brain amyloid-β peptide levels
·         DHED-treated APPswe/PS1dE9 double-transgenic mice had higher cognitive performance compared to untreated control animals
·         DHED treatment faithfully replicated positive neurobiochemical effects and consequent behavioral improvement observed for 17β-estradiol
·         DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment did.  

By the same author Laszlo Prokai: 

Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs

Medicinal Chemistry: Compound could lead to estrogen therapies with fewer side effects

Estrogen levels drop in the brains of women who have gone through menopause or had surgeries to remove their ovaries. This hormone deficiency can lead to hot flashes, depression, trouble sleeping, and memory deficits. Hormone replacement therapies can improve women’s quality of life, but taking estrogen has its own problems, such as increased risk of breast and uterine cancer.

A new compound could avoid the source of these side effects—the action of estrogen on cells outside the.

Laszlo Prokai of the University of North Texas Health Science Center and coworkers identified 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which is converted to the main human estrogen, 17β-estradiol, in the brain and not elsewhere in the body. An enzyme expressed only in the brain reduces DHED to estradiol.

The researchers injected DHED into female rodents without ovaries and showed that estrogen levels jumped in the brain but not in other tissues. Then, through a series of experiments, they demonstrated that the compound had only neurological effects.

“It’s exactly the right strategy for avoiding the cancer risks and gaining the benefits in the brain,” says Bruce S. McEwen, a neuroendocrinologist at Rockefeller University. He thinks the next step is to show that the compound doesn’t have toxicity problems so that clinical trials in people can start.  The researchers are planning such studies in hopes of moving the compound “from the bench to the bedside,” Prokai says.



Why is Estradiol good for your brain?
You may be wondering why I give so much time on this blog to female hormones. There is a lot of evidence beyond RORa, that estrogen/estradiol and its receptors are very important to healthy brain function. 
The paper below is very interesting and worth a read. 

Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer’s disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain. 
However, estrogen actions on mitochondria are not exclusively related to such mechanism. Estrogen also regulates mitochondrial functions through their classical nuclear mechanism, i.e., transcriptional regulation of nuclear-encoded mitochondrial proteins. It is known that estrogen regulates the nuclear transcription of different proteins affecting mitochondrial function such as nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 (PCG-1). Hence, this regulation is critical for the activation of nuclear genes encoding proteins involved in mitochondrial biogenesis as well as in the mitochondrial electron transport chain complexes. It also regulates the transcription of mitochondrial transcription factor A (TFAM), which translocates into mitochondria and initiates transcription and replication of mtDNA

Note PCG-1 above, (a typo for PGC-1, I believe) for all those interested in treating mitochondrial dysfunction.  We saw previously that PGC-1α is a master regulator of mitochondrial biogenesis.
It turns out that Estrogen is key to many aspects of Mitochondria, and the paper  below from 2017 probably deserves its own post. Lack of estrogen or miss-expression of estrogen receptors in the brain is inevitably going to disrupt mitochondrial function.

Estrogens coordinate and integrate cellular metabolism and mitochondrial activities by direct and indirect mechanisms mediated by differential expression and localization of estrogen receptors (ER) in a cell-specific manner. Estrogens regulate transcription and cell signaling pathways that converge to stimulate mitochondrial function- including mitochondrial bioenergetics, mitochondrial fusion and fission, calcium homeostasis, and antioxidant defense against free radicals. Estrogens regulate nuclear gene transcription by binding and activating the classical genomic estrogen receptors α and β (ERα and ERβ) and by activating plasma membrane-associated mERα, mERβ, and G-protein coupled ER (GPER, GPER1). Localization of ERα and ERβ within mitochondria and in the mitochondrial membrane provides additional mechanisms of regulation. Here we review the mechanisms of rapid and longer-term effects of estrogens and selective ER modulators (SERMs, e.g., tamoxifen (TAM)) on mitochondrial biogenesis, morphology, and function including regulation of Nuclear Respiratory Factor-1 (NRF-1, NRF1) transcription. NRF-1 is a nuclear transcription factor that promotes transcription of mitochondrial transcription factor TFAM (mtDNA maintenance factorFA) which then regulates mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed. 
Estrogens exert direct and indirect effects on mitochondrial function in a cell-specific manner through activation of membrane-initiated ERα, ER β, and GPER activity and by direct genomic binding of ERα and ERβ to regulate nuclear gene transcription. While still controversial, estrogens also activate mitochondrial localized ERα and ERβ in a celltype-dependent manner. One key nuclear gene increased by E2 is NRF-1 that regulates the transcription of nuclearencoded mitochondrial genes, including TFAM which increases transcription of mtDNA-encoded genes. Thus, E2 coordinates nuclear and mitochondrial gene transcription via NRF-1. Activation of UPRmt also activates ERα and increases NRF-1. E2 also regulates the transcription of genes regulating mitochondrial morphology, enzymes in the TCA cycle and OXPHOS pathways, and mitochondrial protein Snitrosylation. Depending on the cell type, E2 regulates mitochondrial biogenesis and bioenergetic function.   

17β-estradiol is not only a reproductive hormone that is important only in women but it is also of immense importance for development and health in men. Although there is strong evidence from both human and animal studies that estrogen is protective in various brain diseases however, its adverse effect in classic target tissues such as uterus (17β-estradiol behaves as a full agonist on both estrogen receptor (ER) isoforms) is a matter of debate. ER subtype selective ligands are valuable tools for deciphering the specific roles of ER (α and β) in physiology and diseases. These compounds have a strong potential for development as therapeutics as these initiate estrogen signaling in brain but lack the mitogenic effects in other tissues such as ovaries and breast. Moreover, the existing and newer ERsubtype selective agonists will continue to be very valuable tool for deciphering the specific roles of ERα and ERβ 

Severity of symptoms of schizophrenia is greater in males as compared to premenopausal females. Women have been shown to differ in symptom severity depending on the phase of the menstrual cycle. Higher rates of relapse in women with schizophrenia are also observed during the postpartum period (low estrogens), whereas relapse is low during pregnancy (high estrogens). During menopause, women are at risk of developing a new schizophrenic illness. Additionally, premenopausal women appear to have a superior response to typical antipsychotics compared to men and postmenopausal women. Estrogen plays a protective role in women with schizophrenia. Estrogen treatment may reduce negative symptoms in schizophrenic women. Estradiol may exert neuroprotection by several mechanism that may even vary among different brain regions.


Non drug therapies:-
Overeating and smoking will increase your level of estrogen. We saw earlier that in males testosterone is converted to estradiol in fat tissue. 

Not to forget the other part of the Mediterranean Diet:-



Conclusion
Just as we saw that using high doses of antioxidants is beneficial in numerous medical conditions, where nobody calls it chelation, drugs that reduce testosterone or increase estradiol in the brain are not quack therapies, even when proposed by apparent vultures. It pays to keep an open mind.
Hormone replacement therapy (HRT) is a big business and if you can introduce a drug with less side effects, it should sell at a premium price, meaning DHED really should get commercialized.
DHED should be more effective than estradiol for treating neurological disorders because it can be given at a higher dose. In males there is no risk of feminization.
Contrary to what is sometimes quoted, estradiol lowers the risk of prostate cancer and is used to treat aggressive forms of it. High levels of testosterone are linked to prostate cancer and that is why Lupron is sometimes used.
Circulating levels of estradiol vary dramatically. People with a low level of estradiol might well be able to safely increase body-wide 17β-estradiol, rather than waiting a decade for DHED.
High levels of estrogen/estradiol in males may contribute to the extended healthy life expectancy in those with a soy-rich diet, as we will see in the forthcoming post on the Okinawan Diet and aging.



Spironolactone does have the advantage of increasing potassium levels, so someone with autism who responds to bumetanide and has high testosterone/ low estradiol and/or reduced expression of ERβ might see a benefit; I think it might require a high dose.
DHED looks interesting particularly for those with higher plasma estradiol but reduced ERβ in the brain.
I think the lady from Rock Rapids, Iowa in the earlier press report on Lupron, whose son had very hairy legs and responded to Lupron, should try some estradiol, or just get him to drink a great deal of soy milk.  This really should have a similar kind of effect.
It appears that some mitochondrial disease is linked to estradiol and estrogen receptors ERα and ERβ. DHED might be a very clever treatment to what is otherwise pretty much un-curable. So there will be a post on estrogens regulating life and death in mitochondria.
The implication is pretty simple – more estrogen/estradiol please, if you want to live a bit longer, or if your brain does not work so well.





Thursday 28 September 2017

Making Sense of Abnormal EEGs in Autism


There is no medical consensus about what to do with people who have subclinical epileptiform discharges (SEDs) on their EEG. That is people who do not have seizures but have an abnormal EEG. There is evidence to support the use of anti-epileptic drugs (AEDs) in such people.
About 5% of the general population have SEDs, but a far higher number of people with autism have SEDs.
You are more likely to detect epileptiform activity depending on which test you use. Magnetoencephalography (MEG) detects the most abnormalities, followed by a sleep EEG and then an EEG with a subject wide awake.
It had been thought that epileptiform activity (SEDs) was more common in regressive autism, but that is no longer thought to be the case. It even briefly had a name, Autistic Epileptiform Regression (AER). Subsequent studies indicate that regression is not relevant to subclinical epileptiform discharges (SEDs).
Estimates of prevalence still vary dramatically from Dr Chez at 60% to others believing it is 20-30%.
Epileptiform activity without seizures does also occur in about 5% of neurotypical people.
Dr Chez and some others believe in treating epileptiform activity with anti-epileptic drugs (AEDs), with valproate being the popular choice. Some neurologists believe in leaving SEDs untreated. 
Personally I would consider minor epileptiform activity in autism as pre-epilepsy. We know that about 30% of those with more severe autism will develop epilepsy and we know that in many cases when they start to receive AEDs their autism tends to moderate.
We know that an excitatory/inhibitory (E/I) imbalance is at the core of many types of autism and we should not be surprised that brains in an excitatory state produce odd electrical activity; rather we should be expecting it.
There are different types of possible E/I imbalance in the brain and there are very many different biological mechanisms that can trigger seizures. So nothing is simple and exceptions may be more likely than valid generalizations. So we should not be surprised that in one child valproate normalized their EEG, while in another it makes it worse.
In this post we review the far from conclusive literature.
I think that everything should be done to avoid the first seizure in a child with autism, for some people this may possible using bumetanide, but for others very likely entirely different therapy will be needed. The first seizure seems to lower the threshold at which further seizures may occur. 
Valproate appears to be the preferred AED, but in some people it can actually make epileptiform activity worse. In some people the Modified Atkins Diet (MAD) has normalized epileptiform activity, this is not a surprise given that this diet and the more complex ketogenic diet are successfully used to treat epilepsy.
If an AED can normalize the EEG result and at the same time improve behavior or cognition, it would seem a good choice.
It would be interesting if the Bumetanide researchers carried out a before and after sleep EEG in their autism clinical trials, along with the IQ test that I suggested to them a long time ago. 


Autism Spectrum Disorders (ASD) are an etiologically and clinically heterogeneous group of neurodevelopmental disorders. The pathophysiology of ASD remains largely unknown. One essential and well-documented observation is high comorbidity between ASD and epilepsy. Electroencephalography (EEG) is the most widely used tool to detect epileptic brain activity. The EEG signal is characterized by a high temporal resolution (on the order of milliseconds) allowing for precise temporal examination of cortical activity. This review addresses the main EEG findings derived from both the standard or qualitative (visually inspected) EEG and the quantitative (computer analyzed) EEG during resting state in individuals with ASD. The bulk of the evidence supports significant connectivity disturbances in ASD that are possibly widespread with two specific aspects: over-connectivity in the local networks and under-connectivity in the long-distance networks. Furthermore, the review suggested that disruptions appear more severe in later developing parts of the brain (e.g., prefrontal cortex). Based on available information, from both the qualitative and quantitative EEG literature, we postulate a preliminary hypothesis that increased cortical excitability may contribute to the significant overlap between ASD and epilepsy and may be contributing to the connectivity deviations noted. As the presence of a focal epileptic discharge is a clear indication of such hyperexcitability, we conclude that the presence of epileptic discharges is a potential biomarker at least for a subgroup of ASD.
Finally, it is not known whether currently available seizure medications are effective in normalizing hyperexcitable brain tissue that has not yet become capable of inducing seizures. Scattered reports suggest that a few of these medications may have some efficacy in this regards but further research is needed to examine these efficacies, particularly in newly diagnosed ASD patients.  

Summary: The efficacy of antiepileptic drugs (AEDs) in treating behavioral symptoms in nonepileptic psychiatric patients with abnormal EEGs is currently unknown. Although isolated epileptiform discharges have been reported in many psychiatric conditions, they are most commonly observed in patients with aggression, panic, or autistic spectrum disorders. The literature search was guided by 3 criteria: (1) studies had patients who did not experience seizures, (2) patients had EEGs, and (3) an AED was administered. Most important finding is that the number of “controlled” studies was extremely small. Overall, most reports suggest that the use of an AED can be associated with clinical and, at times, improved EEG abnormalities. Additionally, six controlled studies were found for other psychiatric disorders, such as learning disabilities with similar results. Overall, the use of anticonvulsants to treat nonepileptic psychiatric patients needs further controlled studies to better define indications, adequate EEG work-up, best AED to be used, and optimal durations of treatment attempts.  

What does the Simons Foundation have to say? They are funding a clinical trial. 


Spence and her collaborator, Greg Barnes at Vanderbilt Medical Center in Nashville, plan to test whether an anticonvulsant medication (valproic acid, also known as divalproex sodium or Depakote) can be used to treat children with autism and epileptiform EEGs. The researchers aim to recruit 30 participants between 4 and 8 years old who have been diagnosed with an autism spectrum disorder and who do not have epilepsy or metabolic disorders.


The views of the US National Institute of Mental Health:-  


Autism is a neurodevelopmental disorder of unknown etiology characterized by social and communication deficits and the presence of restricted interests/repetitive behaviors. Higher rates of epilepsy have long been reported, but prevalence estimates vary from as little as 5% to as much as 46%. This variation is probably the result of sample characteristics that increase epilepsy risk such as sample ascertainment, lower IQ, the inclusion of patients with non-idiopathic autism, age, and gender. However, critical review of the literature reveals that the rate in idiopathic cases with normal IQ is still significantly above the population risk suggesting that autism itself is associated with an increased risk of epilepsy. Recently there has been interest in the occurrence of epileptiform electroencephalograms (EEGs) even in the absence of epilepsy. Rates as high as 60% have been reported and some investigators propose that these abnormalities may play a causal role in the autism phenotype. While this phenomenon is still not well understood and risk factors have yet to be determined, the treatment implications are increasingly important. We review the recent literature to elucidate possible risk factors for both epilepsy and epileptiform EEGs. We then review existing data and discuss controversies surrounding treatment of EEG abnormalities.


The now disputed AER subgroup:- 


Autistic regression is a well known condition that occurs in one third of children with pervasive developmental disorders, who, after normal development in the first year of life, undergo a global regression during the second year that encompasses language, social skills and play. In a portion of these subjects, epileptiform abnormalities are present with or without seizures, resembling, in some respects, other epileptiform regressions of language and behaviour such as Landau-Kleffner syndrome. In these cases, for a more accurate definition of the clinical entity, the term autistic epileptifom regression has been suggested.

As in other epileptic syndromes with regression, the relationships between EEG abnormalities, language and behaviour, in autism, are still unclear. We describe two cases of autistic epileptiform regression selected from a larger group of children with autistic spectrum disorders, with the aim of discussing the clinical features of the condition, the therapeutic approach and the outcome.



Dr Chez has a long involvement and his findings have evolved:-

In 1999:- 


Background. One-third of children diagnosed with autism spectrum disorders (ASDs) are reported to have had normal early development followed by an autistic regression between the ages of 2 and 3 years. This clinical profile partly parallels that seen in Landau-Kleffner syndrome (LKS), an acquired language disorder (aphasia) believed to be caused by epileptiform activity. Given the additional observation that one-third of autistic children experience one or more seizures by adolescence, epileptiform activity may play a causal role in some cases of autism.

Objective. To compare and contrast patterns of epileptiform activity in children with autistic regressions versus classic LKS to determine if there is neurobiological overlap between these conditions. It was hypothesized that many children with regressive ASDs would show epileptiform activity in a multifocal pattern that includes the same brain regions implicated in LKS.

Design. Magnetoencephalography (MEG), a noninvasive method for identifying zones of abnormal brain electrophysiology, was used to evaluate patterns of epileptiform activity during stage III sleep in 6 children with classic LKS and 50 children with regressive ASDs with onset between 20 and 36 months of age (16 with autism and 34 with pervasive developmental disorder–not otherwise specified). Whereas 5 of the 6 children with LKS had been previously diagnosed with complex-partial seizures, a clinical seizure disorder had been diagnosed for only 15 of the 50 ASD children. However, all the children in this study had been reported to occasionally demonstrate unusual behaviors (eg, rapid blinking, holding of the hands to the ears, unprovoked crying episodes, and/or brief staring spells) which, if exhibited by a normal child, might be interpreted as indicative of a subclinical epileptiform condition. MEG data were compared with simultaneously recorded electroencephalography (EEG) data, and with data from previous 1-hour and/or 24-hour clinical EEG, when available. Multiple-dipole, spatiotemporal modeling was used to identify sites of origin and propagation for epileptiform transients.

Results. The MEG of all children with LKS showed primary or secondary epileptiform involvement of the left intra/perisylvian region, with all but 1 child showing additional involvement of the right sylvian region. In all cases of LKS, independent epileptiform activity beyond the sylvian region was absent, although propagation of activity to frontal or parietal regions was seen occasionally. MEG identified epileptiform activity in 41 of the 50 (82%) children with ASDs. In contrast, simultaneous EEG revealed epileptiform activity in only 68%. When epileptiform activity was present in the ASDs, the same intra/perisylvian regions seen to be epileptiform in LKS were active in 85% of the cases. Whereas primary activity outside of the sylvian regions was not seen for any of the children with LKS, 75% of the ASD children with epileptiform activity demonstrated additional nonsylvian zones of independent epileptiform activity. Despite the multifocal nature of the epileptiform activity in the ASDs, neurosurgical intervention aimed at control has lead to a reduction of autistic features and improvement in language skills in 12 of 18 cases.

Conclusions. This study demonstrates that there is a subset of children with ASDs who demonstrate clinically relevant epileptiform activity during slow-wave sleep, and that this activity may be present even in the absence of a clinical seizure disorder. MEG showed significantly greater sensitivity to this epileptiform activity than simultaneous EEG, 1-hour clinical EEG, and 24-hour clinical EEG. The multifocal epileptiform pattern identified by MEG in the ASDs typically includes the same perisylvian brain regions identified as abnormal in LKS. When epileptiform activity is present in the ASDs, therapeutic strategies (antiepileptic drugs, steroids, and even neurosurgery) aimed at its control can lead to a significant improvement in language and autistic features. autism, pervasive developmental disorder–not otherwise specified, epilepsy, magnetoencephalography, Landau-Kleffner syndrome.


2004


Epileptiform activity in sleep has been described even in the absence of clinical seizures in 43–68% of patients with autistic spectrum disorders (ASDs). Genetic factors may play a significant role in the frequency of epilepsy, yet the frequency in normal age-matched controls is unknown. We studied overnight ambulatory electroencephalograms (EEGs) in 12 nonepileptic, nonautistic children with a sibling with both ASDs and an abnormal EEG. EEG studies were read and described independently by two pediatric epileptologists; 10 were normal studies and 2 were abnormal. The occurrence of abnormal EEGs in our sample (16.6%) was lower than the reported occurrence in children with ASDs. Further, the two abnormal EEGs were of types typically found in childhood and were different from those found in the ASD-affected siblings. The lack of similarity between sibling EEGs suggests that genetic factors alone do not explain the higher frequency of EEG abnormalities reported in ASDs.



2006:

Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to2005. 


Abstract


Autism spectrum disorders (ASDs) affect 1 in 166 births. Although electroencephalogram (EEG) abnormalities and clinical seizures may play a role in ASDs, the exact frequency of EEG abnormalities in an ASD population that has not had clinical seizures or prior abnormal EEGs is unknown. There is no current consensus on whether treatment of EEG abnormalities may influence development. This retrospective review of 24-hour ambulatory digital EEG data collected from 889 ASD patients presenting between 1996 and 2005 (with no known genetic conditions, brain malformations, prior medications, or clinical seizures) shows that 540 of 889 (60.7%) subjects had abnormal EEG epileptiform activity in sleep with no difference based on clinical regression. The most frequent sites of epileptiform abnormalities were localized over the right temporal region. Of 176 patients treated with valproic acid, 80 normalized on EEG and 30 more showed EEG improvement compared with the first EEG (average of 10.1 months to repeat EEG).

  

An easy to read two page review paper: 


Many authors focused their research on the relationship between EEG abnormalities and autistic regression. Our analysis included only studies that involved autistic children with and without regression, i.e. clinically non-selected samples. We excluded studies involving only children with regression, or only children with EEG abnormalities. A summary of our findings is presented in Table 1.

A large majority of the studies (7 of 9 studies) did not find any significant relationship between EEG abnormalities and autistic regression. Only two studies were positive [10,11]. Of all the studies, Tuchman & Rapin [10] had the largest sample (585 children) but only part of the sample (392 children) had EEGs available (i.e. sleep EEGs; only sleep EEGs were performed in this study). Readers of the Tuchman & Rapin [10] study should note that the overall rate of epilepsy in the autistic sample was quite low (11%), as was the rate of epileptiform EEG abnormalities in non-epileptic autistic patients (15%). In comparison, other studies listed in our summary gave higher rates of epileptiform abnormalities in non-epileptic autistic children, 19% [12], 22% [13], and 24% [14]. The overall rate of epileptiform EEG abnormalities in the whole sample (21%) was also very low, where other comparable studies were in the range of 28 - 48% [5,11,14-17].  



What about Keppra (Levetiracetam) ? Here we have a clinical trial


Subclinical epileptiform discharges (SEDs) are common in pediatric patients with autism spectrum disorder (ASD), but the effect of antiepileptic drugs on SEDs in ASD remains inconclusive. This physician-blinded, prospective, randomized controlled trial investigated an association between the anticonvulsant drug levetiracetam and SEDs in children with ASD.

Methods


A total of 70 children with ASD (4–6 years) and SEDs identified by electroencephalogram were randomly divided into two equal groups to receive either levetiracetam and educational training (treatment group) or educational training only (control). At baseline and after 6 months treatment, the following scales were used to assess each individual’s behavioral and cognitive functions: the Chinese version of the Psychoeducational Profile – third edition (PEP-3), Childhood Autism Rating Scale (CARS), and Autism Behavior Checklist (ABC). A 24-hour electroencephalogram was recorded on admission (baseline) and at follow-up. The degree of satisfaction of each patient was also evaluated.

Results


Relative to baseline, at the 6-month follow-up, the PEP-3, CARS, and ABC scores were significantly improved in both the treatment and control groups. At the 6-month follow-up, the PEP-3 scores of the treatment group were significantly higher than those of the control, whereas the CARS and ABC scores were significantly lower, and the rate of electroencephalographic normalization was significantly higher in the treatment group.

Conclusion


Levetiracetam appears to be effective for controlling SEDs in pediatric patients with ASD and was also associated with improved behavioral and cognitive functions. 


Levetiracetam


Levetiracetam (LEV) is a broad-spectrum antiepileptic agent that has been used effectively for a variety of seizure types in adults and children, and for different psychiatric disorders.39,40

LEV does not have a direct effect on GABA receptor-mediated responses. In vitro findings reveal that LEV behaves as a modulator of GABA type A and of the glycine receptors, suppressing the inhibitory effect of other negative modulators (beta-carbolines and zinc). LEV inhibits the ability of zinc and beta-carbolines to interrupt chloride influx, an effect that enhances chloride ion influx at the GABA type A receptor complex.



And Lamictal (Lamotrigine)? 

This study is in general autism, not autism with epileptiform activity:- 


In autism, glutamate may be increased or its receptors up-regulated as part of an excitotoxic process that damages neural networks and subsequently contributes to behavioral and cognitive deficits seen in the disorder. This was a double-blind, placebo-controlled, parallel group study of lamotrigine, an agent that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11 years (M = 5.8) with a primary diagnosis of autistic disorder received either placebo or lamotrigine twice daily. In children on lamotrigine, the drug was titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per day. This dose was then maintained for 4 weeks. Following maintenance evaluations, the drug was tapered down over 2 weeks. The trial ended with a 4-week drug-free period. Outcome measures included improvements in severity and behavioral features of autistic disorder (stereotypies, lethargy, irritability, hyperactivity, emotional reciprocity, sharing pleasures) and improvements in language and communication, socialization, and daily living skills noted after 12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in improvements between lamotrigine or placebo groups on the Autism Behavior Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably due to expectations of benefits
  

Conclusion

What would be nice to know is whether epileptiform activity is a precursor to seizures, in the way that atopic dermatitis is often a precursor to developing asthma. Perhaps by treating epileptiform activity, some people could avoid ever developing epilepsy.
As I have pointed out before, I think that treating the E/I imbalance in autism with Bumetanide may well reduce the likelihood of later developing epilepsy.
In people with epileptiform activity but no seizures, treatment with AEDs can often normalize this activity within a few years.  Does the possible autism benefit correlate with this normalization? Or do you need to maintain the AED treatment even after the epileptiform activity has gone?
Do some people with autism, but no epileptiform activity, also demonstrate behavioral improvement on AEDs? I suspect some might, but it will depend on the AED.
Since medicine does not fully understand how most AEDs work and there are very many types of epilepsy, we cannot really expect concrete answers.
AEDs help many people with seizures, but a substantial number of people have seizures that do not respond to standard AEDs. Matching the AED to the person with seizures is more art than science and I would call it trial and error.
I did write a post a long time ago on the benefit of low dose AEDs in people with autism, but without seizures.  Given the many and varied effects of AEDs, it is not surprising that some people benefit.
The side effects of AEDs vary widely and some look more suitable than others for people that do not actually have seizures.
You might think based on the currently understanding of how Keppra works, it would not be helpful in someone that responds to Bumetanide.  But anecdotally people do respond to both, so most likely Keppra’s mode of action is not quite what we think it is.
So just like a neurologist applies trial and error to find an effective therapy for his patients, the same method can be applied to those with autism.
Clearly some people with autism do benefit from Valproate, others from Keppra and others from Lamotrigine. In my autism Polypill there is a little Potassium Bromide, the original AED from the 19th century.

If your neurologist does not want to treat your child's sub-clinical epileptiform activity, suggest he or she reads the literature and the very recent clinical trial using Keppra.  It is not guaranteed to improve autism, but you have a pretty good chance that one AED will help.