Please Help My 3 Year Old Son Who His Suffering From Epilepsy

[agnostic]

@Sheila
Thank you for taking the time to write such a detailed posting. I concur with most of what you say. I'm well aware that isolated vitamins in higher doses can easily throw things out of balance. That's why I'm very cautious about introducing new supplements and I only want to give him things that I have extensively tested on myself. One possible problem with B1 in particular, as you said, is that it is sulfur-containing. I read somewhere that sulfur-containing nutrients could feed pathogens in the gut. If this is true, transdermal application would be an option. However, my wife is already very skeptic about supplements in general and probably would never approve that - except if I could get official approval from a neurologist.

The reason why I'm so fascinated with B1 is that it also seems to play a big role in autism spectrum disorders (ASD) and I have the suspicion that my son has at least a mild form of ASD. There is quite a big overlap between ASD and epilepsy in childhood. According to this paper, about 20% of children with ASD also have epilepsy and about 20% of children with epilepsy also have autism:
Epilepsy in patients with autism: links, risks and treatment challenges

Other symptoms that my son has and that also occur in ASD are:
- speech delay (although he has made some progress lately, he is still quite far behind his peers)
- repetitive behaviors and/or a tendency to engage in a restricted range of activities
- irritability and hyperactivity
- sometimes very obsessed with certain routines and rituals

For example, he used to line up his toys, as is typically seen in ASD and he is often flapping with his arms, quite similarly as in this video:


On the other hand, he also shows many behaviors that clearly would not support the diagnosis of ASD. For example, he likes to interact with people and to involve them into his play. He has good eye contact and likes to be hugged. He is also rarely afraid of something and does not seem to be overly sensitive to stimuli.

We are currently doing an extensive examination at an epilepsy clinic with him, that includes a 72-hour EEG. As part of this examination, they will also assess whether he fulfills criteria for ASD.

Here are some studies on Vitamin B1 and autism. There is even a small intervention study that could show that B1 can improve symptoms of autism:
Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. - PubMed - NCBI
The role of trace elements, thiamin (e) and transketolase in autism and autistic spectrum disorder. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pubmed/27330305
http://article.sciencepublishinggroup.com/pdf/10.11648.j.ajpn.20130102.11.pdf

 

[agnostic]

@Amazoniac

Thanks. I have read most recent postings of Travis on immunogenic proteins and also followed with great interest the latest discussions on A2 milk. Interestingly, A2 is currently being tested for Autism:
a2 Milk for Autism and Attention-deficit Hyperactivity Disorder (ADHD) - Full Text View - ClinicalTrials.gov

A recent study has shown that A2 milk was associated with greater increase in plasma glutathione concentrations than A1 milk.
Clinical evaluation of glutathione concentrations after consumption of milk containing different subtypes of β-casein: results from a randomized, c... - PubMed - NCBI

At the same time, children with ASD show reduced glutathione levels and glutathione supplementation has been tested in ASD:
A clinical trial of glutathione supplementation in autism spectrum disorders

Similarly, glutathione is reduced in children with epilepsy
A probable causative factor for an old problem: selenium and glutathione peroxidase appear to play important roles in epilepsy pathogenesis. - PubMed - NCBI

I was therefore thinking about replacing his cow milk with goat milk. However, I am also convinced of the benefits of raw milk. While I can buy raw cows milk where I live quite easily, I have currently no source of raw goat milk.

 

[aquaman]

Given that Peat emphasized Vitamin D and Calcium a lot, I continued to give him Vitamin D and raw cow's milk before bed and in the morning.

1000 iu of Vitamin D, even in the morning, gives me BAD sleep. And I'm 200 pounds. I can't take it. I know garret Smith is mega against vitamin D. Multiple brands of it.

I would suggest green leaf broths, made from boiling a variety of leafy greens with lots of salt and some Bicarb of Soda. It tastes really good by itself, or you can stir in some cream and tomato paste to make a delicious tomato soup that I'm sure your kid would love.

Don't know what it is, but they make me feel amazing, and prevent night time calf twitches and cramping. Relaxes me during the day too.

EDIT: I can't see anywhere if you list exactly what he eats, and at what times. The bulk of all your writing is about supplements you've tried. I find the forum too heavily reliant on supplements at all times. Can you write out an example day of what he eats (including quantities), and what times he eats? Regularity of eating is important as much as what you eat. You've had lots of recommendations for supplements, and yet no one has asked about meal balance and timing. Hmmmm.

 

[Travis]

The etiology of epilepsy has nearly as many explanations as there are people willing to propose one, and I think this is largely because of no clear consensus of how the brain fundamentally operates. But that's not to say that its fundamental cause is 'unknown,' as it could very be like many other instances in which the etiology is known by few yet misunderstood or intentionally obfuscated by many. I think there are many reasons why things tend to operate in this way, perhaps the most important of which is what could be termed a 'subconscious intentional resistance to progress.' I think this occurs because middle aged men—who have more than their fair share of power—tend towards maintaining the paradigms and power structures they are familiar with, really being too old to learn anything new and too proud not to be one-upped by their juniors. There is also an economic aspect to all of this; not many researchers actually want to 'cure' anything, almost subconsciously, as this often would actually put many of them out of a job in a few years. Some of them actually want progress, most of them do not, some of them do but only slowly, and still others only pretend to want progress either to get funding or to be perceived as more philanthropic than they actually are. But I think much of the resistance to progress also lies with apathy and the low brain energy of most Americans consequent of eating things which negatively impact it. Nonetheless, the proper etiologies of widely-misunderstood diseases actually do seem to be known by a small minority of people.

I think it must be due to a relative deficiency of myelin, for a few reasons. Although the Mg²⁺/Ca²⁺ counter-ion pair is absolutely central to muscle contraction, physically, these ions are relatively slow in movement. I'd think a mineral imbalance could cause things like cramps and osteoporosis, but not epilepsy. Many people use topical magnesium chloride, take high-dose calcium supplements, or eat far too much phosphate aren't without much issue; the osteoporotic aren't epileptic. Even the case report I'd read on an acute high fluoride ingestion (suicide attempt) hadn't described epilepsy but only tetany, and this was despite the lowest blood calcium level ever reported (fluoride precipitates plasma Ca²⁺). So I'd think that a Mg²⁺/Ca²⁺ imbalance could certainly exacerbate the issue, yet would be unlikely to be the fundamental cause.

Acetylcholine and its congeners initiate nervous discharge, yet molecules of this type also acting globally don't seem to cause epilepsy (i.e. nicotine, atropine, muscarine). Certain agents can inhibit the enzyme acetylcholinesterase, thereby causing an acetylcholine overload; while true that this does cause tetany, I don't think it's ever been shown to cause an epileptic event. On the other side of the coin the inhibitors of acetylcholine don't appear to initiate epilepsy either, even the ones that work randomly and only at specific locations (such as seen in mysasthenia gravis: a condition where autoantibodies created against gluten peptides bind strongly the brain acetylcholine receptors, causing persistent yet reversible paralysis of certain muscles).

I don't think it's a neurotransmitter issue because LSD doesn't cause epilepsy, and this molecule seems to cause the maximum achievable crosstalk at junctions (synapses). The LSD molecule can bind both dopamine and serotonin receptors, which could perhaps be why some people will 'hear colors' and 'see sounds' while taking it. Although neural information can often inappropriately jump paths at they synapse by neurotransmitter mimetics, this doesn't appear to cause epilepsy.

So I think it must have to deal with the myelin sheath. Myelin is composed of pregnenolone, progesterone, phospholipids, sphinogolipids, and structural proteins (often highly phosphorylated). I'd think a demyelinated area situated on an important conduction pathway could perhaps sporadically 'leak' information, or receive it from the extracellular fluid (this information being either in the form of electrons, photons, or Förster resonance energy). The myelination of nerves can actually be measured by the 'light evoked potential,' a technique in which a flash of light is presented to the eye accompanied by near-simultaneous detection of the electric potential at the back of the head by strategically-placed electrodes which measure skin conductivity. The resultant measured potential varies by individuals, and can even define and diagnose myopia (the light better focused travels quicker). Myelination is also thought to play a role here, an assumption which can only be explained by a mild but progressive 'energy leakage' along the conduction pathway. Myelination is strongly correlated with test scores and reaction time, so it's certainly a thing to consider regardless it's proposed relationship to epilepsy. Pregnenolone has the highest affinity for brain microtubules—the tiny conduits of nervous energy consisting of tubular protein polymers and representing our 'nerves within our nerves'—onto which pregnenolone spontaneously and progressively coats creating layer-by-layer as it electrically insulates. Zellweger's syndrome is caused by reduced myelination due to a broken DHA synthesis pathway. Docosohexaenoic acid is a very unsaturated brain lipid found in the grey matter which acts to repel the sterols cholesterol, pregnenolone, and progesterone from those regions' cellular membranes. This condition is characterized by reduced myelination on account of the grey matters' inability to exclude steroids towards the nerves. The MRI images show white in the grey matter, which would better be found coating the nerves. A search for 'Epilepsy' and 'Zellweger's syndrome' had revealed—besides the obligatory Jerry Maguire pics you get from even thinking about the word 'Zellweger'—that this condition is characterized by both demyelination and epilepsy, what you'd expect of the latter were fundamentally caused by he former. The precursor for DHA is α-linolenic acid, which is the only conditionally-essential fatty acid in my view (conditional upon the ingestion of DHA itself, as found in fish). The ω−6 fatty acids are not essential, and actually hinder the grey matter's ability to properly exclude sterols through arachidonic acid (exclusively derived from linoleate) displacing DHA in the brain. Those diagnosed with Zellweger's syndrome have as much elevated DPA and arachidonic acid as they have decreased amounts of the more effective DHA. So for proper myelination either α-linolenic acid or DHA is 100% necessary despite DHA not being a constituent of myelin like the the sterols cholesterol, pregnenolone, and progesterone.

Demyelinated areas can likely be caused by macrophages, which respond to antibodies and inorganic inclusion bodies on the myelin sheath. Macrophages release hydrogen peroxide and the nitric oxide radical to destroyed an assumed or supposed invader. Autoantibodies can be raised de novo towards foreign proteins which can also have serendipitous affinity for otherwise-unrelated bodily proteins such as receptors, enzymes, and structural proteins. Aluminum has a peculiar affinity for the phosphorlyated proteins surrounding nerves and should be strictly avoided by everyone, perhaps even to the point of getting a vaccine exemption. Immunogenic protein fragments should likewise be avoided by everyone, the most persistent of which can be found in wheat. Also common contributing sources are eggs, oats, and soy; but as they have to be absorbed in long-peptide form the preparation and digestion of such foods can make all the difference. Certain foods can either be made nonimmunogenic or immunogenic through such practices as heat treatment and fermentiation (i.e. sourdough). Enzymes can also help breakdown resistant proteins, and bromelain and prolyl endopeptidase has been used here with success. Melatonin has been shown to chelate aluminum in vitro in at least two separate studies, and it also relaxes the brain's interstices at night allowing for efficient perfusion and CNS fluid transfer (The brain actually is 'cleansed' every night in this manner, through interstitial relaxation subsequent of reduced serotonin release (the entire raphe nucleus being completely shut-down at night).).

 

[Sheila]

Good morning Agnostic

I am delighted to read of you cautious approach and self-testing.

I have observed the cross-over between ASD and epilepsy and that ASD 'symptoms' become more pronounced if 'treatment' (of any hue, and/or diet) is heading in inappropriate directions. Since you are so aware of this, such observational feedback might be useful. Since you test also, you might find similar changes in energy and behavioural tendencies depending on what you do too which may give you further insight. The tricky part here, as with all things, is being sure of the conclusions one is making. And that we are all different - although I have often looked at parents to gain a better understanding of their children and children's context.

With regards to sulphur containing compounds, they can indeed be used by sulphur reducing bacteria to eventually produce H2S. For some, smellier poos are an indicator - you may like to try mag sulph to test this yourself, although since all guts are different, responses to doses can still vary. It tends to depend, I think, and await others to correct me, on where the sulphur containing compound is broken down and absorbed. This also depends on the dose of that compound. For example, 200mg of mag sulph might get absorbed stomach/small intestine and processed eventually through the kidneys for elimination; whereas 1 tsp of mag sulph (~4000mg (4g)) will more likely make it to the lower bowel with greater chance for sulphur reducing bacteria to have a party on it. As I said, I await others to correct me, we are all learning here. That part never stops.

You may have seen this http://www.allnaturaladvantage.com.au/home/wp-content/uploads/2014/11/PST-Pathway1.pdf
and http://www.allnaturaladvantage.com....2014/11/Sulphation-Detoxification-and-ASD.pdf in your researching on ASD. I have not yet looked into this properly and a search of the final diagram attribution gives this The Detoxification System. Part III: Sulfoxidation and Sulfation by. Mark J Donohue. which can be found here Mark J Donohue - Toxipedia with the other parts, one man's journey with chemical sensitivity.

I hesitate to put any of this up because there are parts here which I find wanting, (based on experience, and my current perceptions/orientation of thinking) but have not yet spent the time on a detailed look at Mr Donohue's work. Thus caveat emptor, especially as I am never sure supplementation of trace minerals like Molybdenum without good cause is wise. I used it years ago without obvious harm BUT in those with multiple chemical sensitivity or sulphite sensitivity per se, it won't be long before something else becomes the rate determining step, if it even can be used. As the Allnaturaladvantage chap states clearly, results are variable here. All these pathway discussions can never take into effect the multitude of changes to sensitivity that occur minute by minute in the human body. And as Aquaman carefully pointed out, diet is key here, not supplements alone, if at all. The green broth soup, full of mag and other elements, will surely also negate any gut irritation from mal-digested fiber and/or hedonistic bacterial parties (endotoxin) further down the gut. I have also seen vitamin D sensitivity especially with those with kidney problems. That for what it is worth, not necessarily relevant to your son.

The reason I write all of this is that (I think) I have actually seen repeated benefit with the use of sulphates and magnesium (though not necessarily together, and if they are together as mag sulph externally via warm bath) in refractory epilepsy as well as ASD and anecdotal reports suggest I am not alone. And since thiamine is a sulphur containing compound it may be useful in a related fashion depending on how the sulphur part gets used. I simply have no definitive answer on this at present and there may indeed be no linkage whatsoever.

I would be interested in what your son craves and eats and what he refuses should you wish to share that information.
I wish you much enlightenment to help your son,
Sincerely,
Sheila

 

[agnostic]

My son has now been assessed with a 72-hour EEG-monitoring at the epilepsy clinics, including continuous video monitoring. They registered about 8-10 myoclonic jerks per 24 hours, each lasting about 1-2 seconds. However, they are not completely sure whether these are all myoclonic jerks. Some of them also look like infantile spasms on the video recordings. In between the jerks, his EEG was normal. Unfortunately, he also had about 3-4 jerks at night, which interrupted his sleep. He also once banged his head on the table when he had a jerk while sitting at the table. We also did several neuropsychological tests to find out whether he has developmental delays and whether his symptoms could be part of a autism spectrum disorder (ASD). They ruled out ASD mainly based on the fact that he has no problem with eye contact and likes to engage and communicate with people. However, they also confirmed that he has developmental delays in several areas, particularly in speech, but also in some other areas.

The doctors are now concerned that the jerks (particularly at night) and the sporadic grand mal seizures could be causing his developmental delay. They said that the most probable diagnosis is "infantile myoclonic epilepsy" and that some of the children with this diagnosis have a rather benign course, but others also have a malignant course. The latter is also known under the name Dravet syndrome and they sad that they suspect he might have this type! This was a total shock for us because the Dravet syndrome is a very severe form of epilepsy that is often treatment resistant. Patients with the Dravet syndrome often have moderate to several mental handicaps their whole life. In most cases, the Dravet syndrome is caused by non-hereditary genetic mutation. By testing for these genetic mutations, one can rule in the disease but not completely rule it out. The testing will be conducted in the near future.

However, after having read the wikipedia article on the Dravet syndrome, I consider it rather unlikely that he has this type of disorder and I do not really understand how they came to this conclusion.

For instance,

• Onset of seizures in the first year of life in an otherwise healthy infant -> he had his first seizure with 14 months
• Initial seizures are typically prolonged and are generalized or unilateral -> he never had a seizure that lasted longer than 2-3 minutes
• Presence of other seizure types (i.e. myoclonic seizures) -> yes
• Seizures associated with fever due to illness or vaccinations -> although he had seizures while having the flu, he also had seizures when he was not sick. I never observed a clear relationship with body temperature
• Seizures induced by prolonged exposure to warm temperatures -> never observed that
• Seizures in response to strong lighting or certain visual patterns -> my wife says that she observed a few jerks that were caused by a sudden switch on of the light. Personally, I never saw that.
• Initially normal EEGs and later EEGs with slowing and severe generalized polyspikes -> his eeg was normal in between myoclonic jerks
• Normal initial development followed by slow development during the first few years of life -> yes, but developmental delays seem to be quite common with all kind of epilepsies
• Some degree of hypotonia -> I don't think so
• Unstable gait and balance issues -> yes, but only in the hours/days after a grand mal seizure
• Ankle pronation and flat feet and/or development of a crouched gait with age -> so far, I don't think so

Another thing is, as I've written above, that he developed myoclonic jerks after giving him magnesium and that the jerks completely stopped after stopping magnesium. When we started to give him magnesium again, December last year, the jerks reappeared about 2 weeks later. I had hoped that I could avoid this by only giving him 100 instead of 130 mg and by increasing his Vitamin D dose because there is a medical hypothesis paper that speculated that magnesium induced myoclonic jerks are the result of a lack of calcium and/or Vitamin D:
A nutrient deficiency that can lead to mycolonic seizures or jerks? | Nutrition for Seizures

Now, the doctors did not believe me that the myoclonic jerks could have been caused by magnesium. They think it's impossible that such a low dose of magnesium could cause this. However, both my wife and I have clearly observed it. How can they be so sure? As far as I know, there are hardly any studies on magnesium and myoclonic jerks and I also highly doubt that they have seen many patients on magnesium, since they do not support nutritional supplements and only know their pharmaceutical drugs.

Unsurprisingly, the doctors all agreed that my son should be treated with an anti-epileptic drug immediately. Of course, I would still prefer a natural treatment approach and I'm not fully convinced that the side effects and long-term effects on brain development of an anti-epileptic drugs is less severe than having 8-10 jerks per day, especially when there is good chance that the jerk frequency could be reduced just by lowering the magnesium dose and there are still many natural treatment options left. Also, our former neurologist knew about the jerks and he was not deeply concerned about them. He said, they must not be treated in any case. So, there seems to be no universal agreement among experts. On the other hand, he did not know at that time that they also occur at night and interrupt his sleep.

Anyway, there is no way around medication anymore, because I'm totally isolated with my opinion. My wife agrees with the doctors and does not want to question them, since these are the biggest "authorities" in the country.

Now, the medication they suggested is sodium valproate, which is the same drug as the one that has been initially suggested by the first neurologist after the first seizures had occurred.

 

[aguilaroja]

My son has now been assessed with a 72-hour EEG-monitoring... including continuous video monitoring. They registered about 8-10 myoclonic jerks per 24 hours, each lasting about 1-2 seconds....they are not completely sure
....They said that the most probable diagnosis is "infantile myoclonic epilepsy" and that some of the children with this diagnosis have a rather benign course, but others also have a malignant course. The latter is also known under the name Dravet syndrome

....doctors all agreed that my son should be treated with an anti-epileptic drug immediately.
...My wife agrees with the doctors and does not want to question them, since these are the biggest "authorities" in the country.
....the medication they suggested is sodium valproate...

This describes a general health care picture: The medical authority who speaks most autocratically and insistently wins, especially in situations where knowledge is limited. This also applies when physician opinion is divided. Even thoughtful, concerned families who do research mostly concede.

If not already done, I would suggested directly viewing the videos of the episodes of myoclonic jerks. Parents will always have far more information than a single monitoring session. Since you will be viewing the effects of any pharmaceutical or other approach, you can comment on what response you see in comparison to lab monitoring.

There are over 20 categories of seizure medicines, and over 3 dozen single medications. There has never AFAIK been a thorough comparison study of many categories for even for common, clear seizure issues.

If medication effect is limited or complicated, direct observation and discussion may lead to better choices.

 

[agnostic]

This describes a general health care picture: The medical authority who speaks most autocratically and insistently wins, especially in situations where knowledge is limited. This also applies when physician opinion is divided. Even thoughtful, concerned families who do research mostly concede.

Yes, it's so sad. If you do not comply and the disease get worse, they will always blame you for not following their advice. However, if you follow their advice (i.e. take their drugs) and it does not work out well, they would never admit that their treatment was wrong. They would always blame the disease for being difficult to treat.

Some people might think that its's always better to comply with doctors, because then you don't have to take responsbility and you can at least blame the doctor if something goes wrong. Personlly, however, I don't care about who is to blame at the end, I only care about getting the best possible treatment for my son.

What's even more sad is that my wife and I have big issues and we are getting divorced. Since my son will be living with her most of the time (I only see him 2x per week), my influence is rapidly diminishing. To keep at least a little influence, I'm forced to get along with my wife as good as possible and I cannot act too confrontationally. For instance, if I do not comply with medical authorities, I could be accused for being an irresponsible parent and she would have a reason to take him away from me completely. I'm sure a jury would always take the side of the mother and medical authorities. I'm in a really bad situation.

 

[agnostic]

I did quite a bit of research about sodium valproate, the drug they prescribed. Since my son is only 3 and half years old and his brain is not fully developed, my biggest fear is that this drug could interfer with his normal brain development and that this could affect him for his whole life. The following recent review on antiepileptics and brain development was not really reassuring:

Neurochem Res. 2017 Jul;42(7):2065-2070. doi: 10.1007/s11064-017-2262-4. Epub 2017 Apr 19.
Neurodevelopmental Effects of Antiepileptic Drugs.
Kellogg M1, Meador KJ2.
Author information

Abstract
Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioral domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. To date, valproate is the most widely recognized AED to significantly negatively affect neurodevelopment, and demonstrates greater adverse effects than any other AEDs that have been assessed. Although some AEDs appear to have low risk (i.e., lamotrigine, levetiracetam), other AEDs have been implicated in a variety of studies detailed below, and many AEDs have not been adequately assessed. The purpose of this review article is to summarize our current understanding of the neurodevelopmental effects of AEDs.


It's also a well known teratogenic and prenatal exposure is associated with an increased risk for autism and ADHD in the offspring. In fact, it causes autistic features in animals so reliably that it is used as an animal model for autism:

Exp Neurol. 2018 Jan;299(Pt A):217-227. doi: 10.1016/j.expneurol.2017.04.017. Epub 2017 May 2.
The valproic acid-induced rodent model of autism.
Nicolini C1, Fahnestock M2.
Author information

Abstract
Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism.


Surprisingly, however, as I said above, about 20% of children with autism also have epilpsy and it seems that valproic acid is the drug of choice for treating epilepsy in these children because it has the least potential to negatively affect autistic symptoms:

Front Public Health. 2013 Sep 13;1:31. doi: 10.3389/fpubh.2013.00031.
A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel.
Frye RE1, Rossignol D2, Casanova MF3, Brown GL4, Martin V4, Edelson S5, Coben R6, Lewine J7, Slattery JC1, Lau C1, Hardy P8, Fatemi SH9, Folsom TD9, Macfabe D10, Adams JB11.
Author information

Abstract
Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases and by a panel of experts that treat ASD individuals. Only a few anti-epileptic drugs (AEDs) have undergone carefully controlled trials in ASD, but these trials examined outcomes other than seizures. Several lines of evidence point to valproate, lamotrigine, and levetiracetam as the most effective and tolerable AEDs for individuals with ASD. Limited evidence supports the use of traditional non-AED treatments, such as the ketogenic and modified Atkins diet, multiple subpial transections, immunomodulation, and neurofeedback treatments. Although specific treatments may be more appropriate for specific genetic and metabolic syndromes associated with ASD and seizures, there are few studies which have documented the effectiveness of treatments for seizures for specific syndromes. Limited evidence supports l-carnitine, multivitamins, and N-acetyl-l-cysteine in mitochondrial disease and dysfunction, folinic acid in cerebral folate abnormalities and early treatment with vigabatrin in tuberous sclerosis complex. Finally, there is limited evidence for a number of novel treatments, particularly magnesium with pyridoxine, omega-3 fatty acids, the gluten-free casein-free diet, and low-frequency repetitive transcranial magnetic simulation. Zinc and l-carnosine are potential novel treatments supported by basic research but not clinical studies. This review demonstrates the wide variety of treatments used to treat seizures in individuals with ASD as well as the striking lack of clinical trials performed to support the use of these treatments. Additional studies concerning these treatments for controlling seizures in individuals with ASD are warranted.


What's also nice about valproic acid is that it is a relatively old drug and it's not only effective against epilepsy, but also bipolar disorder, migraine heachaches and even potentially cancer. So, there is a lot of clinical experience with it and thousands of studies. According to wikipedia, It is unclear exactly how valproate works. Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases. Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.

One of the biggest problems of this drug is its toxic effect on the liver. Particularly small children are at increased risk of hepatotoxicity. However, there are several animal studies indicating that the toxic effect on the liver is mediated by increased oxidative stress and that therefore the toxci effect can be mitigated by giving vitamin E. Here are some abstracts on this topic.

The Journal of Basic & Applied Zoology

Volume 67, Issue 4, August 2014, Pages 127-139

Protective role of vitamin E against valproic acid-induced cytogenotoxicity and hepatotoxicity in mice

lEhab M. Abdella Sanaa R.Galaly Hanaa M.Mohammed Sally M. Khadrawy

https://doi.org/10.1016/j.jobaz.2014.03.003

Valproic acid (VPA) is a widely used antiepileptic medication and has teratogenic effects in both animals and humans. The objective of the current study was to investigate the effects of vitamin E (Vit-E) on VPA induced cytogenotoxicity and hepatotoxicity in male albino mice (Mus musculus). Genotoxicity and cytotoxicity were evaluated by bone marrow chromosomal aberration assay and mitotic index respectively, while hepatic dysfunctions were evaluated by light and electron microscopy.

80 mice were used, they were divided into eight groups, group one (G1) served as negative control group and the other seven groups were administered VPA and Vit-E as follows: G2 received VPA (100 mg/kg) and G3–G5 received Vit-E at doses 50, 100 and 200 mg/kg respectively for 21 days. While the treated groups (G6–G8) were administrated with Vit-E in concomitant with VPA for 21 days. The positive control animals administered VPA alone showed toxic histological and genetical manifestations (at P < 0.05). All the histological alterations in liver were greatly abated using Vit-E with significant reduction in chromosomal aberrations and elevation in mitotic index (P < 0.05). On the basis of the present results, Vit-E at dose 100 mg/kg appeared more potent in exerting the ameliorative effect.


J Clin Pharmacol. 1984 Apr;24(4):148-54.

Protection against sodium valproate injury in isolated hepatocytes by alpha-tocopherol and N,N'-diphenyl-p-phenylenediamine.

Buchi KN, Gray PD, Rollins DE, Tolman KG.

The possibility that lipid peroxidation is involved in valproic acid (VPA) hepatotoxicity was explored by testing the ability of the free-radical scavengers alpha-tocopherol (vitamin E) and N,N'-diphenyl-p-phenylenediamine (DPPD) to protect against VPA toxicity. Rat hepatocyte cultures were treated with toxic doses of VPA, in conjunction with varying doses of vitamin E and DPPD. Lactate dehydrogenase (LDH) release into the culture media was used to calculate an LDH index as a measure of toxicity. Vitamin E afforded increasing protection against VPA toxicity at concentrations of 1.0 to 4.0 microM but then leveled off and did not give complete protection at concentrations up to 8.0 microM. No protection was seen at less than 1.0 microM. DPPD showed increasing protection from 0.05 to 0.50 microM, with complete protection at the highest concentration. These data indicate that VPA toxicity can be prevented by simultaneous administration of free-radical scavengers and support the concept that VPA hepatotoxicity is due to lipid peroxidation.

Journal of Medical Sciences, 14: 290-296

Protective Effect of Silymarin and Vitamine-E in Hepatotoxicity Induced by Valporic Acid in Albino Rats

Sanad Fouad Abdou, Mostafa Al- Wakeel and Mahmoud Helmy El- Saied

Administration of valporic acid, the most common medication prescribed against epilepsy produces many metabolic and morphological aberrations in liver due to the fact that liver is the main detoxifying site for these antiepileptic drugs. This experimental work was done for study of the prophylactic role of silymarin and vitamin E in hepatotoxic induced by valporic acid in albino rats. Fifty adult male albino rats weighting 150-200 g were divided into five equal groups, one control and the other four for the drugs. Group I control group is subdivided into two subgroups (IA, IB). Group II ingested valporic acid, group III ingested valporic acid+silymarin, group IV ingested valporic acid+vitamine E and finally group V ingested valporic acid+both drugs, the ingestion was done through orogastric tube for four week. After four weeks biochemical studies (ALT, AST and total bilirubin) were done for all rats in all groups, then the rats were sacrificed and histopathological studies were done for their livers. Biochemical analysis revealed significant increased in AST, ALT and total bilirubin in the group II, III, IV and V in comparison with control groups and revealed significant decrease in the group III, IV and V in comparison with group II. Histopathological examination of the group II revealed necro-inflammatory foci with infiltration of the hepatic lobules with inflammatory cells and inflammation in the portal tract. Histopathological examination of the liver section of group III, IV and V showed mild necrosis and inflammation in hepatic lobules and showed mild inflammation in the portal tract. The liver is highly affected by ingestion of valporic acid. However, ingestion of silymarin and/or vitamine E that is naturally occurring antioxidants can decrease this harmful effect of these drugs on the liver. Therefore, the patient on chronic use of valporic acid must use silymarin and/or vitamin E to protect their livers.


Toxicology. 1996 Aug 1;112(1):69-85.

Cytotoxicity of unsaturated metabolites of valproic acid and protection by vitamins C and E in glutathione-depleted rat hepatocytes.

Jurima-Romet M, Abbott FS, Tang W, Huang HS, Whitehouse LW.

Valproic acid (VPA) and the unsaturated metabolites, 2-ene VPA and (E)-2,(Z)-3'-diene VPA, demonstrated dose-dependent cytotoxicity in primary cultures of rat hepatocytes, as evaluated by lactate dehydrogenase (LDH) leakage. Cellular glutathione (GSH) was depleted by adding buthionine sulfoximine (BSO) to the culture medium. Induction of cytochrome P450 by pretreatment of rats with phenobarbital or pregnenolone-16 alpha-carbonitrile enhanced the cytotoxicity of parent VPA in BSO-treated hepatocytes. The cytotoxicity of 4-ene VPA was apparent in BSO-treated hepatocytes with detectable loss of cell viability at 1 microM of added 4-ene VPA. Depletion of cellular GSH also increased the cytotoxicities of 2-ene VPA and (E)-2,(Z)-3'-diene VPA. The cytotoxicity of 2-ene VPA was comparable to or higher than that of VPA, producing loss of viability at concentrations > or = 5 mM. Time-course evaluation of hepatocyte response to 4-ene VPA in the GSH-depleted state revealed a delayed cytotoxicity with no effect during the first 12 h of exposure followed by a pronounced toxicity between 12 and 14 h. Two major GSH conjugates of 4-ene VPA metabolites, namely 5-GS-4-hydroxy VPA lactone and 5-GS-3-ene VPA, were detected in 4-ene VPA treated hepatocytes. Consistent with this finding, a 50% decrease in cellular GSH levels was observed following 4-ene VPA treatment. Under similar conditions, neither toxicity nor the GSH conjugated metabolite were detected in cells treated with the alpha-fluorinated 4-ene VPA analogue (alpha-F-4-ene VPA). The antioxidants, vitamin C and vitamin E, demonstrated a cytoprotective effect against 4-ene VPA-induced injury in GSH-depleted hepatocytes. These results are in support of hepatocellular bioactivation of VPA via 4-ene VPA to highly reactive species, which are detoxified by GSH. The susceptibility of hepatocytes to VPA metabolite-mediated cytotoxicity depends on cellular GSH homeostasis.


Food Chem Toxicol. 2016 Sep;95:159-67. doi: 10.1016/j.fct.2016.07.011. Epub 2016 Jul 14.

Protective effect of vitamin E on sperm motility and oxidative stress in valproic acid treated rats.

Ourique GM1, Saccol EM1, Pês TS1, Glanzner WG2, Schiefelbein SH1, Woehl VM3, Baldisserotto B1, Pavanato MA1, Gonçalves PB2, Barreto KP4.

Long-term administration of valproic acid (VPA) is known to promote reproductive impairment mediated by increase in testicular oxidative stress. Vitamin E (VitE) is a lipophilic antioxidant known to be essential for mammalian spermatogenesis. However, the capacity of this vitamin to abrogate the VPA-mediated oxidative stress has not yet been assessed. In the current study, we evaluated the protective effect of VitE on functional abnormalities related to VPA-induced oxidative stress in the male reproductive system. VPA (400 mg kg(-1)) was administered by gavage and VitE (50 mg kg(-1)) intraperitoneally to male Wistar rats for 28 days. Analysis of spermatozoa from the cauda epididymides was performed. The testes and epididymides were collected for measurement of oxidative stress biomarkers. Treatment with VPA induced a decrease in sperm motility accompanied by an increase in oxidative damage to lipids and proteins, depletion of reduced glutathione and a decrease in total reactive antioxidant potential on testes and epididymides. Co-administration of VitE restored the antioxidant potential and prevented oxidative damage on testes and epididymides, restoring sperm motility. Thus, VitE protects the reproductive system from the VPA-induced damage, suggesting that it may be a useful compound to minimize the reproductive impairment in patients requiring long-term treatment with VPA.


Dicle Tıp Dergisi 2004

The Protective Role of Folic Acid and Vitamin E Against Toxical Effects of Valproic Acid on Liver Tissue During Period of Gestation

Özlem Pamukçu Baran*, Ayşe Yıldırım*, Murat Akkuş*

Valproic acid is an anticonvulsan drug used in epilepsy. The histopathological changes of valproic acid on liver and the protective effect of vitamin E and also folic acid were observed. 24 adult female Wistar Albino rats were used. The first control, the second valproic acid group that was given 300 mg/kg on 8.9. and 10. days of gestation, the third valproic acid +vitamin E group. Vitamin E was given 250mg/kg via nasogastric intubation before one hour administration of valproic acid on 8.9.10.days of gestation. The fourth valproic acid+ folic acid group; via valproic acid, folic acid was given 400 microgram ordinarily in drinking water per day. In the liver sections of valproic acid group, perivenullar dilatation, swelling of Kuppfer cells, microvesicular steatosis and degeneration were observed. In the second group there was moderate degeneration in hepatocytes,necrotic areas in some places, mononuclear cell infiltration. In valproic acid +vitamin E group normal-like appearance of the structure of Remark cell lines were observed. Under these source of results, we viewed antioxidants decreased the hepatotoxicity on liver tissue by using folic acid and vitamin E .

 

[Sheila]

Dear Agnostic

Firstly, I was saddened to hear of your family circumstances. I appreciate this is a very trying time for all concerned and it is clear you have your child's best interests at heart.

Regarding your observations wrt magnesium and jerkiness, it is possible that his gut is irritated with the magnesium and that is enough to cause jerkiness? Tics, and jerks and restless legs can be due to gut irritation, so why is not magnesium, or any supplement for that matter (and/or its excipients) able to cause direct physical irritation too? Since fuel levels in young children can be highly variable and affect their response to anything accordingly (the lower the energy the more likely the reactivity) that may be something to consider. A physician is unlikely to consider this angle, it's just not on their radar.

I suspect that children with ASD or seizures and/or both and/or others without a 'label' may also have trouble metabolising drugs in general. Note also what Dr Peat says about drugs that have a C-halogen (F, Cl, Br, I) bond and their greater liver burden. Suspect this issue in particular when increasing doses of drugs produce seemingly low levels of the drug in the blood, even though correctly administered. Just something to look out for as more is seldom better in these cases. I did not consider vitamin E in this regard, thank you for posting that link. I have found that regular, warm, mag sulphate baths appear to help with some liver processing that requires adequate sulphate (thought deficient in ASD children?) and a couple of times a week may be perfect for this approach. The only downside I have seen with this is that fuel levels must be maintained, as extra warmth before bed is a metabolic stimulant and running out of fuel in the middle of the night increases stress hormones and with it, seemingly, seizure tendencies.

With my best wishes,
Sheila

 

[agnostic]

Dear Sheila

I have considered the possibility that magnesium could cause jerks through gut irritation before, but concluded that its highly unlikely because the jerks started only about 2 weeks after introduction of magensium and also only stopped about 1-2 weeks upon cessation of magnesium. I think an effect through gut irritation would be more immediate.

Regarding magnesium sulphate: I agree that this a very good form of magnesium and that it is probably particularly effective in epilepsy and ASD because it can support liver detoxification through sulfation, which often seems to be impaired in these patients. It's probably no coincidence that Adelle Davis recommended in her famous bestselling book "Let's get well" (which by the way was also a big inspiration for Ray Peat) to take half a teaspoon of Epsom salt in orange juice. On eartclinics one user claims that this method worked in EVERY case he tried it:
Natural Treatment for Epilepsy

Apart from that, magnesium sulphate is a well established medicine for treating eclamptic seizures:
Magnesium sulfate: past, present, and future. - PubMed - NCBI

Isn't it crazy that - although it has been used for treating eclamptic seizures for 100 years, it has not yet occured to the medical establishment that it also might have a big potential in regular epilepsy?Luckily, the first human trial testing the effect of magnesium sulphate on childhood epilepsy has recently been conducted:
Effect of Magnesium Supplementation for Children With Drug Resistant Idiopathic Epilepsy - Full Text View - ClinicalTrials.gov

I'm eagerly awaiting the results of this trial. I have also contacted the principal investigator of this study by email, but unfortunately did not get a response.

Regarding epsom salt bath: I have tried it a few times with my son. Although I think its beneficial, I'm not fully convinced that large amounts of magnesium and sulphate can be absorbed through the skin. See this study:
Myth or Reality—Transdermal Magnesium?

So, some of the effects of epsom salt baths might also be psychological, or mediated by the warmth or through accidently swallowing some of the water.

 

[agnostic]

I didn't tell the whole story with the doctors in the epilepsy clinic yet. Overall, it was a very disappointing experience, although I must say I did not expect much from the beginning. I met many doctors in my life time and my experience with them was mostly negative.

I said to the doctor that I do not find it a good idea to stop all supplements and start with sodium valproate at the same time because then we can not know which changes are the result of the drug and which are the result of stopping the supplements. She was not really happy about my suggestion, but reluctantly agreed to continue with the supplements for another 1 or 2 months. The only supplement that she encouraged us to continue was vitamin D. Apparently, even the most ignorant doctors nowadays have learnt about the benefits of vitamin D. Everything else she considered unnecessary or even harmful. She was particularly negative about vitamin E and said that, since it's a fat soluble vitamin, it could be easily overdosed, which of course is a very silly argument because we all know on this forum that vitamin E is very safe, especially in the dosage that I give to my son. At that time, I had not yet read the many animal studies that have shown that vitamin E can protect against the liver toxic effect of sodium valproate. So, I could not point that out. Apparently, this doctor has never heard about these studies and she probably was also hardly aware of all the studies that have shown a positive effect of Vitamin E against epilepsy. Otherwise, she would have had a more positive attitude towards vitamin E.

I did a very thorough literature search on Vitamin E and epilepsy and found about 5 randomized controlled trials. Four of them showed positive results, although I have to admit that some of them were published in rather obscure journals or only as conference abstracts. Nevertheless, there are also several positive open label trials and positive results from animal models. To say that there is no evidence at all, is ridiculous. Besides, there is a lot of evidence that epileptic seizures are associated with oxidative stress and that antioxidants can protect from the negative consequences of seizures. So, even if they do not completely stop seizures they can be helpful for protecting the brain. Sadly, mainstream medicine in general - and this doctor was not an exception - has a very negative opinion of vitamin e because several large trials could not confirm that vitamin E could protect against cancer or heart disease. Some, of them even found negative effects. However, as pointed out by Travis and other users of this forum in recent discussions on Vitamin E, most of this trials only used alpha-tocopherol and often even the synthetic dl-alpha-tocopherol. We know know that this can lead to depletion of gamma-tocopherol, which has his own special properties. This should not be the the case with my son, because I use the Health Natura brand, which has a high gamma-tocopherol content.

I also said to the doctor that I'm in contact with nutrition coach that is specialized in treating children wit epilepsy (Lynn Altieri, this is here site: Nutrition for Seizures | Functional nutrition coaching for seizure disorders.). Lynn is the mother of child who had a severe treatment resistent epilpsy and she was able to help him with natural methods. As it was to be expected, the doctor was not open to this suggestion at all. She said, the only diet that is scientifically proven to work is the ketogenic diet and she said it would be too much of burden for the child if we restrict his food or if he has to take supplements. Besides the fact that there also other dietary interventions with scientific evidence and that I would never do the ketogenic diet, I find her argument silly and hypocritical, because she is very compassionate with the child when it comes to diet/supplements, but at the same time apparently does not feel very sorry about the negative side effects and potentially brain damaging effects of her drugs.

 

[agnostic]

I just found out that glycine can also protect the liver against the toxic effects of valproic acid (see study below). So, it's good that we are already giving him magnesium in the glycinate form.

Epilepsia. 1994 Sep-Oct;35(5):1016-22.
Effect of glycine on valproate toxicity in rat hepatocytes.
Vance MA1, Gray PD, Tolman KG.
Author information

Abstract
The interaction between the amino acid glycine and valproate (VPA), an antiepileptic drug (AED) that occasionally causes hepatotoxicity, was studied in rat hepatocytes in monolayer culture. Valproate caused a dose-dependent increase in leakage of lactic acid dehydrogenase (LDH), and glycine prevented this toxic response. L-Carnitine, L-alanine, and L-cysteine did not protect hepatocytes from VPA. Glycine also partially antagonized inhibition of fatty acid beta-oxidation by VPA, as estimated by the generation of acid-soluble products from [14C]palmitic acid. These results are consistent with the hypothesis that glycine prevents VPA toxicity by removing acyl-CoA esters, which accumulate during VPA exposure and interfere with fatty acid beta-oxidation. Glycine, however, also antagonized the toxic effects of acetaminophen on hepatocytes, although at higher concentrations than required to protect hepatocytes from VPA. Because the mechanism of toxicity of acetaminophen probably is different from that of VPA, a nonspecific cytoprotective effect may contribute to glycine antagonism of valproate toxicity. Our results emphasize the importance of glycine in protecting hepatocytes from noxious insult in general as well as from VPA in particular.


There is also evidence that canitine is important (see below). However, since this is not a peaty substance, I would not want to supplement that. However, I will make sure that he eats enough meat.

Clin Toxicol (Phila). 2009 Feb;47(2):101-11. doi: 10.1080/15563650902752376.
Carnitine in the treatment of valproic acid-induced toxicity.
Lheureux PE1, Hantson P.
Author information

Abstract
INTRODUCTION:
Valproic acid (VPA) is a broad-spectrum antiepileptic drug that is now used commonly for several other neurological and psychiatric indications. VPA is usually well tolerated, but serious complications, including hepatotoxicity and hyperammonemic encephalopathy, may occur. These complications may also arise following acute VPA overdose, the incidence of which is increasing. Intoxication usually only results in mild central nervous system depression, but serious toxicity and death have been reported.

VALPROIC ACID AND CARNITINE:
As a branched chain carboxylic acid, VPA is extensively metabolized by the liver via glucuronic acid conjugation, mitochondrial beta- and cytosolic omega-oxidation to produce multiple metabolites, some of which may be involved in its toxicity. Carnitine is an amino acid derivative that is an essential cofactor in the beta-oxidation of fatty acids. It is synthesized endogenously from the essential amino acids, methionine and lysine. VPA inhibits the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se.

CARNITINE SUPPLEMENTATION:
Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy although a correlation between ammonia concentrations and the clinical condition was not always observed. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children, although the clinical benefit in terms of liver protection or hastening of recovery from unconsciousness has not been established clearly. Prophylactic carnitine supplementation is also advocated during VPA therapy in high-risk pediatric patients.

CONCLUSION:
Further controlled, randomized, and probably multicenter trials are required to better delineate the therapeutic and prophylactic roles of l-carnitine and the optimal regimen of administration in the management of VPA toxicity.

 

[agnostic]

I found yet another study showing that B6 can also protect against toxic effects of sodium valproate. So, to summarize, three of the four nutrients that we are already supplementing (Vitamin E, B6 and magnesium glycinate) have evidence that they are protective against toxic effects of sodium valproate and at the same time have antiepileptic effects. Such a shame, that the doctors nevertheless want me to drop them!

Hum Exp Toxicol. 2014 Jun;33(6):623-8. doi: 10.1177/0960327113506233. Epub 2013 Oct 9.
The effects of vitamin B6 on lens antioxidant system in valproic acid-administered rats.
Tunali S1.
Author information

Abstract
Valproic acid (VPA, 2-propyl pentanoic acid) is a broad-spectrum antiepileptic drug (AED) and is commonly used in the treatment of bipolar disorders and epilepsy. AEDs are known to result in vascular disturbances. Vitamin B6 (Vit B6) is water soluble vitamin essential for normal growth, development, and metabolism. In this study, we aimed to investigate the protective effects of Vit B6 against VPA-induced lens damage in experimental animals. In this study, male 4-month-old, Sprague-Dawley rats were used. The animals were divided into four groups. Group I was intact control animals. Group II rats were administered with Vit B6 (50 mg/kg/day) for 7 days. Group III rats were administered with only VPA (500 mg/kg/day) for 7 days. Group IV was given VPA + Vit B6 (in a same dose and time). Vit B6 was given to rats by gavage and VPA was given by intraperitoneally. On the 8th day of experiment, all of the animals were fasted overnight and then killed under ether anesthesia. Lens tissues were taken from animals, homogenized in 0.9% saline to make up a 10% homogenate. The homogenates was used for glutathione (GSH), lipid peroxidation (LPO), protein levels, and enzyme analysis. In VPA groups, levels of lens GSH and LPO and activities of glutathione-S-transferase, glutathione peroxidase, glutathione reductase, and aldose reductase were increased, while superoxide dismutase activity was decreased. Treatment with Vit B6 reversed these effects. These results demonstrated that administration of Vit B6 is potentially beneficial agent to reduce the lens damage in VPA toxicity, probably by decreasing oxidative stress.

 

[agnostic]

It's about 3 weeks now since we have started giving him sodium valproate and about 1 week since he is on the full dose. I immediately noticed that his behavior changed for the worse. In my opinion, he is clearly more irritable, less obedient and more hyperactive. Also, his arm flapping and self-stimulatory behavior slightly increased. Luckily, his sleep and eating behavior did not change. The myoclonic jerks became less frequent on the lower dose and completely vanished on the higher dose. In the first week, while being on the lowest dose, he came down with the flu and - possibly due to this infection - still had another grand mal seizure. Then, he did not have a seizure for two weeks. I already thought that he his now responding to the drug. However, last weekend things changed dramatically for the worse. On Friday 10 a.m., while traveling to my parents place by train, he had a grand mal seizure that lasted about 2 minutes. In the following night at 3 a.m. he had another grand mal seizure, which for the first time in his life did not stop spontaneously after 2-3 minutes. I had to apply an emergency medication to stop the seizure and even with this medication it took about 30 minutes until his breathing was completely normal again. The following night, he had yet another seizure, which luckily ended spontaneously after 2 minutes.

To me, it's pretty obvious that he is not only not responding to this medication, it actually seems to aggravate his seizures. It's highly unusal that he has so many seizures in such a short period of time while not beeing sick and that one seizure did not stop spontaneously. I immediately did a literature search to find out, whether similar cases have been described before and what could be the reason for this paradoxical reaction. I found out that seizure aggravation by antiepileptic drugs is a well known phenomenon. Interestingly, I read that sodium valproate less frequently leads to seizure aggravation compared to other antiepileptics and that a seizure aggravation after sodium valproate is usually due an inborn error of metabolism. Apart from urea cycle disorders, nonketotic hyperglycinemia can be the reason for seizure aggravation under sodium valproate. In fact, there are several case reports describing that a paradoxical reaction to sodium valproate triggered new clinical investigations and eventually led to the diagnosis of non-ketotic hyperglycinemia. For example, see here:
A rare case of glycine encephalopathy unveiled by valproate therapy. - PubMed - NCBI

Nonketotic hyperglycinemia (NKH) is characterized by a defect in the glycine cleavage enzyme system, which leads to elevated glycine levels, paricularly in the CSF. This in turn leads to an overstimulation of the NMDA receptor because glycine is an agonist on this receptor, at least in some brain areas. Sodium valproate further suppresses the glycine cleavage system and thereby aggravates the condition. There is a classical type of NKH, which occurs in the neonatal period and which is more severe and a atypical or infantile variant with a more benign course. Although it's quite a rare condition (the prevalence is estimated to be 1 in 60'000), I think its not totally unlikely that my son has infantile NKH because it does fit his symptoms quite well. For example, it is mentioned that children with NKH frequently suffer from hiccups and even already in utero. This was also the case with my son.

I called the neurologist today and told her what happened over the weekend. To my total disappointment, she did not consider it likely that this is a seizure aggravation. She rather blamed the disease than the drug and claimed that his disease coincidently became worse. She said that the dose is probably still not high enough to suppress his seizures. When I told her about what I had read in the literature, she claimed that they had already ruled out all inborn errors of metabolism, which of course is ridiculous because there are so many and some of them can only be diagnosed with expensive or invasive testing. I pointed out that they had not yet measured glycine levels in the CSF and therefore could not have ruled out NKH. She had to admit that this was true. She then claimed that the symptoms of atypical NKH would not fit the symptoms of my son, which again from my understanding of the literature is not true, because atypical NKH can have a variety of clinical expressions. Infantile NKH is usually characterized by mild to moderate developmental delays and seizures. Children with this condition also frequently suffer from irritabillity and hyperactivity.

 

[Tarmander]

It's about 3 weeks now since we have started giving him sodium valproate and about 1 week since he is on the full dose. I immediately noticed that his behavior changed for the worse. In my opinion, he is clearly more irritable, less obedient and more hyperactive. Also, his arm flapping and self-stimulatory behavior slightly increased. Luckily, his sleep and eating behavior did not change. The myoclonic jerks became less frequent on the lower dose and completely vanished on the higher dose. In the first week, while being on the lowest dose, he came down with the flu and - possibly due to this infection - still had another grand mal seizure. Then, he did not have a seizure for two weeks. I already thought that he his now responding to the drug. However, last weekend things changed dramatically for the worse. On Friday 10 a.m., while traveling to my parents place by train, he had a grand mal seizure that lasted about 2 minutes. In the following night at 3 a.m. he had another grand mal seizure, which for the first time in his life did not stop spontaneously after 2-3 minutes. I had to apply an emergency medication to stop the seizure and even with this medication it took about 30 minutes until his breathing was completely normal again. The following night, he had yet another seizure, which luckily ended spontaneously after 2 minutes.

To me, it's pretty obvious that he is not only not responding to this medication, it actually seems to aggravate his seizures. It's highly unusal that he has so many seizures in such a short period of time while not beeing sick and that one seizure did not stop spontaneously. I immediately did a literature search to find out, whether similar cases have been described before and what could be the reason for this paradoxical reaction. I found out that seizure aggravation by antiepileptic drugs is a well known phenomenon. Interestingly, I read that sodium valproate less frequently leads to seizure aggravation compared to other antiepileptics and that a seizure aggravation after sodium valproate is usually due an inborn error of metabolism. Apart from urea cycle disorders, nonketotic hyperglycinemia can be the reason for seizure aggravation under sodium valproate. In fact, there are several case reports describing that a paradoxical reaction to sodium valproate triggered new clinical investigations and eventually led to the diagnosis of non-ketotic hyperglycinemia. For example, see here:
A rare case of glycine encephalopathy unveiled by valproate therapy. - PubMed - NCBI

Nonketotic hyperglycinemia (NKH) is characterized by a defect in the glycine cleavage enzyme system, which leads to elevated glycine levels, paricularly in the CSF. This in turn leads to an overstimulation of the NMDA receptor because glycine is an agonist on this receptor, at least in some brain areas. Sodium valproate further suppresses the glycine cleavage system and thereby aggravates the condition. There is a classical type of NKH, which occurs in the neonatal period and which is more severe and a atypical or infantile variant with a more benign course. Although it's quite a rare condition (the prevalence is estimated to be 1 in 60'000), I think its not totally unlikely that my son has infantile NKH because it does fit his symptoms quite well. For example, it is mentioned that children with NKH frequently suffer from hiccups and even already in utero. This was also the case with my son.

I called the neurologist today and told her what happened over the weekend. To my total disappointment, she did not consider it likely that this is a seizure aggravation. She rather blamed the disease than the drug and claimed that his disease coincidently became worse. She said that the dose is probably still not high enough to suppress his seizures. When I told her about what I had read in the literature, she claimed that they had already ruled out all inborn errors of metabolism, which of course is ridiculous because there are so many and some of them can only be diagnosed with expensive or invasive testing. I pointed out that they had not yet measured glycine levels in the CSF and therefore could not have ruled out NKH. She had to admit that this was true. She then claimed that the symptoms of atypical NKH would not fit the symptoms of my son, which again from my understanding of the literature is not true, because atypical NKH can have a variety of clinical expressions. Infantile NKH is usually characterized by mild to moderate developmental delays and seizures. Children with this condition also frequently suffer from irritabillity and hyperactivity.

I stumbled on this thread and I have to say, you are courageous, dedicated, and I admire what you have done and are trying to do for your son. At the same time, the people you are surrounded by are frustratingly ignorant. I can't imagine the helplessness you must have felt at times.

It has been a couple years since you have updated. What is happening now? Ever try CBD?

 

[AlexFergus]

@agnostic - I was wondering if you could provide an update on your son's condition?

I have just finished reading your thread as my 3 year old son is also epileptic. Your story resonates with mine - though I admire the amount of research you did!!
Like you, we wanted to resist the powerful medications and tried more natural treatments (including CBD), but unfortunately we had no improvements. Our son was having seizures lasting 15-20minutes, and when he had 2 in a day we decided that was enough and started on Keppra.

We went from an average of one seizure every 3 weeks, to now having seizures only when he falls ill (averaging one every 2-3 months).

His keppra dose is quite high now, which is unfortunate, but given the severity of his seziures we have to do what we can to control them.

I don't mean to hijack this thread, but I will share a few details about his condition in case anyone reading this thinks of anything we could try:

- Born naturally, though came out sunny side up which meant some delays. Healthy weight etc. Delayed cord clamp etc.
- Breastfed for 2.5 years.
- Not vaccinated.
- Had first seizure just before 2nd birthday. Focal Seizure.
- Had tongue tie - cut at a late age (doctors missed it when young). Also had some big issues with eating solids - worked with a specialist to overcome this.
- Lives on a small farm, always outside, with animals etc.
- Has been a terrible sleeper. Even at 3.5 years old I could count on my hands how many times he's slept right through the night.
- I think he has some mild sleep apeana.
- Advanced for his age from a speech and motor control point of view (was riding bikes without trainer wheels at 3 years old, good speech etc, rides his own motorbike on the farm etc)
- Diet has been pretty good - we homekill our beef, chicken and lamb. Catch a lot of fish. Grow some veges in our garden. Eat organic otherwise (most of the time).
- He drinks a lot of milk (A2). Has ice cream most nights. Eats a lot of fruit. Also eats a lot of pasta (rice based as my wife if GF), cheese, meat.

MRI, Spinal tap, urine tests and every blood test he has done has come back normal.

First EEG came back normal. More recent one came back showing focal epileptiform changes in the central left parietal region.

Since he's been on Keppra (1 year now) he's had 4 seizures. Each one was when he was sick (covid, general flu, not sure what the other illnesses were but he had tonsolitis). He gets crazy fevers when he's sick. Even a minor cold triggers a fever.
It's been like this since he was a baby.
His most recent illness he had a temp for 5 days straight and 2 nights his temp was over 40degrees (104).

He also started getting night sweats a few months ago. Though they only occur when he falls asleep (i.e. goes to sleep then starts sweating - we strip all his layers off, and within 2-3 hours he's fine and can sleep under the blankets for the rest of the night).
I've always wondered if theres an HPA issue? Thyroid?

He also has Parasomnias/night terrors (which are horrible).

We're currently supplementing with B6 (originally to control the side effects of Keppra ( levetiracetam ) but I see there are epilepsy benefits as well. And more recently we have started with magnesium supplements in the evening. Though he has still had seizures while on these supplements.

When he falls ill now, we also give him Clobazam - this has anti-seizure properties. We've only used this once (his most recent illness) and we didn't have any events so that was great (though the medication really knocks him around, poor kid, saying that it's better than a 15minute seizure and all the after effects).

I'm at peace with the fact we are using drugs to help with the seizures, but at the same time I would love to discover what causes them, and if there are treatments we can use that have less side effects.

I'm looking into photobiomodulation, there are some animal studies showing it can help with seizures.

Otherwise our neurologist says stick with the current plan, and hopefully he'll grow out of it.

 

[agnostic]

@AlexFergus

It's a strange coincidence that you reactivated this thread yesterday because I was thinking about posting a follow-up just yesterday.

Sorry, that I didn’t post a follow-up for so long but the whole story just became too depressing and for a long time my influence on my son’s treatment was quite limited. At times, I was even threatened to lose custody if I do not follow doctor’s advice. My ex-wife also refused to discuss any alternative treatments with me for a long time.

Here’s what happened after my last post:

The doctors further increased the dose of valproic acid. At first, it seemed to help but after a few weeks while he was under my custody (we spent a few days at my parents place), he had a severe relapse. He started to have generalized tonic-clonic seizures every two hours. Each seizure lasted about three minutes and each seizure was so exhausting that he immediately fell asleep after. So, he was in a constant cycle of grand mal seizure and sleeping and not even a rescue medication (benzodiazepine) could bring him out of this cycle. Even worse, my ex-wife and her family even accused me of having neglected him (by not giving him enough to drink or not giving him his prescribed medication).

We then went to the epilepsy clinic where they gave him intravenous Keppra (Levetiracetam) which finally stopped it. Finally, the doctors agreed with me that valproic acid is not working for him and suggested to change his medication to Keppra and to do this at the hospital. However, they said that they can only reduce valproic acid after Keppra is fully dosed up, which takes about one week. I reluctantly agreed and stayed with him at the hospital for one week while my wife was on vacation.

Unfortunately, the Keppra didn’t cut it and he still had one grand mal seizure almost every morning. Therefore, they didn’t want to wean him off of valproic acid anymore. I was so upset because they had promised it and because I was totally convinced that valproic acid is making things worse. One morning, the chief physician came to our ward for a visit. Since the assistant and senior doctor would not listen to me (even though I am scientist and have PhD in psychology), I thought maybe this one would take me more seriously but it turned out that he was the biggest sociopath of all. He refused to consider that valproic acid has worsened his seizures (because it’s considered the most potent antiepileptic) and threatened me. He said that my son could die if we wean him off valproic acid and that then I could sue him. Obviously, he was more concerned about getting sued than the health of my son. He also said that I should go to another doctor if I don’t trust him.

After about one week in the hospital, I went home with my son. They wanted us to stay longer but I thought at home I can at least control what he eats and give him supplements. Unfortunately, after a few days, he had again about 3-4 grand mal seizures in a row and I had to go the hospital again. However, this time I went to the university children’s hospital because a few weeks earlier we had already visited a professor of child neurology there. We had contacted this doctor because I had the hope that my son’s condition is due to a cerebral folate deficiency (CFD), which could be treated at the root with high dose folinic acid. CFD seems to be quite frequent in children with autism and seizures and there are several randomized controlled trials showing a positive effect of high dose folinic acid on autism. The said doctor was an expert in this and had published papers on CFD. He was much more open minded and not as arrogant as the others. He agreed to test my son for CFD, but since this is a very invasive test and requires lumbar puncture, he suggested to first perform whole exome sequencing. He agreed that Dravet syndrome, which the other clinic had suspected, is very unlikely and couldn’t understand why the epilepsy clinic was not able to perform whole exome sequencing, which nowadays is quite cheap and has a good chance to reveal the true cause. He also immediately ordered various blood and urinary tests to rule out metabolic disorders.

Since, we were now on the ward of this doctor, I suggested to do the MRI and lumbar puncture already even though we didn’t have the results of the genetic testing yet. The doctor agreed. Luckily, my son didn’t have any seizures any more during our stay and so we left after a few days.

A few weeks later we got the genetic test result and it was a complete shock to me. It turned out that he has rare genetic mutation on the CHD2 gene, see:

CHD2 - Wikipedia

CHD2-Related Neurodevelopmental Disorders - GeneReviews® - NCBI Bookshelf

CHD2 is a chromatin remodeler and alters gene expression. It plays an important role in epigenetic processes.

There are only a few dozen documented cases in the literature, but at least several hundred cases have been discovered worldwide so far according to the CHD2 support and research group on Facebook.

The genetic mutation that my son has is de novo since it does not occur in my own or my ex-wife’s genome.

Although the diagnosis of CHD2 fits quite well to my son’s condition, I think one can never be 100% certain that this is the main or only reason for his seizures. It is assumed that the specific genetic mutation that he has (one amino acid in a very long sequence of amino acid is replaced) turns the CHD2 dysfunctional. However, according to my understanding, this is based on a theoretical model and based on the observation that the position that is changed in his genome is preserved across species which indicates that it is necessary for survival. However, no one has produced the exact same mutation in a biological model in a lab and observed the consequences. Almost all children affected by CHD2 mutations have mutations at different locations of the CHD2 gene and phenotype varies a lot. Some children developed seizures very early, are severely treatment resistant and handicapped, others only developed seizures at the age of 9 or even later and are only mildly impaired. Some affected children have no seizures at all, but a diagnosis of autism. In the above-mentioned Facebook group there are also several children who have a parent with the same CHD2 mutation. These parents were unaffected suggesting that CHD2 was not the true cause or that it was only pathogenic in combination with other genes or environmental factors.

Interestingly, a few days later we also got the result of the lumbar puncture and it turned out that my son’s cerebral folate was indeed below the reference level. However, since it was only slightly below the reference level and since we had now found this genetic mutation, which according to our doctor could better explain his seizures, our doctor didn’t consider it pathogenic.

I insisted that it could still play a role and asked for a therapeutic trial with high dose folinic acid. Our doctor agreed to do a trial but suggested to first change his medication since he still had seizures almost daily. I remember one day where he had up to 8 grand mal seizures and he also developed new seizure types, such has short tonic seizures, atonic (drop) seizures in addition to myoclonic and grand mal seizures that he had before. He also regressed a little and was extremely agitated. Keppra was clearly not working. The new doctor prescribed clobazam to stabilize him, weaned him off Keppra and added Lamotrigine. Unfortunately, even though this new doctor was much more open minded, he was also a big fan of valproic acid and strongly advised against stopping it. I could only hope for that best and that his clinical experience is leading him to the right decisions. He had decades of clinical experience and was a professor of neurology. Furthermore, he had not only studied medicine but also physics and was definitely highly intelligent. So, I respected him.

The new doctor also added 4 mg of sustained release melatonin to improve his sleep. Even though, this is not Peat approved, I agreed because there is quite good evidence from both animal and human studies that melatonin also improves seizures. I think this helped him quite a bit.

The change in medication worked quite well, although he never became seizure free, and to my surprise we were able to wean him off clobazam and Keppra without major problems. After he was only on lamotrigine and valproic acid, we were finally able to the therapeutic trial with folinic acid.

At first, the folinic acid seemed to help. He became more alert, his motor function was improved and he started to say more words. Unfortunately, after a few weeks, the honey moon was over and it went downhill again. He was complete mess again.

I had read numerous reports on the CFD facebook groups from parents with epileptic children. Several of these parents reported that folinic acid was tremendously helpful for their children but only in combination with other b-vitamins, particularly B12 and often only after they had stopped anti-epileptic medication.

Although our new doctor was relatively open minded and I could bring up scientific articles (he even encouraged me research the literature), I could not discuss with him anectotal evidence from Facebook. He actually was quite annoyed whenever I brought it up. Even though there are some reports in the scientific literature that folinic acid can aggravate seizures in high doses, he did not seriously consider the possibility.

Anyway, we stopped the folinic acid and at the same time lamotrigine was increased. Up to that point, we still had given a small dose of magnesium glycinate, pyridoxal-5-phosphate, vitamin E and D, although my son mostly lived at my ex-wifes place and often questioned the compliance of my ex-wife with regard to supplements.

The new doctor didn’t object to use supplements as add-on treatment. He didn’t believe they would make much of a difference neither positive nor negative. My ex-wife agreed to give him supplements as long as our doctor approves it. I therefore suggested to give him a well formulated multivitamin powder that contains all the nutrients that I consider important in epilepsy. I wanted to make the provision of the supplements as easy as possible in the hope of increasing the compliance of my ex-wife. After checking out dozens of multivitamins, I finally settled with this one, as it has been researched in autistic children and I thought it would then be easier to get our doctor on board.

[ANRC Essentials]

Luckily, our doctor agreed and so my ex-wife was willing to give it at try. I think it helped a little but not as much as I had hoped. Also, the taste of the powder was quite bad and so it was always a struggle to give it to our son. The magnesium content was also too low in my opinion and some ingredients are not peat approved such as NAC, MSM, NADH etc. So, I was not very happy with this.

Later we also tried a small dose of a full spectrum hemp oil, but it didn’t really work.

About half a year later, I finally managed to convince my ex-wife and the doctor to reduce valproic acid to see whether it’s doing him more harm than good. We agreed to try it during summer vacation in case it’s aggravating his seizures. At first, he had more seizures, but we stick to it and he stabilized again. We had already weaned him off 2 thirds of his original dose and it looked quite promising. He seemed to be more alert, hand flapping was reduced and more talkative. But then school started again and he had a severe relapse. Seizures were completely out of control and I could not prevent that his dose was increased again even beyond the original dose.

Since I was unhappy with his multivitamin, I started to produce my own multivitamin. I bought all the vitamins and minerals as raw powders and produced a batch of mixed powder every two weeks. This way, I could finally use to optimal form and dose of each ingredient. I think this was a very important step and had a big impact.

He was doing much better after we started it but this was mostly attributed to the increased dose antiepileptics by our doctor, my ex-wife and the people at school.

Fast forward, we had more ups and downs. Progress was still very slow. He still had smaller seizures almost every night and even still suffered from the dreaded drop seizures from time to time, which also sometimes led to injuries.

I was still convinced that he never has a chance to become seizure free while being on these drugs and the only chance I saw for him to get him seizure free and getting him off of these drugs would be to do the ketogenic diet. Several parents of children with CHD2 have tried it and reported their results on the CHD2 Facebook groups. It only worked for about half of the kids but it some cases the results were life-changing. In one case, a child who was on five different antiepileptics at once and still had seizures, became completely seizure free and remained seizure free after weaning off all antiepileptics. The mother also reported that the child started to talk at the age of 7 as soon as they had finally weaned off all antiepileptics.

This was giving me hope. However, it took me about 2 years until I could finally convince our neurologist and my ex-wife to give the ketogenic diet a try.

Unfortunately, it didn’t work out for us. After about 2 weeks into the diet, he had one of worst seizures ever. Normally, a grand mal seizure would last for 3 minutes. This time it didn’t stop for about 20 minutes and we had to go to the emergency clinic.

I still didn’t want to give up because the mother from above told me that she didn’t see much improvements in the first few months. So, I managed to convince my wife to continue with the diet. For a few weeks, it went relatively well again and he hardly had any seizures but then he relapsed again and I could resist the pressure any more to stop the diet. At the end, we only did for 6 weeks.

Since then, valproic acid and lamotrigine have been further increased a few times. Both drugs are now near the upper range of the allowed dosages. He also has a small dose of nitrazepam before sleep which was added already a few years ago against my will and never taken off.

He is now 8 years old. At the moment, he is relatively stable. Drop seizures occur very rarely nowadays. Grand mal seizures maybe once every two weeks and mostly during sleep. Short tonic seizures during sleep maybe twice per week.

Luckily, he seems to be quite a happy child. He does not seem to have any pains and almost never cries. He is also not aggressive at all. He can walk, feed himself with a spoon and drink from a glass. However, what saddens me a lot is that he is completely within his own world. Since the age of 3, he has made almost no progress anymore and, in some respect, he has even regressed. He can still only say a few words and a dialogue is impossible. His play is extremely restricted and simple. For example, he likes to put marbles from one vessel to another and could do that for hours. He needs constant supervision and help for everyday tasks, such as dressing up, going to the toilet etc.

I’m sorry that I don’t have any better news. If had found the magical cure I would shout it from the roof tops. I’m still trying to make sense out of all this. I’m a spiritual person and think that everything happens for a reason. But I have not yet found out why this has occurred to me and what lesson I have to learn.

 

[AlexFergus]

Oh my @agnostic, I really don't know what to say.

Reading this - and in particular the last few paragraphs - brought a tear to my eye.
I think of all the stress, anxiety and fear that we have been through - yet your situation is 1000x worst than ours. I really do feel for you and your family and of course your son.

Seeing your child suffer is such a horrible feeling, especially when you are so helpless. I hate it. It's why I respect all the work you have done researching your sons condition and treatments.

For us we are fortunate that the Keppra is controlling the random seizures - it's now finding a way to control them when he's ill (we are using Clobazam as a short term medication when he was sick, he recently had a 5 day fever, and with this new combo we didn't have any seizures, so that was a win).

Of course I'd rather not see him on so many powerful drugs, but the alternative is worst.

I have looked into all the papers you have shared in this thread, and we have also made some tweaks as a result, so thank you.

Curious - have you looked into Photobiomodulation? There seems to be some promising studies on PBM and epilepsy, I'm slowing digging into this - if I find anything amazing I will share it.

 

[agnostic]

@AlexFergus

No, I've not looked into photobiomodulation, but I can share a few other things I've learned over the years. Here is one thing:

I've mentioned earlier in the thread that I was very worried that valproic acid could have led to increased seizure activity due to increased ammonia production. Hyperammonemia is quite a frequent side effect of valproic acid especially in small children and when multiple antiepileptic drugs are combined. Since I could not convince the doctors to wean him off valproic acid, I tried my best to at least provide him with protective factors.

When hyperammonia in people taking valproic acid occurs, it is usually treated with l-carnitine because l-carnitine helps to excrete ammonia and valproic acid is well known to inhibit the biosynthesis of l-carnitine. That's why some doctors have gone so far to always add l-carnitine to valproic acid in children as a precautionary measure. However, l-carnitine is not a peaty substance because it can e.g. reduce thyroid function and some parents of children with epilepsy have reported on some forums that it actually worsened seizures. Interestingly, there is an animal study showing that the mechanism of action by which valproic acid decreases the biosynthesis of l-carnitine is by reducing the levels of alpha-ketoglutarate:

Biochem Pharmacol
1996 Nov 8;52(9):1429-33.
doi: 10.1016/s0006-2952(96)00507-2.

Inhibition of carnitine biosynthesis by valproic acid in rats--the biochemical mechanism of inhibition​

V Farkas 1, I Bock, J Cseko, A Sandor

Abstract​

The anticonvulsive drug, valproic acid (VPA), inhibits the biosynthesis of carnitine, and may contribute in this way to carnitine deficiency associated with VPA therapy. The conversion of [3H]-butyrobetaine into [3H]-carnitine was determined 60 min following a single intraperitoneal (i.p.) dose of 1.2 mmol/kg VPA in rats. The fraction of radioactivity found in [3H]-carnitine in the liver decreased from 63.2 +/- 1.50% to 39.2 +/- 1.11% (mean +/- SEM). Total carnitine in the liver also decreased, whereas the precursor butyrobetaine increased from 5.01 +/- 0.71 nmol/g to 8.22 +/- 0.82 nmol/g (mean +/- SEM). VPA also exhibited a dramatic effect on the conversion of an unlabeled loading amount of butyrobetaine. The increment in total carnitine caused by butyrobetaine in liver was reduced from 161 +/- 15.4 nmol/g to 53.2 +/- 5.11 nmol/g (mean +/- SEM). These data prove that VPA reduces the flux through butyrobetaine hydroxylase (EC 1.14.11.1.). The drug in vitro, however, did not inhibit the enzyme directly. Searching for the mechanism of action, we found that VPA decreased the level of alpha-ketoglutarate (alpha-KG; a cofactor of butyrobetaine hydroxylase) from 73.5 +/- 2.90 nmol/g to 52.9 +/- 2.2 nmol/g (mean +/- SEM) in the liver. The level of 1-glutamate showed a rather dramatic decrease in the liver. Moreover, alpha-KG proved to have a protective role against VPA in the [3H]-butyrobetaine conversion experiment.

Two other animal studies show that alpha-ketoglutaric acid is highly protective against toxic effects of valproic aid:

Pol J Pharmacol
2003 Jan-Feb;55(1):31-6.

Enhancement of circulatory antioxidants by alpha-ketoglutarate during sodium valproate treatment in Wistar rats​

Vidya Murugesan 1, Perumal Subramanian

Abstract​

The effects of alpha-ketoglutarate (alpha-KG) on sodium valproate-induced hyperammonemia and hepatotoxicity were studied in biochemical experiments in rats. The levels of ammonia, urea, serum transaminases, hydroperoxides and thiobarbituric acid reactive substances were significantly increased in sodium valproate-treated rats. These levels were significantly decreased in alpha-KG- and sodium valproate-treated rats. Further, non-enzymatic (vitamins C and E) and enzymatic (superoxide dismutase and catalase) antioxidants were significantly decreased in sodium valproate-treated rats and were increased in alpha-KG- and sodium valproate-treated rats. These biochemical alterations during alpha-KG treatment could be due to (i) its ability to act as an ubiquitous collector of amino groups in body tissues, (ii) the participation of alpha-KG in the non-enzymatic oxidative decarboxylation in the hydrogen peroxide decomposition process and (iii) enhancing the proper metabolism of fats which could suppress oxygen radical generation and, thus, prevent the lipid peroxidative damages in rats.

J Appl Biomed 4:141-146, 2006 | DOI: 10.32725/jab.2006.015
Murugesan Vidya, Perumal Subramanian*
Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar - 608 002, Tamil Nadu, India

Effects of α-ketoglutarate on antioxidants and lipid peroxidation products in rats treated with sodium valproate​

Murugesan Vidya, Perumal Subramanian*Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar - 608 002, Tamil Nadu, India
Oxidative stress may cause free radical reactions to produce deleterious modifications in membranes, proteins, enzymes and DNA. Valproic acid is a major anti-epileptic drug with a broad spectrum of anti-epileptic activity. Chronic treatment with valproic acid can lead to elevated serum ammonia levels and specific oxidative metabolites of valproic acid have been associated with the drug's toxicity. The influence of sodium valproate treatment on lipid peroxidation and lipid profiles and the detoxifying effects of α-ketoglutarate on sodium valproate induced toxicity were studied in rats. The levels of thiobarbituric acid reactive substances, hydroperoxides and lipid profile variables (cholesterol, phospholipids, triglycerides and free fatty acids) were significantly increased in sodium valproate treated rats. Further, non-enzymic antioxidants (reduced glutathione) and the activities of the enzymic (superoxide dismutase, catalase, glutathione peroxidase) antioxidants were significantly decreased in sodium valproate treated rats. The levels were observed to be normal in α-KG + sodium valproate treated rats. These biochemical alterations during α-KG treatment could be due to (i) its ubiquitous collection of amino groups in body tissues, (ii) the participation of α-KG in non-enzymatic oxidative decarboxylation of the hydrogen peroxide decomposition process and (iii) its role in the metabolism of fats which could suppress oxygen radical generation and thus prevent lipid peroxidative damage.

I also found to other animal studies showing the alpha-ketoglutaric acid is anticonvulsive:
Protection against cyanide-induced convulsions with alpha-ketoglutarate - PubMed
Effect of alpha-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice - PubMed

There is also also a very interesting review paper reporting that it has antioxidative function and that it improves energy production

Biomed Res Int. 2018; 2018: 3408467.
Published online 2018 Mar 21. doi: 10.1155/2018/3408467

The Antioxidative Function of Alpha-Ketoglutarate and Its Applications​

Shaojuan Liu, 1 , 2 Liuqin He, 1 , 2 and Kang Yao

1

Abstract​

Alpha-ketoglutarate (AKG) is a crucial intermediate of the Krebs cycle and plays a critical role in multiple metabolic processes in animals and humans. Of note, AKG contributes to the oxidation of nutrients (i.e., amino acids, glucose, fatty acids) and then provides energy for cell processes. As a precursor of glutamate and glutamine, AKG acts as an antioxidant agent as it directly reacts with hydrogen peroxide with formation of succinate, water, and carbon dioxide; meanwhile, it discharges plenty of ATP by oxidative decarboxylation. Recent studies also show that AKG has alleviative effect on oxidative stress as a source of energy and an antioxidant in mammalian cells. In this review, we highlight recent advances in the antioxidative function of AKG and its applications in animals and humans.

I also sent these studies to Ray Peat and had the following discussion with him:

Me:
Do you think it would be a good idea to give alpha-ketoglurate to my son as a protective measure against side effects of valproic acid?

Ray Peat:
It does seem to have the right effects, but the large amount they used would probably be hard to incorporate into foods. A low phosphate, high calcium diet, vitamin D, and progesterone are basic anti-seizure brain protective things.

Me:
Regarding the dosage of alpha-ketoglutarate, Dr. Jon Pangborn, who pioneered the use of alpha-ketoglutarate in autistic children to lower ammonia, considered 50-200mg per kg body weight a good dosage, which I think would not be too hard to integrate into his diet. One problem is that pure alpha-ketoglutarate is hard to find. Kirkman labs sells alpha-ketoglutarate capsules but it also contains silicone dioxide. Other companies sell alpha-ketoglutarate that is bound to ornithine, arginine or creatine. I was thinking that alpha-ketoglutarate bound to creatine could be particularly beneficial as creatine was also demonstrated to have anticonvulsive effects in several animal studies and there is even a small human study in which creatine has been tried in epileptic children on a ketogenic diet and it was found to be rather helpful. At least, no child experienced a seizure worsening:
https://www.oatext.com/pdf/IMM-6-357.pdf

Creatine could also be particularly beneficial for patients taking valproic acid as this drug also seems to interfere with creatine production:
Valproate adverse effects on creatine metabolism and transport in a patient under drug therapy
Rise in brain GABA to further stress the metabolic link between valproate and creatine - PubMed

Creatine alpha ketoglutarate is available in capsules without fillers. Do you think this would be a good idea?
https://goodstate.com/products/good...eatine-alpha-ketoglutarate-650mg-120-capsules

Regarding progesterone, I think it would not be feasible to give it to my son [...]. What progesterone dosage do you think would be adequate for a 5 year old boy that weighs about 18kg?

We already supplemented about 1000 I.U. Vitamin D during winter and spring and have recently stopped as he should get enough sunshine during the summer.

The calcium-phosphate could indeed be a problem since we had mostly eliminated milk products from his diet the last few months after suspecting that he does not tolerate it very well and a lot of people with seizures report better seizure control without dairy. He also eats quite a lot of phosphate rich meat. I will now consider giving him more calcium as a supplement. I know you consider calcium carbonate a good form. I recently also read good things about calcium acetate and it's now available as pure powder from bulksupplements.com. What do you think of calcium acetate as a supplement?

Sorry, for posing you so many questions. Thanks again for your help. I really appreciate it.

Ray Peat:
Has he had blood tests for hormones and vitamin D? The carbonate with calcium supports its antiseizure effect; I think, especially with the high intake of phosphate relative to calcium, that acetate would increase the tendency toward lower ionized calcium.

Me:
Thanks again! We haven't checked vitamin d recently. Last time we did, about 2 years ago, it was 43ng/ml. Which hormones would be important to check? Did I understand you correctly, that calcium acetate would not be a good form of calcium in context of a high phosphate intake? How much calcium carbonate would you give?

Ray Peat
I think calcium intake should be at least equivalent to phosphate. Calcium acetate reduces phosphate absorption slightly more than calcium carbonate does, but the acetate that’s absorbed is likely to lower ionized calcium harmfully. TSH and parathyroid hormone tests could be helpful.

Me:
Thank you very much. Unfortunately, the parathyroid hormone was never measured and TSH was only measured once at the age of 16 months, when seizures started. It was at 2 mlU/l at that time. I will ask the doctor to measure these hormones the next time blood is taken.

I started to give him calcium carbonate (250mg elemental calcium 3 times per day). So far, he seems to tolerate it fine and he didn't have a major seizure the last two nights.

I realized that calcium could also be taken in the form of calcium alpha-ketoglutarate. Wouldn't that be a very good form for him, given that alpha-ketoglutarate protects against sodium valproate toxicity and is potentially anticonvulsive in itself?

I found some very interesting studies about calcium alpha-ketoglutarate. It seems to be a very good phosphate binder and treatment for secondary hyperparathyroidism and there is even a study showing that it extends lifespan in rats. See below:

Miner Electrolyte Metab . 1996;22(1-3):196-9.

Long-term Treatment With Calcium-Alpha-Ketoglutarate Corrects Secondary Hyperparathyroidism
E Zimmermann, S Wassmer, V Steudle

Calcium-alpha-ketoglutarate (Ca-ket) is known as a highly effective phosphate (P) binder in hemodialysis (HD) patients. In addition, alpha-ketoglutarate has been shown to improve metabolic alterations. We investigated the effect of long-term P-binding therapy with Ca-ket to determine whether P accumulation is the main reason of secondary hyperparathyroidism (HPT) in HD patients or not. Ca-ket was prescribed to 14 HD patients as a soluble preparation in a mean dosage of 4.5 g/day (0.975 g elemental Ca) for a period of 36 months. Serum P continuously dropped from prestudy 2.6 +/- 0.1 (mean +/- SEM) to 1.9 +/- 0.07 mmol/l (p < 0.001), whereas serum Ca increased from 2.2 +/- 0.1 to 2.47 +/- 0.08 mmol/l (p < 0.05). Thus, Ca/P ratio in serum converted significantly from 0.91 +/- 0.02 (prestudy) to 1.28 +/- 0.01 (p < 0.001). Intact parathyroid hormone (iPTH) continuously normalized in all patients from 29 +/- 5 to 8 +/- 2 pmol/l (p < 0.001). The present data show that long-term treatment with Ca-ket normalizes secondary HPT by simultaneously P binding and correcting Ca/P ratio in serum without vitamin D treatment.


Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice
Azar Asadi Shahmirzadi, Daniel Edgar, Chen-Yu Liao, Yueh-Mei Hsu, Mark Lucanic, Arash Asadi Shahmirzadi, Christopher Wiley, Rebeccah Riley, Brian Kaplowitz, Garbo Gan, Chisaka Kuehnemann, Dipa Bhaumik, Judith Campisi, Brian K Kennedy, Gordon J. Lithgow
doi: http://sci-hub.st/10.1101/779157

The decline in early life mortality since the 1950s has resulted in dramatic demographic shift towards aged population. Aging manifests as a decline in health, multiple organ dysfunction and increased vulnerability to diseases, which degrades quality of life. A verity of genetic and pharmacological interventions, mostly from non-vertebrate models, have been identified that can enhance lifespan. Whether these interventions extend healthspan, the disease free and functional period of life, has only sometimes been tested and is often a matter of debate. Human aging indices have been developed to assess elements of functional decline with aging (e.g. sarcopenia, cognitive function). However, corresponding comprehensive indices in mice are seldom applied to aging studies. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically-relevant healthspan measurements. Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

Ray Peat
It sounds very good. Supplements always contain manufacturing contaminants, so it would be good to test it on an adult for a few days. I notice some supplements have toxic additives such as silica.


Since Ray Peat had approved calcium alpha-keto-glutarate I ordered it as a pure powder and started to give it to my son. It seemed to have quite a positive effect although it did not magically heal him from this epilepsy of course. I give him 2400mg calcium alpha-ketoglutarate in two divided doses per day which corresponds to 500mg of calcium per day. We have kept this dosage since about 2 years now.

I think Peat's emphasis on the calcium to phosphate ratio is spot on because we also noticed several times that too much meat increases seizure activity in my son.

Calcium alpha-ketoglutarate is quite a fascinating supplements because it also seems to have positive effect on the microbiome and to lower intestinal inflammation. It even has been shown to increase butyrate production. This is huge, because intenstinal inflammation is well known to increase seizure activity and butyrate has shown anti-convulsive effects in animal studies. Here are some studies (https://www.sciencedirect.com/.../abs/pii/S0377840117300834, https://europepmc.org/article/med/21196226, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732704/)

I also made a separate thread on calcium-alpha-ketoglutarate here:
Calcium Alpha-ketoglutarate. A Calcium Supplement With Added Benefits?