Showing posts with label Modified Atkins. Show all posts
Showing posts with label Modified Atkins. Show all posts

Wednesday, 18 January 2017

The Clever Ketogenic Diet for some Autism

I have covered the Ketogenic Diet (KD) in earlier posts. 

There are more and more studies being published that apply the KD to mouse models of autism.

Calling the KD a diet does rather under sell it.  The classic therapeutic ketogenic diet was developed for treatment of pediatric epilepsy in the 1920s and was widely used into the next decade, but its popularity waned with the introduction of effective epilepsy drugs.

There are various exclusion diets put forward to treat different medical conditions; some are medically accepted but most are not, but that does not mean they do not benefit at least some people.

When it comes to the ketogenic diet (KD) the situation is completely different, this diet is supposed to be started in hospital and maintained under occasional medical guidance. The KD was developed as a medical therapy to treat pediatric epilepsy.  It is very restrictive which is why it is used mainly in children, since they usually will (eventually) eat what is put in front of them.

The KD was pioneered as a medical therapy by researchers at Johns Hopkins in the 1920s, over the years they have shown that most of the benefit of the KD can be achieved by the much less restrictive Modified Atkins Diet (MAD).  The first autism mouse study below suggests something similar “Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior”.

What about the KD in Autism?

Most people with autism, but without epilepsy, will struggle to get medical help to initiate the KD.  Much research in animal models points to the potential benefit of the KD.

·        Drug treatments are poorly effective against core symptoms of autism.

·        Ketogenic diets were tested in EL mice, a model of comorbid autism and epilepsy.

·        Sociability was improved and repetitive behaviors were reduced in female mice.

·        In males behavioral improvements were more limited.

·        Metabolic therapy may be especially beneficial in comorbid autism and epilepsy.

The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence that supports the efficacy of ketogenic diets in treating the core symptoms of autism spectrum disorders in animal models as well as limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5 weeks of age. Beginning at 8 weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder in a sex- and test-specific manner; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice, with limited effects in males. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.

·        The BTBR mouse has lower movement thresholds and larger motor maps relative to control mice.

·        The high-fat low-carbohydrate ketogenic diet raised movement thresholds and reduced motor map size in BTBR mice.

·        The ketogenic diet normalizes movement thresholds and motor map size to control levels.

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder characterized by deficits in sociability and communication, and restricted and/or repetitive motor behaviors. Amongst the diverse hypotheses regarding the pathophysiology of ASD, one possibility is that there is increased neuronal excitation, leading to alterations in sensory processing, functional integration and behavior. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used in the treatment of medically intractable epilepsy, has already been shown to reduce autistic behaviors in both humans and in rodent models of ASD. While the mechanisms underlying these effects remain unclear, we hypothesized that this dietary approach might shift the balance of excitation and inhibition towards more normal levels of inhibition. Using high-resolution intracortical microstimulation, we investigated basal sensorimotor excitation/inhibition in the BTBR T + Itprtf/J (BTBR) mouse model of ASD and tested whether the KD restores the balance of excitation/inhibition. We found that BTBR mice had lower movement thresholds and larger motor maps indicative of higher excitation/inhibition compared to C57BL/6J (B6) controls, and that the KD reversed both these abnormalities. Collectively, our results afford a greater understanding of cortical excitation/inhibition balance in ASD and may help expedite the development of therapeutic approaches aimed at improving functional outcomes in this disorder.


Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBRT + tf/j (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile.


Juvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10–14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals.


Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.

·        We evaluated, throughout a systematic review, the studies with a relationship between autism and ketogenic diet.

·        Studies points to effects of KD on behavioral symptoms in ASD through the improve score in Childhood Autism Rating Scale (CARS).

·        Reviewed studies suggest effects of KD especially in moderate and mild cases of autism.

·        KD in prenatal VPA exposed rodents, as well in BTBR and Mecp2 mice strains, caused attenuation of some autistic-like features.

Autism spectrum disorder (ASD) is primarily characterized by impaired social interaction and communication, as well as restricted repetitive behaviours and interests. The utilization of the ketogenic diet (KD) in different neurological disorders has become a valid approach over time, and recently, it has also been advocated as a potential therapeutic for ASD. A MEDLINE, Scopus and Cochrane search was performed by two independent reviewers to investigate the relationship between ASD and the KD in humans and experimental studies. Of the eighty-one potentially relevant articles, eight articles met the inclusion criteria: three studies with animals and five studies with humans. The consistency between reviewers was κ = 0.817. In humans, the studies mainly focused on the behavioural outcomes provided by this diet and reported ameliorated behavioural symptoms via an improved score in the Childhood Autism Rating Scale (CARS). The KD in prenatal valproic acid (VPA)-exposed rodents, as well as in BTBR and Mecp2 mice strains, resulted in an attenuation of some autistic-like features. The limited number of reports of improvements after treatment with the KD is insufficient to attest to the practicability of the KD as a treatment for ASD, but it is still a good indicator that this diet is a promising therapeutic option for this disorder.


Since very many parents do not want to use drugs to treat autism, it is surprising more people do not try the ketogenic diet (KD) or at least the KD-lite, which is the Modified Atkins Diet (MAD).
I think you have to be pretty rigid about the MAD, if you go MAD-lite you will likely achieve little; rather like thinking you have a Mediterranean diet because you buy the occasional bottle of olive oil.
Many children with epilepsy who started out on the KD continue in adulthood with the Modified Atkins Diet (MAD).
There is anecdotal evidence that people with mitochondrial disease benefit from the KD.
All in all, it is hard to argue that the KD/MAD should not be the first choice for those choosing to treat autism by diet. It really does have science and clinical study to support it.

In some people with autism it appears that when you eat is as important as what you eat.  There can be strange behaviors just after eating, presumably caused by a spike in blood sugar, or for others before breakfast. 

In regressive autism (AMD) Dr Kelley, from Johns Hopkins, wrote that:- 

Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.  In some children, early morning symptoms can be a consequence of compromised mitochondrial function, whereas, in others, a normal rise in epinephrine consequent to a falling blood glucose level in the early morning hours can elicit agitation, ataxia, tremors, or difficulty waking.  In children who normally sleep more than 10 hours at night, significant mitochondrial destabilization can occur by the morning and be evident in biochemical tests, although this is less common in AMD than in other mitochondrial disorders.  When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period.  Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours.

I still find it rather odd that none of Dr Kelley's work on treating regressive autism has been published in any scientific or medical journal.  After all, he was a leading staff member at one of the world's leading hospitals.  He is no quack.  It is extremely wasteful of knowledge and clinical insights that could help improve the lives of something greater than 0.2% of the world's young children.  That is a lot of people.

Sunday, 17 January 2016

Autism PolyPill vs Personalized Medicine and the KD/MAD diet

The idea behind personalized medicine is the realization that humans are all slightly different and that some of the diseases they suffer, like autism, are also all slightly different.  In order to treat them optimally, you would need to use drugs and dosages customized to each person.

Here below are three slides used to illustrate Personalized Medicine in cancer care.  Instead of treating “cancer”, four sub-types are identified and then treated using four different drugs.  Each person only receiving the effective drug.

Autism is not cancer, but understanding cancer gives you a much better concept of what can underlie a highly complex disease like autism.  You need to consider multiple hits as in cancer, which is very similar to Russian Roulette.

The thing that does not seem to exist in cancer is the "double tap", when in a minority of cases, a moderate case sudden changes to a severe case.  This is caused by a new factor coming into play, or an existing factor that had been dormant. In cancer, metastasis is a progression of the existing condition, not something unrelated.  

In the above case there were just for four types of cancer and all you have to so is to find the molecular biomarker for each one.  Then you treat each person with the appropriate drug and avoid side effects from the wrong drugs.

Autism is much more complex because it has "layers" and these may change over time. You have to treat the outer layer first.  This explains why some effective autism treatments appear to "stop working".  Something else has started to work and now forms the outer layer.  This could be related to mast cells, mitochondrial dysfunction or probably a whole host of other factors.

The autism equivalent graphic above, would have people in multiple colours as if dressed.  Just as people change the colour of their clothes, some of the colours of each figure might vary over time and this is what really complicates things.

People with oxidative stress might be represented by having blue socks, reductive stress red socks and "no" stress black socks. There would be lots of blue socks and very few of red or black socks.

NAC for those with blue socks.


So my idea of a PolyPill arose from the idea that when a non-verbal three year old with some odd behaviors goes to his doctor, he might not come home empty handed, and not with those wholly inappropriate psychiatric drugs.  The PolyPill might contain some ingredients that were not necessary, but it would show that a single pill could produce marked improvements in the majority of cases.  All without any complicated and expensive genetic or metabolic testing.

Since I only treat one person, my PolyPill is really a perfect example of personalized medicine.  As time passes, it becomes even more tailor-made.

Monty’s big brother did recently ask why don’t you actually make the PolyPill?  Good question. I did look into this in some detail and even gave a presentation to the European drug regulator (EMA).  There are enormous barriers, few of which relate to developing the drug itself.

If I was James Simons (of the Simons Foundation) that is exactly what I would do, make a PolyPill that could help hundreds of thousands of people.  But unless I receive a call from them, I’ll be sticking with a personalized medicine called Monty’s PolyPill.

The huge advantage of Personalized Medicine is that it minimizes the number of drugs and quasi-drugs that you give.  Let's not pretend that nutraceuticals and OTC supplements are not drugs. This is a concern raised on this blog, just how many ingredients can you (safely) have?  

It certainly can be a bother dispensing them.  Your typical multivitamin contains 14+ ingredients, who would give their child 14 pills at breakfast?  Almost nobody.  But a single little multivitamin pill is just fine. Do they even need all 14?  Unlikely.

So, how many drugs can a PolyPill have?

That was Agnieszka's point in a recent comment.  Things do interact and this does include supplements as well as drugs.  It can be time consuming preparing all these ingredients, not to mention having to swallow them.

This is why someone took Dr Kelley's mitochondrial therapy and packaged it up and sell it as a single product, Mitospectra.

DAN! and Diets over Time

Another vaguely related issue is what happens to autism therapies over time.

It is clear that while allergies may moderate over time and hormonal changes have secondary effects, the core dysfunctions in autism are likely to be permanent.  You can treat them, but you probably cannot cure them.  None of my therapies seem to be disease changing.

So what happens to the thousands of kids, mainly in the US, who follow DAN therapies and diets?  This was raised recently on a popular autism blog and the conclusion was that, after a few years, the great majority of people give up.

This is rather sad.  It shows that the majority of those therapies had no significant effect on the majority of people that tried them, otherwise they would not have given up.

An example being the blog author, with one of those children who had a "second tap", that shifted him to the very severe kind of autism.  This became a new "outer layer", in Peter-speak.  What if that second tap was due to mitochondrial dysfunction (as appears to be relatively common)?  If that was the case, it is not surprising that the gluten free diet did not help, nor  HBOT etc.  Surprisingly, there actually is a diet that might have helped.  No, not the GAPS diet, but the Ketogenic Diet (KD); more a medical therapy than a diet, so well worth reading about.

I was surprised how much evidence there is that indicates that the Ketogenic Diet (and hence likely also the Modified Atkins Diet, MAD) MIGHT  help those with mitochondrial disease. There is no reason to think unrelated diets would do any good whatsoever.

In some cases the Ketogenic Diet can have disease changing effects, meaning you do not need to stay on it for life.  Many people transfer to the MAD.

So if you have a case of severe autism, resulting from a second tap, or a late regression, and nothing covered in this blog seems to help, test for mitochondrial disease.  

If Dr Kelley's therapies reverse the decline, but progress is painfully slow thereafter, it could be worth trying the KD or MAD.

Wednesday, 10 December 2014

Biotin/Biotinidase Deficiency in Autism and perhaps Autistic Partial Biotin Deficiency (APBD)?

Crete, as seen from the International Space Station
By ISS Expedition 28 crew (NASA Earth Observatory) [Public domain], via Wikimedia Commons

In this blog there is a tab at the top called “Disorders leading to Autism”.  This includes a long list of, supposedly rare, known conditions that lead to the development of autism.

In that list is Biotin deficiency and I even put the name of the gene that is thought to be dysfunctional.  The BTD gene encodes an enzyme called Biotinidase, that in turn allows the body to use and recycle biotin.

Biotin deficiency is a known cause of autism, but it seems that the assumption is made that the cause is Biotinidase deficiency.  The usual test done is for Biotinidase deficiency.

In good hospitals they routinely test for many of these dysfunctions when a child is originally diagnosed with autism.  When I say good hospitals, I mean big US hospitals attached to a university.  In other countries such testing rarely takes place, nor is it even mentioned.

We will see later that even these good hospitals may be getting the result wrong.  They are likely testing for the wrong defect, and so getting a "false negative" in some cases.

The take home message is that Biotin Deficiency may not be rare in autism, only Biotinidase Deficiency is rare.  Both are treatable.

How rare is Biotin Deficiency?

Biotin deficiency is supposed to be extremely rare.

One of this blog’s readers made reference to a recent Greek study.  They checked 187 children in Crete, diagnosed with autism, for various metabolic dysfunctions.

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

As the reader pointed out, the results are very odd.

The researchers identified 13 children whose results suggested something strange was going on with biotin.  When they did the further tests for biotin deficiency, which is usually caused by deficiency in  biotinidase, they could find nothing unusual.

Nonetheless, they implemented the standard therapy for biotin/biotinidase deficiency.  This involved large doses of oral biotin, which is very cheap and seemingly harmless.

The researchers found that 7 of the 13 made clear advances.  This indicates that they suffered from a biotin deficiency, but not a biotinidase deficiency. Biotinidase is used by the body to recycle its biotin.

Biochemical abnormalities suggestive of IEM

For 12/187 (7%) of patients, urinary 3-hydroxyisovaleric acid (3-OH-IVA) was elevated and sera methylcitrate and lactate levels were also elevated in two of these patients. Despite these biochemical abnormalities, defects in biotinidase, or holocarboxylase synthetase could not be demonstrated in either sera or fibroblasts. Of interest, none of these 12 patients was undergoing valproate intervention, the latter a potential source of 3-OH-IVA elevation in urine. Despite an absence of confirmatory enzyme deficiencies in these 12 patients, we nonetheless opted to treat empirically with biotin for 3 weeks, 2 × 10 mg and then for 6 months at 2 × 5 mg, which led to a clear therapeutic benefit in 7/13 consisting of improvement in the Childhood Autism Rating Scale (CARS; Table Table2).2). For those benefiting from biotin intervention, the most impressive outcome centered on a 42 month-old boy whose severe ASD was completely ameliorated following biotin intervention. This patient was subsequently followed for 5 years, and cessation of biotin intervention (or placebo replacement) resulted in the rapid return of ASD-like symptomatology. This patient currently attends public school without any clinical sequelae and remains on biotin at 20 mg/d.

In the following table are the results showing the effect on the CARS rating scale, before and after treatment with biotin.

Patient #1

Just look at what happened to the first patient in the above table.

For those benefiting from biotin intervention, the most impressive outcome centered on a 42 month-old boy whose severe ASD was completely ameliorated following biotin intervention. This patient was subsequently followed for 5 years, and cessation of biotin intervention (or placebo replacement) resulted in the rapid return of ASD-like symptomatology. This patient currently attends public school without any clinical sequelae and remains on biotin at 20 mg/d.

He went from severe autism to no autism.  (and back, when he stops the biotin)

Yet, if he was tested for the standard biotin(idase) disorder, even at the best center for autism in the world, nothing would show up

Biotin Deficiency

Genetic disorders such as Biotinidase deficiency, Multiple carboxylase deficiency, and Holocarboxylase synthetase deficiency can also lead to inborn or late-onset forms of biotin deficiency. In all cases – dietary, genetic, or otherwise – supplementation with biotin is the primary method of treatment.


Of 187 children, 13 were identified for biotin treatment and 7 responded .  None of these children would have been noticed by the normal diagnostic procedures of even the best laboratory, which look for biotinidase deficiency.

Also of interest is the effect of partial biotin deficiency.

·        profound biotinidase deficiency (<10% of mean normal serum activity)
·        partial biotinidase deficiency (10%–30% of mean normal serum activity).

Children with partial biotinidase deficiency and who are not treated with biotin do not usually exhibit symptoms unless they are stressed (i.e., prolonged infection)

Partial biotinidase deficiency isusually due to the D444H mutation in the biotinidase gene

Profound biotin deficiency would hopefully be noticed

Mild symptoms linked to biotin deficiency:-

  •        Loss of hair colour
  •         Loss of hair
  •         Fine and brittle hair


The results of clinical studies have provided evidence that marginal biotin deficiency is more common than was previously thought. A previous study of 10 subjects showed that the urinary excretion of biotin and 3-hydroxyisovaleric acid (3HIA) are early and sensitive indicators of marginal biotin deficiency.

It does seem that biotin deficiency is usually caused by things that lead to biotinidase deficiency, so let’s look at the data on frequency (Epidemiology)

Biotin Deficiency – Epidemiology
Based on the results of worldwide screening of biotinidase deficiency in 1991, the incidence of the disorder is: 5 in 137,401 for profound biotinidase deficiency

·         One in 109,921 for partial biotinidase deficiency
·         One in 61,067 for the combined incidence of profound and partial biotinidase deficiency
·         Carrier frequency in the general population is approximately one in 120.

Both parents need to carry the genetic defect, for a child to inherit it.

So something odd is going on (in Greece).

In 61,067 people we would expect 600 people with autism.

It seems that in 600 Greek children with autism there may be 22 with a biotin dysfunction.  This is vastly higher than we would expect.

Not everyone with biotin dysfunction has autism and even if they did, in Greece there would be 22x greater incidence than elsewhere.


I think we (and the Greeks) have likely discovered some new phenomenon “autistic partial biotin deficiency”, APBD, which is not caused by the usual lack of biotinidase.  Somehow the dietary biotin is insufficient in these people, even though biotinidase is present.

APBD does not seem to cause all the severe symptoms of biotin deficiency, just the neurological ones and so remains undiagnosed.

Perhaps one of the other odd metabolic disorders in autism is affecting the biotin metabolism?  Remember that Harvard study suggesting the oxidative stress in the autistic brain reduces the activity of a key enzyme D2, that is needed to convert the thyroid pro-hormone T4 into the active hormone T3.  This would mean that despite a “normal” set of thyroid lab results from your doctor, you might well be hypothyroid inside the brain (low on T3).

Those with access to a good laboratory might consider sending a urine sample to measure 3-hydroxyisovaleric acid (3HIA).

Those without these options might have to settle with the option of trying 10-20 mg of Biotin for a short period and see if it has any effect.

Biotin appears to be one of those vitamins, like B12, where even huge doses may have no ill effect; they are just excreted.  The supplement companies are selling 10 mg pills of biotin;  the RDA for a 10 year old is 0.03 mg which is 333 times less.

Based on the Greek study, you would expect about 4% of autistic people to show a clear benefit, without first doing the 3HIA urine test.

A small chance of success per child, but a chance nonetheless.

Note on the study
I have referred to this Greek study once before. On that occasion I was talking about the ketogenic diet and modified Atkins diet.

It is widely accepted that the ketogenic diet can greatly reduce epileptic seizures, so it is not really surprising that it can also help some people with autism (but which ones?).

In the Greek study, via laboratory tests, they identified 9 % children who might benefit from this diet.  Just over a third of these identified children did indeed improve on the diet.

16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD).

This remarkable study was published one year ago.

It has been cited just one time in subsequent literature (although twice now in this blog); this really tells us a lot. (nobody is interested)

Changing diet can require a great deal of effort and, if a fussy eater is involved, it can be even more difficult.  If biomarkers exist to narrow down who would benefit from a modified diet, this is really very significant.

You can easily try biotin pills for a couple of weeks, trying a ketogenic diet just on the "off chance", requires much more bother.   

Saturday, 1 March 2014

PPARα (Peroxisome proliferator-activated receptor alpha) - and why PEA might be an alternative to the Ketogenic Diet in Epilepsy and Potentially useful in Autism

There is no doubt that most parents’ ideal autism therapy would be a special diet.  The most popular diet is the gluten and casein free diet; in a sub-type of autism this diet clearly is very effective. Another very interesting diet is the Ketogenic diet and its easier to implement cousin, the Modified Atkins diet.  There is also the GAPS diet.

Many scientists are very skeptical of the therapeutic value of special diets.

I am always looking for connections in the science.  If I can find from multiple starting points the same conclusion, this triggers my interest, regardless if anyone else has highlighted the area as an issue for autism.

Today my reinforcing arguments is indeed a diet; the Ketogenic diet.
Remember that epilepsy is highly comorbid with autism, and trials have shown the ketogenic diet to reduce the incidence of seizures by half.
This post was supposed to be a short one, but it just kept growing.  You can skip the complicated parts and go to the conclusions.
Ketogenic Diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet forces the body to burn fats rather than carbohydrates. Normally, the carbohydrates contained in food are converted into glucose, which is then transported around the body and is particularly important in fuelling brain function. However, if there is very little carbohydrate in the diet, the liver converts fat into fatty acids and ketone bodies. The ketone bodies pass into the brain and replace glucose as an energy source. An elevated level of ketone bodies in the blood, a state known as ketosis, leads to a reduction in the frequency of epileptic seizures.

The original therapeutic diet for paediatric epilepsy provides just enough protein for body growth and repair, and sufficient to maintain the correct weight for age and height. This classic ketogenic diet contains a 4:1 ratio by weight of fat to combined protein and carbohydrate. This is achieved by excluding high-carbohydrate foods such as starchy fruits and vegetables, bread, pasta, grains and sugar, while increasing the consumption of foods high in fat such as cream and butter. 

Modified Atkins

First reported in 2003, the idea of using a form of the Atkins diet to treat epilepsy came about after parents and patients discovered that the induction phase of the Atkins diet controlled seizures. The ketogenic diet team at Johns Hopkins Hospital modified the Atkins diet by removing the aim of achieving weight loss, extending the induction phase indefinitely, and specifically encouraging fat consumption. Compared with the ketogenic diet, the modified Atkins diet (MAD) places no limit on calories or protein, and the lower overall ketogenic ratio (approximately 1:1) does not need to be consistently maintained by all meals of the day. The MAD does not begin with a fast or with a stay in hospital and requires less dietitian support than the ketogenic diet. Carbohydrates are initially limited to 10 g per day in children or 20 g per day in adults, and are increased to 20–30 g per day after a month or so, depending on the effect on seizure control or tolerance of the restrictions. Like the ketogenic diet, the MAD requires vitamin and mineral supplements and children are carefully and periodically monitored at outpatient clinics.

The modified Atkins diet reduces seizure frequency by more than 50% in 43% of patients who try it and by more than 90% in 27% of patients. Few adverse effects have been reported, though cholesterol is increased and the diet has not been studied long term.

Why does ketosis reduce seizures?

For a change, Wikipedia cannot tell you why ketosis is good for epilepsy.
If you look deeper in the research you can find a very good likely reason why it may be so effective; we have yet another tongue twister, Peroxisome proliferator-activated receptor alpha, known as PPARα.
It is PPARα which is the connection to my early post all about growth factors in autism. It is my belief that Growth Hormone (GH) and its related growth factors are of key importance in understanding and treating autism.   In that very lengthy post I introduced PEA (Palmitoylethanolamide) as an interesting substance that, amongst other things, modulates the release of nerve growth factor (NGF) from mast cells.  PEA has been extensively researched and has interesting effects including treating pain, inflammation and indeed epilepsy.
I started to look into how PEA works and to see what that mechanism might be.  After a dead end looking at Endocannabinoids, I found what I was looking for – PPARα.

PEA - Pain Relief and Neuroprotection Share a PPARα -Mediated Mechanism

So it appears there is an interesting connection linking the apparently successful Ketogenic diet, and the supplement PEA.  The Ketogenic diet does have some side effects and drawbacks; apparently PEA has no side-effects or contra-indications.
Another interesting point is that a diet very rich in olive oil has been shown to have the benefits of the Ketogenic diet and olive oil directly raises oleylethanolamide (closely related to palmitoylethanolamide) and also a PPARα activator. 

Peroxisome proliferator-activated receptor alpha
PPAR-alpha is a transcription factor and a major regulator of lipid metabolism in the liver. PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.  Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation. PPAR-alpha is primarily activated through ligand binding. Synthetic ligands include the fibrate drugs, which are used to treat hyperlipidemia, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators. Endogenous ligands include fatty acids and various fatty acid-derived compounds.
You may recall from earlier post that in autism there appears to be strange things going on with the lipid mechanism.  Here is a paper for those interested:- 
PPARα and the ketogenic diet (and cancer) 
The following paper does cover the role of PPARα in the ketogenic diet (KD) but its main thrust is the use as a cancer therapy.  We have already come across other autism drugs that have potential in cancer therapy.  NAC was shown to be beneficial in cases of both prostate cancer and breast cancer.
I know some readers are also interested in some forms of cancer, so I have included the cancer part.  Others may want to skip this part. 


Calorie restricted KetoCal diet significantly decreased the intracerebral growth of both tumor types and decreased the intratumoral microvessel density.  Implementation of this diet resulted in elevation of plasma concentrations of ketone bodies, which might trigger the energetic imbalance in the tumors, since tumor tissue showed reduced activity of the enzymes required for ketone body oxidation: hydroxybutyrate dehydrogenase and succinyl-CoA: 3- ketoacid-CoA transferase comparing to conlateral normal brain tissue. Moreover, in some cases of advanced malignant tumors (anaplastic astrocytoma and cerebellar astrocytoma), patients respond well to CRKD dietary regimen. The question about the safety of CRKD in patients who are likely to develop cachexia due to tumor burden may arise, nevertheless malnutrition or undernourishment have not been reported. 

Remarkably, ketogenic diet is also beneficial for patients with neurological disorders, especially in epilepsia. The first observations revealed that starvation – mimicking diet, and CRKD in particular, have anti-seizure properties. Further investigation stated that both high fat content and reduced total caloric intake are important because they induce hormonal responses favoring ketogenesis: low insulin and high glucagon, as well as increased cortisol blood levels promote acetyl-CoA conversion to ketone bodies and release to circulation. Increase in blood fatty acid concentration, which physiologically activates PPAR α, was observed in CRKD as a result of fat reserves mobilizationand high fat intake  Fig. (3). Ketone bodies are avidly consumed by brain tissue during glucose deprivation. In limited glucose availability, astrocytes protect neurons from the energetic stress by performing fatty acid oxidation and ketogenesis and supply the surrounding neurons with ketone bodies. Ketone bodies are prioritized energetic substrates and they are metabolized before glucose and free fatty acids. Their cellular uptake is mediated by monocarboxylate transporter MCT1, which transcription is positively regulated by PPAR. Importantly, both endogenous (free fatty acids) and synthetic PPARα  ligands are free to flow through the blood-brain barrier and they may reach high levels in the brain tissue. In addition to the role in brain tumors, ketogenesis may also become a prognostic factor in colon carcinoma. 3-Hydroxy-3-methylglutaryl-CoA synthase is severely downregulated by c-Myc in colon cancer cell lines with high activity of Wnt/ 􀀂-catenin/ T cell factor 4 (TCF-4)/ c-Myc pathway. Ketogenic capability and HMGCS expression levels are positively correlated with enterocyte differentiation and decreased in colon or rectal carcinomas, especially those poorly differentiated. 

In theory, PPAR α activation could counteract c-Myc induced alterations of mitochondrial metabolism by restoring the HMGCS and ketogenesis levels and by inhibiting glutaminolysis through transcriptional repression of the two enzymes crucial for this pathway: glutaminase and glutamate dehydrogenase. Moreover, PPAR α and pan-PPAR agonists like bezafibrate stimulate oxidative  hosphorylation and respiratory capacity by inducing PGC-1􀀁 mediated mitochondrial biogenesis. Although this activity goes in line with c-Myc action, which was reported to stimulate mitochondrial proliferation, this could cause either normalization of cancer cell energetic balance or induce a 'metabolic catastrophe' in the cells with genetically impaired mitochondrial function. 

Recent studies on mice bearing different tumors revealed that dietary restrictions do not affect those with constitutive activation of PI3K/Akt pathway. Other cancer characterized by transformed HRAS/ KRAS, BRAF or with loss of TP53, show a significant decrease of the growth rate and increased apoptosis when the host animals were subjected to dietary restriction. Resistance to dietary restriction depended on the Akt phosphorylation status and its activation, which lead to FOXO1 phoshorylation and cytoplasmic sequestration. When arrested in the cytoplasm, FOXO1 is unable to exert its proapoptotic functions. There are several proteins that negatively affect Akt activity, namely protein phosphatases PTEN, SHIP and PPA2 that directly dephoshorylate Akt; and TRB3 (mammalian homolog of Drosophila protein tribbles), a protein that binds to Akt and blocks its phosphorylation. TRB3 expression in liver rises during fasting and is driven by PGC-1􀀁 in PPAR α dependent manner, as there are functional PPRE elements in the TRB3 promoter. Metabolic function of TRB3 is to block insulin dependent Akt activation in fasting, in parallel to PGC-1􀀁 / PPARα induced gluconeogenesis and fatty acid oxidation. This seems to be a part of a SIRT1/ LKB1/ AMPK/ PGC-1􀀁 pathway which constitutes an adaptive response to CR, because in mice with muscle – specific LKB1 knockout in which the PGC-1􀀁, PPAR α and TRB3 were severely decreased. Interestingly, TRB3 upregulation in lymphocytes is induced by fibrates in PPAR α independent fashion with utilization of C/EBP and C/EBP homologous proteins.

Therefore it is reasonable to speculate that pharmacological PPAR 􀀁 activation together with CRKD might improve the anticancer outcome in case of dietary restriction resistant tumors with overactive PI3K or nonfunctional PTEN. The
situation would probably be different in tumors with constitutively active plasma membrane associated Akt mutants (with activating Akt mutations or in model systems with the introduction of myristoylated Akt), as in these cases TRB3 possibly would not affect the already phosphorylated Akt.

Although these hypotheses need to be verified, the negative influence of TRB3 on Akt phosphorylation seems to be a general phenomenon.



PPAR α activators have a great potential of supplementing conventional anticancer therapies by modulating cancer cell energy metabolism and signaling pathways. This notion is based on multiple observations, which include PPAR α-mediated inhibition of two prominent oncogenes: c-Myc and Akt Fig. (3). In this inhibitory action, PPAR α suppresses glutaminolysis and glutamine catabolism in mitochondria, as well as activates ketogenesis by promotion of fatty acid oxidation and transactivation of HMGCS. In cancer cells these processes are c-Myc regulated. Next, PPAR 􀀁 actions slow down glycolysis by inhibiting Akt and blocks Akt induced fatty acid synthesis by repressing PDH activity in mitochondria

via PDK4 upregulation. Finally PPAR α functionally cooperates with AMPK, SIRT1 and PGC-1􀀁 in regulating the cellular response to calorie restriction. In perspective, it would be important to elucidate the details of possible interplay between these regulatory proteins, and to verify the role of PPAR α activation in the of CRKD applied to in vivo cancer models. Of note, the potential use of clinically tested synthetic ligands for PPAR α  against cancer, although seems to be a straightforward and fairly safe procedure, it still requires our careful consideration. There are still debates over fibrate drugs safety and three main caveats have been are presented : (1) fibrate ability to bind hemoglobin which reduces its affinity to oxygen; (2) fibrates may disrupt mitochondrial electron transfer chain particularly by inhibiting complex I; and (3) fibrates induce mitochondrial ROS production. These potentially harmful activities are presently understood to be receptor-independent, which implies the need for new generation of PPAR α ligands which would possess improved physiological and pharmacological characteristics.

“The roles of PPARs in brain and, more specifically, the functional consequences of PPARα activation, have been discussed previously. PPARα plays a key role in regulating ketogenesis (an obvious hallmark of the KD) and a more extended role in regulating hepatic amino acid metabolism with the potential consequences on neurotransmitter concentrations if PPARα is activated within brain .”
“There is now increased understanding of the KD and the implications for the actions of small molecule anticonvulsants that interact with PPARα. Especially, with the emerging evidence that PPARα is expressed at low but functionally significant levels in many nerve cells throughout the body, the possibility exists for common modes of action of different anticonvulsants in spite of their differential seizure-type efficacy. For example, although valproate, palmitoylethanolamide, and the KD have a limited overlap in seizure-type efficacy, they may still share a common mechanism of action, taking into account their pharmacodynamic/pharmacokinetic differences acting on a common but widely distributed molecule such as PPARα”

PPARα and the high olive oil diet 

“However, a recent report shows that a 30% fat diet enriched in olive oil directly raises oleylethanolamide (closely related to palmitoylethanolamide and also a PPARα activator) within rat brain. Thus, modifications to the fatty acid profile of the much higher (80%) classic ketogenic diet may also be predicted to directly modify PPARα-activating molecules in brain, potentially providing a broader spectrum of anticonvulsant effect.”

The above actually refers to rats, but here is the abstract of that paper:-

Influence of dietary fatty acids on endocannabinoid andN-acylethanolamine levels in rat brain, liver and small intestine.



Endocannabinoids and N-acylethanolamines are lipid mediators regulating a wide range of biological functions including food intake. We investigated short-term effects of feeding rats five different dietary fats (palm oil (PO), olive oil (OA), safflower oil (LA), fish oil (FO) and arachidonic acid (AA)) on tissue levels of 2-arachidonoylglycerol, anandamide, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide, linoleoylethanolamide, eicosapentaenoylethanolamide, docosahexaenoylethanolamide and tissue fatty acid composition. The LA-diet increased linoleoylethanolamide and linoleic acid in brain, jejunum and liver. The OA-diet increased brain levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol) without changing tissue fatty acid composition. The same diet increased oleoylethanolamide in liver. All five dietary fats decreased oleoylethanolamide in jejunum without changing levels of anandamide, suggesting that dietary fat may have an orexigenic effect. The AA-diet increased anandamide and 2-arachidonoylglycerol in jejunum without effect on liver. The FO-diet decreased liver levels of all N-acylethanolamines (except eicosapentaenoylethanolamide and docosahexaenoylethanolamide) with similar changes in precursor lipids. The AA-diet and FO-diet had no effect on N-acylethanolamines, endocannabinoids or precursor lipids in brain. All N-acylethanolamines activated PPAR-alpha. In conclusion, short-term feeding of diets resembling human diets (Mediterranean diet high in monounsaturated fat, diet high in saturated fat, or diet high in polyunsaturated fat) can affect tissue levels of endocannabinoids and N-acylethanolamines.
So it does appear that you should choose your fat wisely.  Olive oil (OA) seems the wise choice.

PPARα and PEA (Palmitoylethanolamide)
Here are two papers that show that PPARα mediates the anti-inflammatory effects of PEA:-

PEA attenuates inflammation in wild-type mice but has no effect in mice deficient in PPARα. The natural PPARα agonist oleoylethanolamide (OEA) and the synthetic PPARα agonists GW7647 and Wy-14643 mimic these effects in a PPARα dependent manner.

These findings indicate that PPARα  mediates the anti-inflammatory effects of PEA and suggest that this fatty-acid ethanolamide may serve, like its analog OEA, as an endogenous ligand of PPARα.

Repeated treatments with PEA reduced the presence of oedema and macrophage infiltrate, and a significant higher myelin sheath, axonal diameter, and a number of fibers were observable. In PPAR-α null mice PEA treatment failed to induce pain relief as well as to rescue the peripheral nerve from inflammation and structural derangement. These results strongly suggest that PEA, via a PPAR-α-mediated mechanism, can directly intervene in the nervous tissue alterations responsible for pain, starting to prevent macrophage infiltration. 
The present results demonstrate the neuroprotective properties of PEA in a preclinical model of neuropathic pain. Antihyperalgesic and neuroprotective properties are related to the anti-inflammatory effect of PEA and its ability to prevent macrophage infiltration in the nerve. PPAR-α stimulation is the common pharmacodynamic code.

Ketogenic Diet & Autism 

A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and 10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 +/- 1.41[mean +/- SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88 +/- 3.14[mean +/- SD]), and minor improvement (2-8 units) in eight patients (pre-Scale: 45.25 +/- 2.76 [mean +/- SD]). Although these data are very preliminary, there is some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy. 

 Martha Herbert again:-

We report the history of a child with autism and epilepsy who, after limited response to other interventions following her regression into autism, was placed on a gluten-free, casein-free diet, after which she showed marked improvement in autistic and medical symptoms. Subsequently, following pubertal onset of seizures and after failing to achieve full seizure control pharmacologically she was advanced to a ketogenic diet that was customized to continue the gluten-free, casein-free regimen. On this diet, while still continuing on anticonvulsants, she showed significant improvement in seizure activity. This gluten-free casein-free ketogenic diet used medium-chain triglycerides rather than butter and cream as its primary source of fat. Medium-chain triglycerides are known to be highly ketogenic, and this allowed the use of a lower ratio (1.5:1) leaving more calories available for consumption of vegetables with their associated health benefits. Secondary benefits included resolution of morbid obesity and improvement of cognitive and behavioral features. Over the course of several years following her initial diagnosis, the child’s Childhood Autism Rating Scale score decreased from 49 to 17, representing a change from severe autism to nonautistic, and her intelligence quotient increased 70 points. The initial electroencephalogram after seizure onset showed lengthy 3 Hz spike-wave activity; 14 months after the initiation of the diet the child was essentially seizure free and the electroencephalogram showed only occasional 1-1.5 second spike-wave activity without clinical accompaniments. 

PEA clinical trials and dosage in pain therapy
The following paper gives a great deal of information about the clinical use of PEA:-

While many kids with autism are given fish oil supplements, it is olive oil that I make a point of using extensively.  Today’s post indicates that olive oil is a potent PPARα activator and so another reason to use olive oil liberally.
PEA (Palmitoylethanolamide) itself almost looks too good to be true.  It does not interact with other drugs and it seems to have no side effects.  It has been trialed on many occasions, mainly as a pain therapy, rather than in its anti-inflammatory capacity.
PEA also seems to have potential as an adjunct anti-cancer therapy, rather like NAC also does.

It would be reasonable to expect a benefit from PEA in autism, at least in certain subtypes – high histamine and seizures - and particularly where a sibling has epilepsy, but no ASD.