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Thursday, 24 May 2018

An Autism Case History - EpiphanyASD in a Pill





It is not quite that easy!


Initials:                        LT
Age:                           14 years old

Year
of Birth:              2003

Sex:                            Male

Date:                           24 May 2018

Diagnosis      
LT was diagnosed with autism in January 2007, at a multi-disciplinary assessment in London, at the age of 3 years 6 months.  At that time, LT was non-verbal but had some emerging vocalization. No tics, no seizures, no unusual physical features, no self-injury, no sleep disorder, no feeding disorder. Toilet trained. Very limited attention span. No imaginative play. Liked to jump.

IQ not tested.
No CARS (Childhood Autism Rating Scale) assessment.
TEACCH and PECS were recommended as therapy.
Further medical testing or referrals – none recommended (standard practice in the UK) 

LT has an older brother who is intelligent, multilingual and highly social.
Comorbidities
GI disease:                   None
Epilepsy:                       None
Asthma:                        Yes, mild asthma from early childhood
Allergy:                         Pollen
Sleep disorder:             None 

General Health          
Very healthy and almost never ill. When visiting his GP at the age of 14 the doctor commented how she had not seen him for three years, whereas she has seen his older brother twice a year.

Born via a planned caesarean section, without complications, APGAR score was 10.


Growth                      
Body is well proportioned, no obvious macro/microcephaly. No physical features of any syndromes/metabolic anomalies.

However, LT was initially on the 90th percentile for height and dropped to the 20th by the time he was 5 years old. He was a very muscular baby.  At the age of 10 his bone age (X ray of left hand) was estimated to be two years delayed.  IGF-I was normal, FT3 was slightly above the reference range.

At birth he fitted the research description of hyperactive pro-growth signaling pathways, even though there was no macrocephaly.

Regression at age 8              
Aged 8, a big regression took place with self-injurious behavior (SIB) and aggression to others. He would slam his head into walls, other people, car windows, punch himself etc, but he was still small enough to be physically controlled/restrained by larger adults. He could not be controlled by smaller/older adult family members.

This aggression could occur immediately on waking until finally falling asleep at night, it was not predictable.  At that time in the afternoons, LT had a male 1:1 assistant with experience from a school for severe autism and in the mornings a very firm-minded tall female 1:1 assistant. LT’s father imposed a policy of zero acceptance of any SIB, to avoid it becoming a permanent acquired behavior. SIB was physically blocked.
The regression was triggered by the departure of his long time full-time 1:1 female assistant. It was an emotional trauma.  Occasional visits from her just made the situation worse.  In response no drugs were used, just a consistent firm behavioral approach. Over a ten month period the situation slowly stabilized, but skills were lost and bad habits (SIB) were acquired.  LT subsequently did see his assistant again and sees her regularly to this day.
Throughout this time his classmates and teacher at school were remarkably understanding. He was never excluded from school. His assistant ensured nobody at school got hurt.
Since assistants will inevitably come and go, from the age of 8 LT has had two part-time assistants rather than one full time.  As and when subsequent assistants have left, he has not had any troubling emotional reaction. 

Summer-time raging and loss of cognitive function
Summertime raging with self injurious behavior and aggression to others developed from the age of 9.

Later it became clear that in addition there was a loss of cognitive function during the summer months. This became evident once it was possible to teach mental math, from aged 9 onwards.  For example, at the age of 11, simple verbal tasks like 7 x 8 = ?, that had previously been mastered, could not be answered in the summer months.

The raging and cognitive loss were ultimately treatable.

Winter-time raging

Summertime raging was resolved and then winter-time raging developed. This was traced back to the cytokines released to signal reabsorption of milk teeth roots (a proves that takes months) and the eruption of permanent teeth. It was not tooth ache, i.e. pain. LT has retarded bone age and apparently this applied to his teeth development as well.

He lost his later milk teeth always in the winter.

The winter time raging did not respond to his summertime therapy, but responded very well to a low dose of ibuprofen. Summertime raging does not respond to Ibuprofen 

PANS-like episode aged 13
At Christmas time, following a minor viral infection, LT developed acute onset profound verbal tics. LT does not have Tourette’s type autism and had never exhibited such behavior previously. The tics were treated as a PANS/PANDAS flare-up with 5 days of prednisone. Over a two week period the tics faded away and have never returned.

Intellectual disability 
IQ was never measured, LT’s ABA consultant said there was no point, but the very much more rigorous ABBLS was completed, see below. Evidently, prior to pharmacological treatment at the age on 9, there was a 5 year developmental delay.
With hindsight, IQ pre-treatment was probably in a similar range to Down Syndrome (DS) meaning less than 70.

At the age of 14, LT’s academic performance now puts him in the top half of his class of 12 year old neurotypical peers. His grades are mainly As, with maths and computing being particular strengths. 

Other testing:    No genetic testing, MRI or EEG.

Family History:          

LT has a 7 years younger, very distant cousin who is non-verbal with autistic disorder. They have shared great great great maternal grandparents. The cousin has parents who are both doctors and were high academic achievers as medical students.

The father’s family has a large number of Cambridge-educated doctors on both the grandmother's and grandfather's side; one gave his name to the scale still used to assess severity of Ulcerative Colitis and helped develop the first H2 anti-histamine drug. The father and uncle are engineering graduates from top universities. One distant cousin was a math’s protégé at Oxford University.  One distant cousin has bipolar. One uncle has type-1 diabetes.

The mother is an academic alpha female in a stressful creative profession. The maternal grandmother was a teacher and grandfather was an army Colonel.
The maternal grandmother and her children all had premature hair greying, which may be linked to Bcl-2 expression and Wnt signaling, both implicated in autism. Thickness and greying of hair share biological mechanisms, which overlap with those controlling development of dendritic spines. LT and his father have very dense hair, mother has thin hair.
Maternal grandparents both smoked and the grandfather has COPD (Chronic Obstructive Pulmonary Disease). Oxidative stress is a core feature of COPD, because anti-oxidant genes are silenced; these effects are known to be heritable via epigenetic tags. 
The family fits the high IQ  type of autism (some autism genes are linked to intelligence and some bipolar genes are linked to creativity, which helps explain why some actors/artists are bipolar) with oxidative stress raised during pregnancy, anti-oxidant response possibly weakened, no oxytocin surge during delivery and no microbiota transfer at birth (C-section delivery).  No pets at home during pregnancy (a good source immuno-stabilizing bacteria).  No obesity in the family.

Education
LT has attended the same mainstream international school, following the English curriculum, since the age of 3. Class sizes are very small, about 12 pupils. From the age of 4 he has had a 1:1 assistant eight hours a day, throughout the year.
LT commenced a parent-managed ABA (Applied Behavioral Analysis) inspired home program shortly after diagnosis.  Both parents attended a 2 day training program to learn the use of PECS (Picture Exchange Communication System).  PECS was applied and shortly thereafter LT became partly verbal at the age of 4, speaking single words.
1:1 assistants were recruited mainly from the local University and trained to apply ABA, with elements from Floortime and the Canadian Hanen Program. There was some supervision from US-trained Behavioral Consultants that would fly in for training. A large collection of specialist training material was acquired from the US. 
Extensive use was made of professional (i.e. expensive) special needs language teaching software (Laureate Learning) from the age of 4 until 8 years old.
Later, web-based reading software (Headsprout) was used and years later special maths teaching software (Math Wizz). Neither are made for special needs, but both are very compatible with an ABA approach.
LT spent an extra year in kindergarten and in primary/junior school was held back 2 years at the age of 9, following a request from the parents.
In primary school (English system) he went Year 1, Year 2, Year 3 (started bumetanide) then back to Year 2, then Year 3, Year 4, Year 5, Year 6 and currently attends Year 7 in secondary/high school
The equivalent in the US system would have been, he went K, 1st, 2nd, then 1st, 2nd 3rd, 4th etc.
From the age of 13, LT attended school full time, prior to that he attended only the morning and then went home after lunch to work 1:1 with his assistant for three hours.
During school holidays LT has a 1:1 home learning program.
LT learnt to read and write at home as result of the unrelenting efforts of his assistant. He started to learn maths from the age of 8, prior to that he could not master the basic concepts, or understand the relevant vocabulary.
From the age of 9, LT has been able to keep up with his new peer group at school, two years his junior.
At the age of 14, in a class with 12 year old neurotypical children, LT takes the same assessments as the rest of the class and his grades currently place him in the top half of the class. He is now particularly good at things like arithmetic, algebra, coordinates, spelling and has neat handwriting (very unusual in autism). He is still clearly autistic and his speech is limited to what he wants to say; there is no small talk.
LT started to learn the piano aged 8. He progressed from an extremely basic level and a desire to hit his teacher to his current level 4 of the popular Faber Music piano course (there are just 5 levels). When he plays in public people are very surprised, he does not play like someone with any cognitive impairment. His peers as school have asked “how can he play like that?” 

Motor Skills
Like many people with classic autism LT had problems with both fine and gross motor skills as an infant. After a great deal of 1:1 therapy, motor skills are now normal.
LT started to learn to ski at the age of 5 with a special needs instructor. Progress was initially slow, but 9 years and one broken collar bone later, LT can confidently ski on red slopes and deal with all the various types of lifts you encounter in the Alps.
Stamina improved considerably after starting to take Agmatine, which is evident at school where they are timed to run 2.5 km (1.5 miles) and when swimming.

Behavioral Treatment (age 3- 8)
From diagnosis aged three, until nine years old, therapy was exclusively based on behavioral interventions. Extensive use of ABA (Applied Behavioral Analysis) and VB (Verbal Behavior) with 40 hours a week with a 1:1 Assistant.
At the aged of 9, LT had mastered almost all the skills in the very extensive ABBLS (Assessment of Basic Language and Learning Skills) assessment. The language skills and other basic learner skills that are tracked by this tool are those that are acquired by most typically developing children by the time they reach four to five years of age. LT’s elder brother had acquired these while he was three years old.
LT’s skill acquisition to the age of eight was seen by the ABA consultants as nothing unusual in someone with classic autism. There was slow but continuous progress. 
All learning was taking place at home with school attended mainly for socialization.

Pharmacological Treatment (age 9 onwards)
In late 2012 a small clinical trial was published by Ben Ari and his clinical associate Lemmonier; it showed the benefit of the NKCC1/2 blocker bumetanide in autism. This paper was studied by LT’s father and contact has been maintained for several years with Dr Ben Ari, who originated and patented this therapy.
Bumetanide (1mg per day) was commenced just before Christmas December 2012, unknown to the school, or LT’s assistants.
On returning to school in January 2013 the Head Teacher summoned LT’s father and asked what had happened to LT. He was “so joyous” and “like a different child”.
At the suggestion of his original ABA consultant, LT’s father had been asking LT every school day for 5 years “what did you have for lunch at school today?”. The usual answer would be no answer, the wrong answer, but sometimes a brief correct answer. From now on LT would say precisely what he had eaten “peas, potatoes and chicken – cake for dessert”. The assistant was there to confirm what had really been eaten for lunch. 
LT’s 1:1 assistant at that time described the effect of bumetanide as making him “more present”. Since his assessment at the age of 3, it was always noted that LT had a very short attention span and would not be able to focus on the class teacher for more than a couple of minutes. LT was never hyperactive, quite the opposite. He was physically present but not mentally.
Later on it would be realized that the most potent effect of long term bumetanide use in strictly defined autism (SDA) is enhanced cognition, which leads to accelerated acquisition of new skills.  IQ has long been seen as the best predictor of more favorable outcomes in autism.  
Bumetanide use has continued for five years, with occasional pauses to confirm it still works.  Different doses were tested and currently the dose is 2mg once a day.
When stopping bumetanide for a week and returning to his web-based maths learning program, LT was unable to complete previously mastered tasks, no matter how many times he tried. Having recommenced bumetanide, the same maths problems were attempted a week later and could be solved. 
Blood potassium levels were checked regularly at the beginning, but were always high normal (5.0 mmol/L).  Bumetanide is taken with 250mg of K+ per 1mg of bumetanide. Diet is rich in potassium, with bananas and other fruit.
Dehydration, another potential problem, is entirely self-regulated with LT drinking more water. Total consumption is 2.5 to 3 liters per day.
Diuresis occurs mainly within one hour of taking bumetanide and has never caused a problem at home or school. LT takes his bumetanide at least an hour before leaving home for school.
Bumetanide’s suggested mode of action is lowering intracellular chloride via blocking NKCC1 cotransporters in the brain.  Bumetanide crosses the blood brain barrier very poorly and many researchers are dubious it can have any effect. Bumetanide is a partial solution.
A new drug is being developed by Dr Ben Ari that will cross the blood brain barrier more effectively than bumetanide and have less effect on NKCC2, so producing less diuresis.
An alternative strategy discussed in the literature is to improve the pharmacokinetics of bumetanide, by slowing its excretion via OAT3 (organic anion transporter 3) and thus increasing plasma concentration. There are many OAT3 inhibitors, the best known and most potent is probenecid, used to treat gout by increasing the excretion of uric acid. Some foods are OAT3 inhibitors. One readily available substance is chlorogenic acid (more precisely 1,3- and 1,5-dicaffeoylquinic acid) which is sold as a coffee-based weight loss supplement. Interestingly, coffee, but not caffeine, has been shown to reduce the risk of gout.
Little is known about exactly how bumetanide is transported/excreted across the blood brain barrier.
Bumetanide’s autism benefit appears to be from lowering intracellular chloride and hence making GABAA become more inhibitory. Excitatory-Inhibitory (E/I) imbalances are widely believed to be at the core of autism.  An E/I imbalance during so-called Critical Periods, will result in permanent changes to the developing brain, nonetheless it appears that correcting an E/I imbalance in later years can still be highly beneficial, though not curative. 
Another experimental therapy also makes GABAA become more inhibitory. This uses very low doses of clonazepam to modify the behavior of GABAA receptors that contain the α3 sub unit.  In LT the effective dose of clonazepam is just 0.03mg, which might be considered sub-clinical, but as predicted by Professor Catterall, it does have a beneficial effect (a bumetanide-like effect). It has no side effects and there is no tolerance develops at this tiny dose, after four years of use.
At the time low dose clonazepam was introduced, LT would go swimming at 5pm most days. He was not really interested to do much independently in the water, he was very passive. This passive behavior was notably changed once the effective clonazepam dose had been found. He became more like a typical child playing in a swimming pool. Instead of sitting on the steps he wanted/demanded interaction/play with the attending adult.  The effect was not as profound as that seen in the first months of bumetanide, but noticeable nonetheless.
After 4 years of bumetanide the effect was still there, but there was a desire to accelerate skill acquisition to keep up with neurotypical school peers.
A new strategy was adopted to further reduce intracellular chloride, this time using a method first documented in the 1850s, when potassium bromide (KBr) was used to treat epilepsy. Reading old case studies from Great Ormond Street Hospital in London it appeared to LT's father that some children with epilepsy, MR/ID and undiagnosed autism improved behaviorally and developed age-appropriate play when treated with KBr. Lack of age-appropriate play is a hallmark of autism.  Modern research shows that bromide ions compete with chloride ions to enter cells and the result is a lower intracellular concentration of Cl-. The limiting factor in the use of KBr is that it increases mucous secretions and so causes acne (and can make asthma worse), in a dose dependent fashion. At a low dose of 400mg per day there is a cognitive gain without significant spots. KBr is still used at high doses to treat pediatric epilepsy in Germany and Austria. Some leading US neurologists regret they cannot prescribe it; technically they could ask the FDA for permission on a patient by patient basis.

Another strategy to reduce intracellular chloride is to target chloride ions that enter neurons via the AE3 exchanger, this is possible using Acetazolamide (Diamox). This therapy does seem to work for some people, but was not tolerated by LT, it caused reflux.
KBr has a very long half-life and so it takes 4-5 weeks to reach the maximum effect. 
Bumetanide took about two weeks to lower chloride and show behavioral and cognitive improvements.
Low dose clonazepam takes three days, as was predicted by its half-life.
The cognitive loss in severe autism has parallels with that in Down Syndrome (DS). Bumetanide has been patented as a therapy for DS by Ben Ari, based on the results from mouse studies.
In mouse models of Down Syndrome both a negative allosteric modulator and a selective inverse agonist of α5 sub-unit of the GABAA receptor improve cognition. 
Mouse research has shown that poor learners have greater GABRA5 expression than good learners and that in mice GABRA5 expression can be normalized by eating cinnamon, or its metabolite sodium benzoate (NaB); this makes a poor learner become a good learner, at least in mice.
So it may be that increasing the effect of α3 sub-unit of the GABAA and reducing the effect of the α5 sub-unit of the GABAA can both improve cognition. For the moment the latter remains unproven. NaB is an approved food additive, E211. Ceylon cinnamon, which is safe for long term consumption, is metabolized to NaB. People who are histamine intolerant have to avoid DAO inhibitors such as cinnamon and NaB. 

Summertime raging and loss of cognitive gains
From the aged of 8 it became apparent that summer provoked behavioral deterioration. At this point there was no obvious allergy, but behavior improved when moving to the mountains in summer. At first, OTC mast cell stabilizers were investigated; some common H1 antihistamines are partial mast cell stabilizers. Rupatadine, azelastine, ketotifen, loratadine and cetirizine were all tried, as was the flavonoid quercetin.
Some of the above did indeed help reduce the summertime self injury, but not to a satisfactory level.
A final solution was found in a small dose of the Cav1.2 blocker, verapamil. 
When mast cells degranulate, one step requires activation of an L-type calcium channel. This is why most mast cell stabilizers are actually calcium channel blockers.
It should be noted that mutation in the CACNA1C gene, which encodes the Cav1.2 ion channel, leads to a severe kind of autism called Timothy Syndrome. Because Cav1.2 is widely expressed in the heart those affected have a very poor prognosis.
In addition, verapamil blocks the potassium ion channel Kv1.3.  Potassium channels, Kv1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production. Kv 1.3 is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases.  Research has shown that peptides from parasitic worms that suppress the body's immune response do so by blocking Kv1.3. A drug therapy based on these peptides is being developed.
Verapamil also upregulates autophagy, which is impaired in many neurological disorders, such as Huntington’s. Lack of autophagy has been linked to the synaptic pruning deficits found in autism.
Verapamil has a short half-life of about 3 hours. Only a small dose is required to prevent the onset of SIB and the preceding agitation (described by LT as “spray the fire in my head”).
From the age of 10, LT’s summertime raging has been treated with 40-80 mg of Verapamil split into 2-3 doses from May until late November.
On the occasions that he has missed his 1pm dose in the peak allergy period, he has repeatedly developed aggression and self-injury by 4 or 5pm.
When he has taken verapamil there has never been any aggression and or self-injury.
Once self-injury was removed as a concern, learning progressed during the long summer school holidays. It became clear that during summer cognition was reduced as if bumetanide was no longer working.
It has been shown that the expression KCC2, the cotransporter that allows Cl- to leave neurons is affected by inflammatory cytokines like IL-6. It therefore appears plausible that the histamine and IL-6 released directly and indirectly by mast cell degranulation was causing an increase in neuronal Cl- and thus undoing the good work being done by bumetanide. Inflammation also increases α5 GABAA receptor activity and can thus reduce cognitive function.
At this point, the bumetanide dose was raised from 1mg once a day to 2mg in the morning and on occasion 1mg in the late afternoon.
The combination of an increased dose of bumetanide and the use of verapamil, cetirizine and azelastine has produced a very favorable result (no SIB and minimal summertime cognitive decline). Perhaps of note is that cetirizine is an eosinophil stabilizer, which may also be helpful and not just for asthma.
OTC therapies that have a helpful effect in summer are L-histidine, curcumin and L. reuteri DSM 17938 (sold as Biogaia Protectis). The amino acid histidine is a precursor to histamine and it seems that the body’s feedback loops can be tricked into not degranulating mast cells by slightly increasing the level of circulating histidine. The immunomodulatory effects of L. reuteri DSM 17938 have been well studied; the effect however does not continue after prolonged use. Curcumin is a very widely studied natural substance that performs much better in vitro than in vivo, due to very poor bioavailability. Modified versions of curcumin have been developed and there is a marginal benefit. Histidine is extremely cheap and easy to administer. Modified curcumin and L. reuteri are quite expensive.
It is reported by others that at a higher dose verapamil is as effective as an H1 antihistamine in treating allergy. 

IPR3
It appears that aberrant calcium channel signaling is a key feature of much autism. Gargus has suggested that IP3R is a nexus for different dysfunctions that lead to autism. IP3R controls the release of calcium stored within cells (the endoplasmic reticulum).
Excessive calcium within cells is known to be damaging. L-type calcium channels that remain open will raise intracellular calcium and the same is true with IP3R. Caffeine can be used to inhibit calcium release via IP3R.
Gargus has not proposed an IP3R therapy.  


RORα

RORα is another proposed nexus where different dysfunctions  that lead to autism may converge. One potential RORα agonist is estradiol.  We know that in much autism there is elevated testosterone and reduced estradiol; we also know that estrogen receptor beta is under-expressed. Estradiol is known to be highly neuroprotective and may help protect females from developing autism. Females lacking in estradiol, for example in Turner Sydrome, may exhibit features of autism. A logical therapy would be to either use estrogens, or reduce testosterone (effectively the same thing). Ideally you would do this just in the brain; a brain selective pro-drug of estradiol, called DHED, actually exists. Less ideal therapies range from estradiol itself, to phytoestrogens or a high soy diet, to drugs reducing testosterone, like spironolactone; these will have effects beyond the brain.

Wintertime raging
Having solved summertime raging, wintertime raging appeared. As expected, verapamil had no effect.
Ultimately the likely trigger was traced back to the very slow loss of milk teeth and eruption of permanent teeth. Both reabsorption of roots and the eruption new teeth is signaled using pro-inflammatory cytokines.
Moderate use of Ibuprofen, as and when behavior began to deteriorate, resolved the problem. Ibuprofen has no effect on summertime raging.

PANS-like episode aged 13
PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) and PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) are infection-induced autoimmune conditions that disrupt a patient’s normal neurologic functioning, resulting in a sudden onset of Obsessive Compulsive Disorder (OCD) and/or tics and cognitive loss.
The import part is acute-onset; behavior changes overnight.
LT exhibits the classic traits of autism including stereotypy/stimming but never tics, which are a feature of Tourette’s-type autism.
Just before Christmas LT was recovering well from what presented as mild viral infection that had not warranted any medical intervention. He suddenly developed very loud verbal tics.
It is well known in PANS that delayed treatment severely affects prognosis. The sooner the patient is treated, the more complete recovery will be. Diagnosis is based on a very specific set of laboratory tests, only available in the US.
LT was treated from the third day of the tics as if he had PANS flare-up. He was treated with 40mg of prednisone for 5 days, requiring no taper.
Over a two week period the tics faded away. There have been no more tics.

Use of antioxidants
A recurring feature in autism research is oxidative stress. Two clinical trials have shown the benefit of the antioxidant NAC (N-acetylcysteine) in autism.
In LT the effect of NAC is the immediate disappearance of stereotypy and a type of anxiety. Without NAC, LT always wants to know what is happening next, to the point of obsession.
Oxidative stress has been shown to vary throughout the day and LT’s therapy is tailored to match it. Oxidative stress causes a cascade of further disruptions and causes many of the side effects of type-1 diabetes, for example.
LT takes 2,400 mg of NAC per day (a dose slightly lower than in the clinical trials). He has 600mg immediate release NAC at 7am, 600mg sustained release at 7am and then 600 mg sustained release at 1pm and 5pm. 
There have been no side effects after more than 4 years. 

Anti-inflammatory
Numerous studies (e.g. Ashwood) show elevated pro-inflammatory cytokines and reduced  anti-inflammatory cytokines as a feature of autism; but specific subgroups exist. Activated microglia is another feature of autism, which also suggests chronic inflammation.
Numerous anti-inflammatory strategies have been researched.
Atorvastatin has potent anti-inflammatory effects that are very well studied. It also affects the autism/cancer proteins RAS, PTEN and BCL2.
RASopathies are associated with MR/ID and indeed autism. Mutations in PTEN generally cause loss of function in PTEN and are associated with macrocephaly, enlarged corpus callosum, MR/ID and autism. Loss of function of PTEN is also found in some cancers, for example prostate cancer.
Because autism is polygenic and hundreds of genes are over/under expressed, it is not necessary to have a mutation to have misexpression. The mutation is just the extreme case (be it Cav1.2 or PTEN).
The effect of Atorvastatin is visible from the first dose and fades away the next day if therapy is stopped. The effect is very specific, it releases cognitive inhibition; it is as if the person with autism has the desire and capability to do something, but some barrier prevents him from doing it.
In broader severe autism, this is very important, Why does a child with autism who can verbalize never speak?
At the age of 9, LT was having piano lessons at home twice a week. He would practice the piano only if his assistant or father sat beside him. He never played independently.
After taking 10mg Atorvastatin for the first time, the next day LT went himself to his piano and started playing, without any prompting of any kind. He then began to practice on a daily basis.
As a child aged 3, LT had the habit of coming to the entry of the room with the television and watching from around the corner of the wall. He wanted to watch but could not enter the room. At the time it was thought he somehow just liked the visual sensation of peering around corners.
When he later moved to a multi-level house, LT would not come downstairs by himself; he would wait at the top of the stairs for someone to lead him down, every morning.  With atorvastatin not only did this behavior disappear, but it reappeared the day after Atorvastatin was withdrawn.
During one test withdrawal of the treatment, he got “stuck” in the kitchen and could not leave the room.

Sulforaphane Nrf2 and HDAC
In 2014, and again in 2017, Talalay/Zimmerman published research that sulforaphane from broccoli showed a benefit in autism. Sulforaphane is an HDAC inhibitor and thus has potential epigenetic properties, like some cancer drugs. Sulforaphane may also activate the Nrf2 redox “switch” and so be protective in conditions associated with oxidative stress.
LT’s father did contact the researchers and shortly after the first research was published LT started to take a broccoli sprout supplement. It did produce a very obvious effect and within 30 minutes; LT was laughing so much, be went to look at himself in the bathroom mirror. The more general effect was an unmissable increase in speech.
After three years of use the positive effect of sulforaphane/broccoli is no longer visible, even trying alternative brands.
In the 2017 clinical trial the authors found one responder retained the benefit of sulforaphane after the trial ended. They suggest an epigenetic switch may have been activated.  

Mitochondria and Microvasculature
A distinct type of autism has been characterized by Kelley at Johns Hopkins, Autism Secondary to Mitochondrial Disease (AMD). Kelley suggests that almost all regressive autism is caused by mitochondrial dysfunction and usually deficiency of the rate-limiting complex 1.
By stabilizing the mitochondria with antioxidants and then trying to stimulate more complex 1, a gradual improvement can occur.
Mitochondrial disease effectively starves the brain and body of energy (ATP), so lack of exercise endurance is exhibited in people with a genuine mitochondrial dysfunction.
One feature of autism is that growth factors (BNDF, IGF-1, NGF, VEGF etc) are disturbed, but the disturbance varies greatly by the type of autism.  Vascular endothelial growth factor (VEGF) in particular and its receptors are known to be disturbed and this has implications for microvasculature. Studies suggest that unstable, rather than reduced blood flow occurs in autistic brains.
In sports medicine, exercise endurance is a key target and it can be raised by improving the energy production from mitochondria and by improving the circulation of blood throughout the body by targeting eNOS (Endothelial Nitric Oxide Synthase) and NO (Nitric Oxide).
In Mild Cognitive Impairment (MCI) studies have shown the benefit of improved cerebral blood flow using cocoa flavanols to indirectly affect NO and hence improve memory.
Studies show that eNOS and NO can be safely increased by Agmatine and NO can be increased  using L-citrulline, which then produced more L-arginine. These supplements are widely used by sportsmen and women.
A small dose of Agmatine (1 g) has a near immediate substantial effect on LT, making him far more energetic.  It moved him from being rather passive physically, to being active. This has been very evident from his performance at school during physical activities, where it has been widely noted. At home LT started trampolining before breakfast and late in the evening.

Sensory Overload and Sensory Gating
An apparent over-sensitivity to sensory stimuli is a common observation in autism and is often the precursor to behavioral problems. In some younger children these can be trivial, but in more severe autism it can produce profound behavioral problems that never fade away.
Hypokalemic sensory overload and hypokalemic periodic paralysis are described in the literature. LT had sound sensitivity as a young child, in particular an inability to cope with the sound of crying. Tests were carried out to establish whether LT’s tolerance to the sound of crying improved after oral potassium. He consistently tolerated a high volume of a recording of this sound, when played 20 minutes after 250mg of potassium. Following ABA, he was purposefully exposed to this sound and taught to understand why people cry and modify his response, to the extent that his response changed to laughter, which again has to be modified towards empathy. 
Aged 10, LT developed a phobia to traveling in elevators/lifts. This was because the elevator he regularly used to visit his Grandparents was the old-fashioned type, with an internal sliding gate that you close by hand, which is extremely noisy.  He refused to use the elevator from that point on.  People with autism very easily form habits, or are allowed to form them, following the path of least resistance.  Elevators are a part of modern life and hard to avoid.
After a few weeks of this behavior, LT was given 500mg of potassium and half an hour later willingly entered the elevator and coped with the ride. The behavior has never recurred.
Sensory gating is another common issue in autism and schizophrenia, the individual is not able to filter out repetitive background sounds, like a clock ticking or the sound of a noisy eater. Sensory gating can be measured by looking at the P50 response on an EEG. α7 nicotinic acetylcholine receptor (α7 nAChR) agonists, like nicotine, can correct impaired P50 gating. A low dose of a PDE4 inhibitor is another suggested therapy
LT does exhibit was presents as impaired P50 gating. It is really only evident when his pharmacological therapy is halted for a few days. Then he finds all kinds of unavoidable noises very annoying, even the sound of a person sitting next to him eating. 

Typical Psychiatric Drugs
LT has never been treated with any of the usual antipsychotics, stimulants, anti-depressants, or anti-anxiety drugs sometimes prescribed in autism. His use of clonazepam is at a dose far below its standard clinical use.

Current status
In September 2017 LT moved to secondary/high school where some of the teachers recall how he used to be 10 years previously. Initially there was some trepidation and the view by some that a boy with classic autism should not be there. The school does have a boy with Asperger’s. However, LT surprised his new teachers, achieving grades placing him in the top half of his class. He is now extremely attentive in class, no attention deficit anymore, and has clearly not reached his intellectual limit. He has likely already far surpassed his intellectual limit, had he remained untreated.
As the end of the first year of high school approaches, LT continues to keep up academically with his peers. His agmatine-boosted physical performance has been maintained and he competes very well in long distance running and swimming.
LT is still intellectually far away from the trajectory followed by his older brother, but LT is keeping up academically with many of his classmates who are neurotypical, with average IQs.
A significant number of people diagnosed very young with autism do indeed make dramatic progress by the age of 6.  Zappella proposed his Dysmaturational Syndrome that he says applies to about 6% of early childhood autism, but they all have Tourette’s type autism (with tics).   There is an additional group without tics that also achieve what Fein calls Optimal Outcome, essentially they lose their autism diagnosis. In total it is 10-15% of cases that seem to “get better” all by themselves, regardless of intervention. As more diagnosis takes place even before 2 years of age and autism threshold grows ever wider, Optimal Outcome may become even more common.  
The definition of autism has been greatly watered down in recent years (DSM3 to DSM5). LT started with DSM3-type autism and by the age of 8 he still had it. DSM5 autism includes very much milder variants, some of which are trivial.
Each therapy used by LT has been found to be reversible based on careful withdrawal trials.



People with strictly defined autism (SDA) start to acquire skills with a delay compared to NT peers and thereafter acquire skills at a slower rate and hence fall ever further behind, making inclusion at school a delusion. The aim is to have similar skills to NT peers to make inclusion effective.
People with SDA often leave high school with an educational level of a 7 to 10 year old.

From the age of 12, LT ceased having any autism-specific learning curriculum; he just follows the curriculum of his mainstream school.  

Anecdotal Evidence
LT’s piano teacher exclusively teaches people with disabilities (mainly severe autism and a few with Asperger’s) and so has great experience of the disorder. She says while she has taught people who learnt to play as well as LT does today, this has never happened before with a child who started in his kind of condition at 8/9 years old.
The American ABA consultant (with Ph.D. and 20 years of experience) knowing LT from the age of 8, before he started bumetanide, told the family that of all her clients, LT is the one she sees the least but has improved the most and how strange that is. 


Current Therapy

The current therapy, called the Autism PolyPill, may be found in the link below.  

https://epiphanyasd.blogspot.com/p/polypill-for-autism.html

Autism is a highly heterogeneous condition, but there appear to be broad sub-types. At least some people with an autism diagnosis respond to each individual therapy in the PolyPill. Some people respond to almost the entire combination of therapies; other people respond to none.


Future Therapy

Some other interesting therapies remain to be investigated and it is clear that more improvement is possible because short term therapy with the flavones nobiletin and tangeretin produces a marked change in cognition and behaviour. The effect only lasts two or three days.  Tangeretin is a PPAR gamma agonist, among other properties. It reduces cholesterol when used long term, but its autism benefit is transient.  

The ketone Beta-Hydroxy Butyrate (BHB) also looks interesting; it has epigenetic properties amongst its other effects. 






54 comments:

  1. Excellent summary post, Peter!
    Have you seen the Hyperlipid blog at http://high-fat-nutrition.blogspot.co.uk/ written by another Peter? He is very knowledgeable on Complex 1, BHB, fat vs glucose based energy systems, etc. Perhaps he has some ideas/suggestions that could be useful to you.
    Keep up the good work!
    Aspie2

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  2. Thanks for this mega-summary Peter.
    It makes me very happy to see how Montys life has got so much more opportunities with the PolyPill. :)

    ..and some more reading:
    "NKCC1 Inhibition Attenuates Chronic Cerebral Hypoperfusion-Induced White Matter Lesions by Enhancing Progenitor Cells of Oligodendrocyte Proliferation."
    https://www.ncbi.nlm.nih.gov/pubmed/29502291

    Yes, bumetanide is mentioned.

    /Ling

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  3. Thank you for sharing our son is on risperdone would bumetandine interact with it we would really want to trial this bumetandine please do tell us if e can use both or not waiting on your reply Sue

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    Replies
    1. Sue, for drug interactions you have to check with your doctor.

      One side effect of risperidone is that it may reduce blood pressure, and hopefully your doctor has checked whether this has happened in your son.

      Bumetanide is normally used to lower blood pressure, by reducing the amount of fluids in the body. For autism we do not want this effect and so the child has to drink more fluids to not become dehydrated. My son dinks 2-3 litres of water a day.

      If risperidone reduced blood pressure and you took bumetanide and did not drink more fluids you would create a problem.

      Bumetanide does reduce potassium levels which need to be maintained by a potassium supplement and increased dietary potassium (e.g. banana, kiwi, avocado).

      A small number of people are allergic to common class of drugs called sulfonamides, of which bumetanide is a member.

      Most people can take bumetanide long term without any negative effects, but you do need to be responsible.

      Delete
    2. Out provider will say No as usual but the pressure is fine he is on a very tiny amount .I think I will try this discretly have seen it advertised on anoff shore site thank you I’m not looking for miracles,but might be pleasantly surprised .Thank you both Peter Lipitor would that be a problem as well he has always responded to calcium negatively ....does that have any bearing thanks Sue

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    3. Sue, the amount of calcium in 10mg of atorvastatin calcium is tiny. Some people take 500mg of calcium in supplements. It is relevant that calcium makes a problem, but I really doubt the amount of calcium in atorvastatin will have any effect.

      Delete
  4. Critically evaluating your child's progress and trying to be objective is a very hard thing to do, especially when it is easier to absolve yourself from responsibility by simply shifting it to a panoply of health care providers and then if nothing works, you can blame the doctors or the entire health care system or just accept failure as "the best doctors can do", rather than accepting responsibility as a parent in looking at all possible options to give your child the best chance at life. If you asked me a year or so ago if my largely non-verbal 9 year old son could read and write and actually intentionally spell words he has learned accurately, I would have had strong doubts even though he has improved in many other ways from his basis point, but now after school is about to end, one activity he loves to do is simply get a bunch of magnetic letters and spell everything he comes across. I can ask him to spell many different words and he does it accurately, even though I still can't have a back and forth conversation with him. He is also getting better on his own to infer what other people want without needing to be prompted which is also a very good sign among many other things.

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  5. As summer is now almost here and school will soon be out, I came across an interesting study that shows how heavy leg exercise is very important in stimulating neurogenesis as well as the maturation of oligodendrocytes which seem to not be doing their jobs properly in autism and perhaps may be part of the problem with executive brain networks functioning properly as their functionality depends on myelinated axons that go from the front to the back of the brain:

    Press Release:

    https://www.sciencedaily.com/releases/2018/05/180523080214.htm

    Paper:

    https://www.frontiersin.org/articles/10.3389/fnins.2018.00336/full

    The inspiration for this research was the observation that people on bedrest for an extended period of time as well as people who have had their motor functions compromised through stroke or injury end up declining cognitively as well. My own grandmother had a precipitous decline into dementia after falling and breaking her hip. This seems to be the norm in these situations so the researchers wanted to know why.

    What they found out (in mice) was that restricting the hindlimbs (legs) rather than the forelimbs (arms) from exercising would cause a significant reduction in stem cell differentiation in the primary area of the brain that produces new neurons, especially after a brain injury such as that of a stroke. In particular, heavy exercise of the legs seemed to cause the most neural stem cell activation.

    So this got me thinking of how to employ this kind of physical therapy in my son or else some method I could ask his occupational therapist to look into and I thought of American Football training which involves a lot of heavy leg work (especially for linemen). So I asked a local football coach for some ideas from the many training exercises they employ for this purpose and he suggested two good ones. The first was to simply get a barbell plate (he uses 45 pound ones with his players) and put it on grass or preferably artificial turf and have the subject simply push the plate across the ground using their hands. This requires being crouched down on your knees and even though you can push the barbell plate with your hands and arms, it is easier to use your legs and body weight to push it forward with your legs. The second suggestion was to simply get a stretch band and wrap it around the waist of the subject and have that person run as fast as they can while another person holds on from the other end to provide some resistance. If the subject is too strong, you could attach the stretch band to a wall (this apparatus is common in CrossFit gyms).

    Only time will tell as to whether this will have significant results on my child, but it is a safe intervention and at least has some scientific evidence behind it to suggest it could help with autism in potentially helping with myelination issues and therefore overall cognition, while sadly many physical therapy and occupational therapy practices in use today clearly do not.

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    1. Tyler,

      This is really helpful and I wil ask my sons occupational therapist if some exercises cab be disigned around that though I could not open the link. Could you resend it.

      Delete
    2. Ok..the second link is opening up. Problem with the first one.

      Delete
    3. HIIT with sprinting definetely helped me throughout the years, need to be carefull not to do overdo it though. People with autism/asd have poor exercise tollerance, the whole lowered baseline glutathione levels, elevated CK, elevated LDH, this needs carefull approach, sometimes less is more. Personally I only do about 10 sprints of 30seconds with 90second rest in between. If I do anymore than that the man with the hammer visits me next day, brainfog, extremely sore muscles, long recovery time.

      Cardio is important too, I cannot stress this enough, it has been linked to improved endothelial function, better NO production, better HDL:LDL ratio (coq10 also helps loads for HDL in me personally), improves mood through neurotransmitters. The improvement in endothelial/NO-production obviously will reflect in more brain blood flow aswell (cocoa/citrulline/icariin/taurine helps lots too).

      Delete
  6. Peter, thinking of all your additional interventions for chloride, do you feel that Bumetanide has got less effective with time? (Or, eventually, that the need for inhibition has grown with age - I think NMDA signalling is enhanced in adulthood?)

    /Ling

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    Replies
    1. Ling, I think bumetanide had the most dramatic visible effect at the beginning, but it has not stopped working. I think as a child gets older it becomes even harder to keep up with NT kids. Academically speaking, Monty came from far behind to catch up and indeed overtake some of his NT classmates over the 5 year period, at least in some subjects. Ideally you would start with the most potent Cl- reducing therapy. Bumetanide makes GABA more inhibitory, but likely not as inhibitory as is should be.

      It might be as you get older the BBB becomes less permeable and so less bumetanide passes through.

      There is no reduction in the NKCC2 diuresis effect, so I guess the NKCC1 effect does not fade. It might be there are feedback loops so that the more you block NKCC1, the more new NKCC1 transports are created.

      Delete
    2. Even with feedback loops there should be some upper limit as to how many NKCC1 channels can be available. Especially after 5 years of use you would think that that upper limit must have been hit. So, either it has something to do with the BBB as you point out, or there are developmental changes that for some reason demand greater inhibitory force from GABA.

      I wish there were more data on neurological development. We all know that at some ages, children generally get more anxious/moody/oppositional, and these phases are probably related to neurological changes. One small example is the switch and gradient change of subunit composition of NMDA receptors.
      https://en.wikipedia.org/wiki/NMDA_receptor#/media/File:NR2B-NR2A_switch_in_human_cerebellum,_microarrays,_Bar-Shira_et_al_2015.png
      It is not far fetched to see that if some developmental changes are not in perfect timing with each other (or happening at all), you get odd behaviours, at least for a while.

      /Ling

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    3. Taurine inhibits K+-Cl- cotransporter KCC2 to regulate embryonic Cl- homeostasis via with-no-lysine (WNK) protein kinase signaling pathway.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375508/

      "Thus, taurine and WNK-SPAK/OSR1 signaling may contribute to embryonic neuronal Cl− homeostasis, which is required for normal brain development."

      Not sure how much relevance this is, but could taurine help prevent further explosion of the autism pandemic? Hope this helps.

      Delete
    4. To add a comment to the picture mentioned above: Isn't it an interesting coincidence that the NR2A/NR2B (subunits of NMDAr) switch happens at the same time window as is proposed for the GABA excitatory/inhibitory switch?
      Of course, many things happens at the very beginning of life.
      /Ling

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    5. Taurine looks like it does the opposite to what Peter is doing; it keeps Cl- inside neurons while Peter tries to keep Cl- out.
      Ponstan/mefenamic acid is another substance that like Taurine keeps Cl- inside neurons. It has had a beneficial effect in a few autism cases like mine, but it could also be due to other of its properties. All this is a bit confusing, and I don't know if Peters case and mine represent total opposites of autism or if they are more alike.

      If Bumetanide is a p38 inhibitor (like Astaxanthin which also reduces NKCC1), as speculated in the paper I posted earlier above, this should have interesting consequences, both good and bad. But I have never heard of anyone with a bad cognitive effect from Bumetanide(?)

      Unfortunately I am still clueless to if Astaxanthin/Krill oil is a really really good OR a really bad idea for my daughter. Whichever it is, anything going on in the PKA/ERK/CREB triangle is extremely interesting for me and it is populated by p38, MSK and RSK, and promises of memory enhancement and myelination.

      p38 seem to have to do with migration and ERK1/2 with proliferation and I guess both are needed but it also looks like inhibition of either one activates the other. Then we have something called phospho-p38 which I don't know what it is, but wish I did.

      :)

      /Ling

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    6. If taurine does the oposite of what is wanted, you might want to look into beta-alanine (which competes with taurine for the same transporter and is basically a taurine-antagonist so to speak).

      Looking at mefenamic acid, horrible potential side effects, I would never even consider taking that, but each to their own.

      Also Ling have you tried bumetanide yet? To be honest taurine has strong anxiolytic effects in me, its like the savest and pro-longevity 'amino acid' out there, increases brain and blood antioxidant levels, neuroprotection, does about everything good a supplement can do.

      Now beta-alanine.... when I tried it, horrible horrible horrible experiences, I freaked out! Like one of the only supplements I responded so bad too, literally got scared to go on the street and yup gaze aversion and fears were back. I get gaze aversion aswell with ALCAR but instead of that making me fearfull it makes me irritable.

      Delete
  7. Peter,I decided to try azithromycin long term,a 500 mg capsule or 250 mg each day? Should I change to Nystatin after a month to avoid resistance?
    Valentina

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  8. A new paper just came out which elucidates what may be the primary anti-seizure benefit to a ketogenic diet:

    Press Release:

    https://www.sciencedaily.com/releases/2018/05/180524141700.htm

    Paper:

    https://www.cell.com/cell/fulltext/S0092-8674(18)30520-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867418305208%3Fshowall%3Dtrue

    The findings are rather complex in that what they found was that not one, but two species of bacteria in the gut microbiome were required during a ketogenic diet to get the anti-seizure benefits. They confirmed this via having seizure prone mice on a ketogenic diet after first either having the mice being born germ free or else wiping out the mouse microbiome with antibiotics and noticing that there were no anti-seizure benefits under these circumstances. They then took these two strains of bacteria and colonized germ free mice and the anti-seizure benefits from a ketogenic diet transpired.

    Specifically, an enzyme I am unfamiliar with called gamma-glutamyltranspeptidase was inhibited which confers seizure protection somehow and this enzyme was inhibited by the two bacteria causing GABA levels to raise and the GABA/Glutamate ratio to increase as well.

    This is all very interesting because if you factor in the hygiene hypothesis and the sterile clean homes of suburban living plus the fact that in the United States you have levels of Caesarian section being performed that would be unbelievable several generations ago which means that many babies not delivered naturally may not be exposed to the right kind of healthy bacteria from the mother, it makes you wonder how many diseases are prevented or attenuated by a healthy microbiome and that some of the rise in neurodevelopmental disorders and metabolic disorders may indeed be the result of underlying problems being exposed, rather than those problems being caused directly be the environment itself.

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    1. Tyler, you may find this article interesting:-

      Missing microbes 'cause' childhood cancer
      http://www.bbc.com/news/health-44199844

      The research shows that the rise is childhood leukaemia is linked a lack of exposure to microbes in the first year of life, that fails to teach the immune system to deal with threats correctly.

      The genetic mutation for leukaemia is by itself insufficient to trigger the disease.

      Delete
    2. Yes that is very interesting. In parts of my extended family, there is an anecdotal trend of excessive cleanliness and severe allergies/asthma. Bringing up the hygiene hypothesis and studies on Amish families being devoid of these types of maladies does not go over well with people who are literally afraid of "germs".

      Not to change the subject, but I just came across this nugget that suggests a strong link to placental stress and an explanation for why in many neurodevelopmental disorders, including autism, you have a skewed gender ratio favoring males over females:

      Press Release:

      https://www.sciencedaily.com/releases/2018/05/180528124001.htm

      Paper:

      https://www.nature.com/articles/s41591-018-0021-y

      This paper mostly discusses schizophrenia, but alludes to the alphabet soup of neurodevelopmental orders where there seems to be a strong link to a development dysfunctional cascade beginning in utero.

      This may be one of those situations where it is assumed that an pro-inflammatory state in the mother can lead to direct problems in her offspring, whereas the maldevelopment could be happening indirectly via the placenta. If this is the case, it may be possible in high-risk mothers to treat the placenta with some sort of injection to relieve stress on the organ and therefore give the baby a better chance at having a healthier pattern of development.

      I have not really looked into placental health before, probably because it is not seen as something that is necessarily part of the mother or the baby (some people in fact will actually eat the placenta for so-called "health benefits"). Nevertheless, I have not seen it discussed much in autism research one way or another and I don't think you have covered it before in the massive library of blog posts you have now accumulated so far.

      Delete
    3. Tyler and Peter, does this paper imply that microbiome modification is enough to replicate ketogenic diet effect?

      They say: "transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet."

      What does it mean in practice? Is there a way to increase Akkermansia and Parabacteroides without using KD?

      I have just been told that indeed this can be achieved with SCFA use, but I don't know the details.

      If so, what is the role of cirulating ketone bodies? My son has been on exogenous BHB for a while now and I can see a range of positive effects, although I need some more time to make a final conclusion. Trying not to rave too early as with my memantine trial which eventually proved to be problematic rather than helpful.

      Delete
    4. https://www.cell.com/cell/fulltext/S0092-8674(18)30520-8

      Agnieszka, I think this means that if your only problem is epilepsy all you may need is to increase the amount of these 2 bacteria. So somebody should develop a probiotic pill for epilepsy.

      But the KD benefits many diseases, even Alzheimer's, where the problem is glucose not being converted properly to ATP, so there you need ketones as an alternative fuel.

      I think we will find that the KD helps different groups for entirely different reasons. It will be of no help to many people.

      Even within epilepsy there are completely different causes, some may need the HDAC inhibiting effect of the ketone bodies, while others might just need the proposed effect on GABA from the 2 bacteria.

      As to what may help autism it would certainly be helpful and easy to study these 2 bacteria in autism mouse models. Maybe contact Elaine Hsiao at UCLA and suggest this?

      Delete
    5. Agnieszka, the paper said nothing about circulating ketone bodies but was quick to point out that there can be multiple factors in the positive effects of a KD diet with respect to neurodevelopmental disorders such as schizophrenia. My reading of it all was that the levels of Akkermansia and Parabacteroides are dependent upon whether a KD diet is employed or not. Bacteria in the microbiome are both regulated by the immune system as well as by each other, so bacteria that enjoy munching on carbohydrates or protein may out-compete Akkermansia and Parabacteroides, whereas when ingested levels of carbs and protein are low, Akkermansia and Parabacteroides are able to find the breathing room to increase their numbers.

      One other interesting tidbit was that the paper sort of indirectly suggested that a big oral intake of plain GABA might achieve the same effects. They did not say this directly, but to me this is what I gathered from it all, even though GABA is not supposed to easily cross the blood brain barrier even though some have hypothesized that the vagus nerve may act as a conduit for intestinal GABA and many other substances.

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    6. Thank you both for comments. It would be indeed great to learn what helps for autism in ketogenic diet and are there easier ways to achieve this. And also it would be good to know if children with 'fever effect' are in ketosis during febrile illness.

      Delete
  9. Peter, I could find fluconazol to use with azithromycin,not nystatin, he is having an excellent reaction to azith this time.Fluconazol could avoid yeast while using azith long term?
    Valentina

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  10. Peter, why this time my questions have no answear? I rally don't now if using azith with fluconazol is a good idea.
    Valentina

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    Replies
    1. Valentina, you have to ask a doctor these questions. Azithromycin does have immunomodulatory properties and some doctors prescribe it long term to treat chronic conditions like cystic fibrosis and sometimes autism. There is clinical knowledge about possible side effects and what to do about them.


      Meta-Analysis of the Adverse Effects of Long-Term Azithromycin Use in Patients with Chronic Lung Diseases
      http://aac.asm.org/content/58/1/511.full

      Delete
  11. Peter, have you had any experience with probiotics / prebiotics? What are your thoughts re: the leaky gut hypothesis as well as the use of B fragilis?

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    Replies
    1. My son reacts well to Biogaia Protectis (L.reuteri DSM 17938), which helps with allergy and give the oxytocin effect. On the rare occasion he has GI problems he responds well to Bacillus coagulans.

      A high fiber diet clearly helps produce a healthy microbiome. Junk food has been shown to reduces the variety of gut bacteria.

      My son eats very well and when I tried inulin it had no effect. If you do not eat a healthy diet you might well see a benefit from inulin.

      The critical time for bacteria is during pregnancy, birth and the first couple of years of life. The bacteria are conditioning the baby's immune system, this can only occur very early in life.

      It is clear that some people do have a leaky gut and bacteria can help, just like they help in ulcerative colitis.

      Some bacteria have both good and bad effects.

      Probiotics are really a class of drug. So you really need to know what you are doing. I am sure in the next decades much better use will be made of bacteria as therapy.

      Delete
    2. Peter,

      What are your thoughts on the following:

      OCD is obviously associated with serotoninergic dysfunction and has (partial overlap) with behavior in autism such as repetitive behavior. A common displayed 'ritual' in OCD is excessive cleaning behavior and fear of bacteria. Could it be (maybe, just maybe!) that the host (the person with OCD), does this in an attempt to maintain gut homeostasis, in this case a prefered state minimal exposure to pathogens/bacteria.

      On top of that, look at the amount of reports of return of normal behavior in those with autism after use of antifungals, these are somehow influencing a shift in gut homeostasis causing a more optimal setting for them, as reflected by improvement in behavior and quality of life.

      Could one of the most widely prescribed antibiotics amoxicillin/clavulanate "augmentin" be a risk factor for autism?
      https://www.ncbi.nlm.nih.gov/pubmed/15607562

      For example the discussion in that study, after that you might ask yourself (and so should scientists) which strains actually get depleted.

      Just as they should look at the gut population in OCD, these might give clues and allow us to get to the root of the problem.

      Look at this, alcoholism is associated with an increase in lactoballicus and bifidobacterium strains!!!

      Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease
      https://www.ncbi.nlm.nih.gov/pubmed/15607562

      " Interestingly, each of the two factors was associated with the expressed ENRICHMENT IN MANY BIFIDOBACTERIUM AND LACTOBACILLUS—but the exact set of the species was different between alcoholic dependence and liver cirrhosis." <<<<<<---------------

      Antibiotic resistance of lactic acid bacteria and Bifidobacteriumspp.isolated from dairy and pharmaceutical products
      https://zdoc.site/antibiotic-resistance-of-lactic-acid-bacteria-and.html

      Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens.
      https://www.ncbi.nlm.nih.gov/pubmed/15374659

      Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006292/

      They used VSL#3 (a widely available and well known probiotic which contains mainly... you guess it lactobacilli and bifidobacteria strains!)

      More evidence regarding the powerfull effects of gut-modulation:

      Alterations of the Host Microbiome Affect Behavioral Responses to Cocaine
      https://www.nature.com/articles/srep35455

      "Groups of mice were treated with a prolonged course of non-absorbable antibiotics via the drinking water, which resulted in a substantial reduction of gut bacteria. Animals with reduced gut bacteria showed an enhanced sensitivity to cocaine reward and enhanced sensitivity to the locomotor-sensitizing effects of repeated cocaine administration. These behavioral changes were correlated with adaptations in multiple transcripts encoding important synaptic proteins in the brain’s reward circuitry. This study represents the first evidence that alterations in the gut microbiota affect behavioral response to drugs of abuse."

      In other words, messing with gut homeostasis controls both reward systems and motivation.

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    3. Aspie1983, I think you have to look very critically about everything published relating to autism.

      The Italian paper regarding VSL#3 use, is one I myself referred to a while back. It is about a boy with severe irritable bowel disease (IBD), suspected celiac disease and autism. VSL#3 is effective in many people with IBS/IBD and improving these inflammatory conditions is guaranteed to help the associated autism. So VSL#3 for IBS/IBD but not necessarily for autism.

      The paper on the antibiotic Augmentin is by Joan Fallon, also referred to earlier in this blog. It is very weak and in effect comes down to her one sentence.

      “Since the introduction of clavulanate/amoxicillin in the 1980s there has been the increase in numbers of cases of autism.”

      Our reader Seth wrote a paper where he correlated the rise in autism to the increase in vitamin D used to fortify food.

      Overuse of antibiotics is bad, but there are old people today with impaired hearing, or even deafness, because they were not given antibiotics for an ear infection in childhood.

      The microbiota clearly plays a key role in all aspects of health and we are at the very early stages of understanding this.

      By developing too fast and changing how we live dramatically, human bodies have not had time to evolve. We now pay the price in a rise in auto-immune conditions and neurological conditions like autism, ADHD, OCD etc. Overall people are living longer and healthier than ever, but there is some collateral damage.

      The answer is to put back what modern life has removed. Things like growing up around animals, healthy amounts of varied bacteria, mother’s milk, not formula milk etc. I expect one day this will be put back artificially, so as not to disturb our modern life.

      Delete
    4. Eventually, life expectancy in severe autism in Europe is now 39,5 years, similar or less to how it is in some countries in Subsaharan Africa far from modern life.

      In my 'previous life' I was involved in some research in immunity and infectious disease in rural Africa and it seemed to me that children there were able to mount antiinflammatory response I could never see in persons from Europe. One professor of immunology told me it is impossible and probably I made some mistake in the lab. Perhaps I didn't. Seems like we paid a high price.

      Delete
    5. Peter, are you aware of this:

      https://www.microba.com/preorder/

      It costs 420australian dollars, which corresponds to 270€ and 320USD. I have mailed them asking about if they are going to operate on an internation level, they are starting june 2018!

      After my dramatic success with l. reuteri (still improving every day!!!) I digged up some more information last night, seems reuteri also affects PKC/DAG signalling (remember my whole inositol/phosphatidic acid experience!), also they mention the use H2 antagonists is linked to crohns and how atcc 6475 restores this balance by acting upon both H1 and H2 histamine receptors.

      Now CB1 signalling (often underactive in asd social issues) - multiple studies this - involves 2-AG (endogenous precursor to endocannabinoids) signalling.
      DAG lipase and DAG kinase control this, the paper I found on atcc 6475 shows that reuteri inhibits DAG kinase and this one of its mechanisms (very complex), but the end results they claim is PKC inhibiting and anti-cancer. I got a suspision this would indirectly increase DAG lipase and increase 2-AG concentrations in the body thus increasing CB1 signalling, now CB1 signalling increase VTA dopaminergic tone, once again atcc 6475 showed in the autims model it altered the GABA/dopamine balance in social wanting dysfunction in mouse model. This would also explain the copious amounts of oliveoil I consume and nuts and peanutbutter (all precursors to endocanniboids).

      I hope I can get the money together and order the test, no doubt insurance will not pay for it.

      I think everyone who reads this should do 2 things, wether their son/family or themselves have regressive autism/autism/asd:

      * get 23andme, I cannot stress this enough, this has confirmed ALL my suspisions and explains why I have responded to certain supplements and why I have averse reactions to some others.

      * be one of the first to the gut microbiome online tests. excessive amounts of random antifungals without knowing the actual contents of the gut can do alot of wrong aswell, I see alot of people on here who give their kids random antifungals and praying/anticipating an outcome. If you know whats actually inside your kid their guts its a good point to start from!

      Delete
  12. Hi Peter, excellent post ! I'm not sure where to post this question.,I hope that you read and answer it, please. I'm not sure if it is advisable to avoid ingesting chlorine, due to the GABA inversion. There are some ionic Magnesium supplements, in liquid, that are the best in absorption. But they are Magnesium Chloride. Could you tell me if it is better look for another form, without chlorine ? Thank you very much !

    ReplyDelete
    Replies
    1. Luis, if it was me I would find a magnesium without the chloride.

      Delete
  13. Peter, my son is responding better than expected to azithromycin,5 day ago, and the improvement in his hypotonia, handwriting, sleeping and anxiety is very remarkable.The question is for how long could he take it without developing resistance. Another alternative? We cant use Nystatin due to strep.What is this telling me about my son?
    Valentina

    ReplyDelete
    Replies
    1. Valentina, this tells you that young son may have a dysfunctional immune system of a type that responds to the modulatory effect of azithromycin.

      Some people use this long term, there is a new drug in development that would give the benefits but is not an antibiotic.

      He might also respond to other immunomodulatory therapy, but you cannot really predict which one. Perhaps some people with cystic fibrosis have found alternatives. It is worth investigating.

      Delete
    2. Peter, could search two drugs with immunomodulatory effects used in cystic fibrosis:Thymosin and Doxycycline, both suppress hyperinflammatory response.
      Valentina

      Delete
    3. Here i can get Doxycycline OTC.
      Is not cheap without prescription.
      It is sold as antimicrobial.
      Valentina

      Delete
    4. Valentina, Doxycyline is a tetracycline type antibiotic, so you have the same problem as with Azithromycine. You really want something that is not an antibiotic.

      Delete
    5. Peter, i think that i will continue with cinnamon as immunomodulator.
      Also immunoglobulins could help?
      If you know something better please let me know.
      Valentina

      Delete
    6. Valentina, as a safe long term option I think the baking soda idea is worth investigating. It now has a sciientific basis and many people already use it for other reasons, so I think we would know about any adverse effects.

      Delete
    7. Peter, I was using baking soda but stopped when started Diamox because of the risk of kidney stones when used together.What do you think,is it better stay with baking soda?
      Valentina

      Delete
    8. Valentina, I would make a two week trial with baking soda to see if you get some of the benefits you saw from Azithromycine. You need to see what really helps and has no side effects then you can decide what to use long term.

      Delete
  14. Peter you were looking for a good drug to hit estrogen receptor beta selectively, well here is one candidate being studied for its use in remyelination in MS:

    Press Release:

    https://www.sciencedaily.com/releases/2018/05/180529153103.htm

    Paper:

    http://www.pnas.org/content/early/2018/05/24/1721732115

    There is not much else to say other than the main benefit here with indazole chloride is selectively hitting estrogen receptors in the brain without many of the overt feminization aspects of any sort of serious estrogen therapy on males.

    Also, after a quick google search on indazole chloride, it looks like it has been seriously studied for quite a while for MS, however I could not find any commercialization of the drug as the only links I could find discussing its purchase were from chemistry labs.

    ReplyDelete
    Replies
    1. Tyler, very interesting. It appears that the benefits of estrogen in MS are well known. During periods of high estrogen during pregnancy, females with MS go into remission and then after birth as estrogen levels tumble, back comes the MS.

      It does seem to take forever to translate such knowledge into medicine. Such a ER beta agonist would be great for some autism, and possibly mitochondrial disease, not just MS.

      Delete
  15. Thanks a lot for the great post. Regarding the ineffectiveness of sulforaphane, we noticed that we had to increase the dosage in time. We are keeping my son on sulforaphane(SGS-crucera) for the past 3.5 years, started with 20mg/day. Now he is at 175mg/day. Somehow he is also aware of the positive effect. Sometimes, when he feels like the stims are coming back, he says his head feels funny and asks to take the evening dose earlier.

    We also experienced the waning effect of L. reuteri.

    ReplyDelete
    Replies
    1. It is great that sulforaphane still works and that your son can feel the effect and when it fades. It is like living in a science experiment.

      Delete
    2. Great to see you still are seeing some positives from it despite having to increase the dose, the boyd probably develops some tollerance to the nrf2 inducing effect and this could be one of the reasons.

      With regards to reuteri, could you go into details about how long, what dose and what the experience has been so far with it, would be greatly appreciated.

      Delete
  16. We did 5 drops/day of BioGaia for about 4-5 months. First few weeks we saw very good effects socially. However, after the first month, things started turning negative, my son started complaining about tummy ache, so we completely stopped it.
    I believe as he grows up in size and he is more responsive to outside stimuli, his neural circuit develops more connections and his NRF2 pathway will require more sulforaphane.

    ReplyDelete
  17. This might seem like a question out of the scooe of this blog, but it is really a bother - how do you give so many supplements and pills to a child of 5 years - old enough to know that sour stuff (most of it is sour) is not fun and too young to swallow large pills and capsules? any ideas? especially the large doses of NAC are impossible for us to achieve.

    ReplyDelete
    Replies
    1. TP, many people are crushing pills and adding to food or drink.

      There is expensive NAC that is sold as an effervescent tablet (PharmaNAC, Fluimucil, Sandoz ACC etc).

      Delete

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