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Showing posts with label KBr. Show all posts
Showing posts with label KBr. Show all posts

Thursday 26 May 2022

Bromide for Autism? Plus ça change, plus c'est la même chose!

 

Hôtel de Ville (City Hall) Tours, France, Gateway to the Loire Valley and Home to iBrain

Source: https://commons.wikimedia.org/wiki/user:Tango7174

 

We do seem to be going round in circles in this blog.  One doctor reader contacted me recently to tell me about Pentoxifylline for cognitive improvement. I told him that I am not surprised and that in the world of autism Pentoxifylline has been known to be beneficial for half a century. 

The abstract below is from a Japanese paper in 1978

 

On our experience in using pentoxifylline for abnormal behavior and the autistic syndrome

Abstract

Describes the successful use of pentoxifylline (150–600 mg/day) with 3–15 yr old children with abnormal behavior (e.g., self-mutilation, aggressiveness, and hyperkinesis) and with autism. It is noted that while the drug was effective in reducing symptoms of autism, developmental factors in the disorder should not be ignored.

 

You might wonder why it has not been widely adopted, at least for some people with autism. 

When it comes to Potassium Bromide (KBr) I found a case history from 150 years ago of its successful use in a little girl with epilepsy, autism and impaired cognition. She was treated at what is today London’s top children’s hospital, Great Ormond Street.

KBr was the original treatment for epilepsy.  It is still used in countries following German medicine; indeed, it is can be the only effective treatment for those with Dravet Syndrome.

Interestingly, Great Ormond Street Hospital has restarted the use of KBr in childhood epilepsy, specially importing its drugs from Germany.

 

Bromide for epilepsy – Great Ormond Street Hospital

            https://www.gosh.nhs.uk/conditions-and-treatments/medicines-information/bromide-epilepsy/

 

In the US, KBr is only used for canine and equine epilepsy.  It does not work well on cats, incidentally.

Back in 2016, I did propose KBr as an add-on therapy for those with autism who respond to bumetanide.  This was part of my effort to develop a “super bumetanide”, to increase the bumetanide effect.

 

In a quote from today’s feature paper, from iBrain at the University of Tours, France:- 

“beneficial effects (of bromide) were superior to those of chronic bumetanide administration” 

in one mouse model of autism. 

When I was asked to give a presentation in the US on bumetanide for autism, there was one condition, “please don’t mention potassium bromide … we don’t want people trying it.”

Yes, it’s OK to talk about treating autism, but please don’t actually do it.

Move forward a few years and a doctor friend recently highlighted to me a new paper from France proposing Sodium Bromide for autism.

I did rather think here we go again, been there done that.

My conclusion back in 2016 was that yes it does provide a benefit; but it does have some drawbacks.  It has a very long half-life, meaning if you keep taking the same daily amount, it will take 5 weeks to reach its peak level in your bloodstream.

It does increase mucous secretions, in a dose dependent fashion.  This is not a problem in canine epilepsy, but in humans it will lead to spots (bromo-acne).  It could make asthma worse.

In the case of children with Dravet Syndrome, they have a high rate of death from epilepsy, or SUDEP (Sudden unexpected death in epilepsy).  So, I don’t suppose parents are going to worry about a few spots.

 

Potassium bromide in clinical trials for Dravet Syndrome

Potassium bromide has not been tested in randomized clinical trials specifically for Dravet syndrome patients. Some small studies suggest, however, that it might benefit Dravet syndrome patients.

retrospective study analyzed data from 32 Dravet syndrome patients carrying an SCN1A mutation. Six patients received potassium bromide temporarily as monotherapy, while 26 patients received the medication as add-on therapy. The mean treatment duration was 47 months with a mean maximum daily oral dose of 63.2 mg per kilogram (kg) body weight of potassium bromide.

Three months after treatment began, 31 % of the patients experienced complete seizure control. Seizures were reduced by more than 75% in 6% of the patients, and by more than 50% in 19% of them.

 

My old post from 2016:

 

Potassium Bromide for Intractable Epilepsy and perhaps some Autism


My idea was to see if you can get a meaningful benefit from a low dose and avoid any side effects. Rather than the 63.2 mg/kg for Dravet Syndrome seizures, I thought a reasonable dose was 8 mg/kg to further treat the E/I imbalance in Bumetanide responsive autism.  Why 8mg/kg? Well, that was half a tablet. 

 

Sodium Bromide for Autism, proposed by the French researchers

 

Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

 

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behavior. To date, no pharmacological treatment has been approved that ameliorates social behavior in patients with ASD. Based on the excitation/inhibition imbalance theory of autism, we hypothesized that bromide ions, long used as an antiepileptic medication, could relieve core symptoms of ASD. We evaluated the effects of chronic sodium bromide (NaBr) administration on autistic-like symptoms in three genetic mouse models of autism: Oprm1−/−, Fmr1−/− and Shank3Δex13-16−/− mice. We showed that chronic NaBr treatment relieved autistic-like behaviors in these three models. In Oprm1−/− mice, these beneficial effects were superior to those of chronic bumetanide administration. At transcriptional level, chronic NaBr in Oprm1 null mice was associated with increased expression of genes coding for chloride ions transporters, GABAA receptor subunits, oxytocin and mGlu4 receptor. Lastly, we uncovered synergistic alleviating effects of chronic NaBr and a positive allosteric modulator (PAM) of mGlu4 receptor on autistic-like behavior in Oprm1−/− mice. We evidenced in heterologous cells that bromide ions behave as PAMs of mGlu4, providing a molecular mechanism for such synergy. Our data reveal the therapeutic potential of bromide ions, alone or in combination with a PAM of mGlu4 receptor, for the treatment of ASDs.

 

Compromised E/I balance in ASD may result from several neuropathological mechanisms. On the excitation side, glutamatergic transmission was found altered both in patients and animal models, although in different directions depending on genetic mutations/ models [9, 18, 19]. On the inhibition side, decreased levels of GABA [20] and expression of GABAA and GABAB receptors (postmortem analyses, [21, 22]), as well as genetic polymorphisms in GABAA receptor subunits [23, 24], have been detected in patients with autism. Accordingly, decreased GABAergic neurotransmission has been reported in several ASD models [25–29]. Alternatively, it was proposed that GABA neurons remain immature in ASD, maintaining high intracellular concentrations of chloride ion (Cl−) whose efflux through activated GABAA receptor induced neuronal depolarization [30]. Intracellular Cl− concentration is under the control of the main Cl− importer NKCC1 (Na+-K+-2Cl− cotransporter) and its main exporter KCC2. Therefore blocking NKCC1 using the loop diuretic and antiepileptic drug [31, 32] bumetanide appeared a promising therapeutic approach in ASD. Accordingly, bumetanide improved autistic-like phenotype in rodent models of ASD [33] and relieved autistic behavior in small cohorts of patients [34, 35].

 

Bromide ion (Br−) was the first effective treatment identified for epilepsy [36] and long used as anxiolytic and hypnotic [37]. With the advent of novel antiepileptic and anxiolytic drugs, its use was progressively dropped down, although it remains a valuable tool to treat refractory seizures [38, 39]. At molecular level, Br− shares similar chemical and physical properties with Cl−, allowing it substituting Cl− in multiple cellular mechanisms. These include anion influx through activated GABAA receptor, with higher permeability to Br− compared to Cl− resulting in neuronal hyperpolarization [40], and transport through the NKCC and KCC cotransporters [41, 42]. In view of the E/I imbalance theory, these properties point to Br− as an interesting candidate for ASD treatment.

 

Here we assessed the effects of chronic sodium bromide administration on core autistic-like symptoms: social deficit and stereotypies, and a frequent comorbid symptom: anxiety, in three genetic mouse models of autism with different etiologies: Oprm1−/−, Fmr1−/− (preclinical model of Fragile X syndrome) and Shank3Δex13-16−/− mice, lacking the gene coding the mu opioid receptor or the FMRP protein for the formers, or the exons 13−16 of the Shank3 gene, coding for the PDZ domain of the SHANK3 protein, for the later. Altered E/I balance and/or modified expression of involved genes have been reported for these three models [28, 43–47]; the Oprm1 knockout model presents the advantage of limited impact on learning performance [44]. We evidenced that Br− treatment alleviates behavioral deficits in these three models and increases expression of various genes within the social brain circuit of Oprm1 null mice. We unraveled that Br− not only increases mGlu4 receptor gene expression but also potentiates the effects of the positive allosteric modulator (PAM) of mGlu4 VU0155041, in Oprm1−/− mice and in hetero[1]logous cells. Our data reveal the therapeutic potential of Br− administration and its combination with a PAM of mGlu4 receptor for the treatment of ASD. 

 

RESULTS

Chronic sodium bromide relieved autistic-like symptoms in Oprm1−/− mice more efficiently than bumetanide

Chronic sodium bromide relieved social behavior deficits, stereotypies and excessive anxiety in Fmr1−/− and Shank3Δex13-16−/− mice

Chronic sodium bromide modulates transcription in the reward circuit of Oprm1−/− mice

Synergistic effects of chronic bromide and mGlu4 receptor facilitation in Oprm1 null mice

Bromide ions behave as positive allosteric modulators of the mGlu4 glutamate receptor

 

In conclusion, the present study reports the therapeutic potential of chronic bromide treatment, alone or in combination with a PAM of mGlu4 receptor, to relieve core symptoms of ASD. Beneficial effects of bromide were observed in three mouse models of ASD with different genetic causes, supporting high translational value. Moreover, bromide has a long history of medical use, meaning that its pharmacodynamics and toxicity are well known, which, combined with long-lasting effects as well as excellent oral bioavailability and brain penetrance, are strong advantages for repurposing.

 

 

Conclusion

The doctor treating Ida at Great Ormond Street 150 years ago noted that after treatment with KBr she developed age-appropriate play skills.  That is very much the same effect as bumetanide in a young child with severe autism and IQ<70.

My trials of 400mg of KBr produced a “bumetanide+” effect and feedback from other bumetanide super-responders was in line with this. Higher doses than mine were used.

The effects of KBr overlap with those of Bumetanide, but it is possible that there may be more KBr responders than Bumetanide responders.  KBr has interesting effects beyond those of Bumetanide. It is definitely worth considering KBr, even if the person is not a bumetanide responder.

The French researchers in today’s paper propose that Bromide be repurposed for autism – they definitely have the right idea.  They did note the 8-14 day half-life in humans.

In the advisory from Great Ormond Street it is noted:

“Your child will need to have regular blood tests to monitor the amount of bromide in their blood – this usually happens around four weeks or so after starting to take the medication, or four weeks after the dose is increased. 

I think the aim should be maximize the benefits of KBr, without incurring the side effects that will occur at high doses.  KBr might be best as an add-on therapy in autism.

The 60mg/kg dose from Dravet Syndrome is 8 times the bumetanide add-on dosage I suggested.

One of the models used in the French trial was that for Fragile X syndrome, the others were the Mu Opioid Receptor Null model and the Shank3B−/−, lacking the PDZ domain.

Fragile X is one of the most common types of human autism and is apparent from facial features. Bromide for human Fragile X ?

In case you are wondering, whether to choose sodium bromide (NaBr) or potassium bromide (KBr), it is the bromide ions (Br-) that are critical to its effect on the E/I imbalance.  Personally, I prefer KBr, because most people have too much sodium and too little potassium in their diet.  People taking bumetanide should be taking extra potassium anyway.

Interestingly, from the UK guidance: -

“Salt and salty foods can reduce how well bromide works. Try to limit the amount of salty foods your child eats and do not add salt to cooked foods if possible.

One other medical formulation of bromide is called triple bromide and contains three different variations of bromide:  ammonium bromide, potassium bromide and sodium bromide.

Hopefully it will not take 50 years to establish the usefulness (or not) of bromide as an autism therapy.

It was mentioned first in this blog, back in 2016.

In 2017 some French people filed a patent, claiming to be the inventors of bromide as a treatment for autism.


WO2018096184- BROMIDE SOURCE FOR USE IN TREATING AUTISM SPECTRAL DISORDER








Tuesday 29 September 2020

Is the Door about to Close on Alternative Medical Treatments for Autism in France? Plus, more on Dravet Syndrome and RIP Charlotte Figi

 

I was talking to the organizers of an autism conference in the US and one question that came up was, do I know a clinician who prescribes potassium bromide (KBr).

It is a question that illustrates the problem in treating autism. In Germany, Austria and some neighbouring countries KBr is an established treatment for pediatric epilepsy and particularly some specific conditions like Dravet sydrome. Dravet syndrome is a rare, catastrophic, lifelong form of epilepsy which begins in the first year of life.  It is one of those conditions where parents in the UK are begging to use cannabis. Dravet syndrome may be accompanied by an autism diagnosis.  In the US KBr is currently only used for canine epilepsy.

Regular readers of this blog may recall that Dravet syndrome responds to potassium bromide (KBr) and should respond to low dose clonazepam (it works in the mouse model).

I proposed KBr as an autism therapy and even found an “autism” case history from 150 years ago. KBr was the only effective therapy for epilepsy back then, so a child with epilepsy and severe autism might be lucky and get KBr prescribed, as in the case history I highlighted.  It worked well for that little girl and she developed the ability to play appropriately with a doll - that is what caught my attention.

Is KBr a widely used autism therapy in Europe?  Definitely not.  Only a handful of people use it for autism, but it is an approved safe therapy for pediatric epilepsy.

KBr will have a similar effect on GABA as bumetanide, but via a different mechanism, (some Cl- gets replaced by Br- inside neurons, this lowers the Cl- concentration and so changes the effect of GABA).

The drawback with KBr is bromo-acne, or spots.  I suppose if your child has Dravet Syndrome, or very severe autism, you will not be bothered by some spots. 

150 years ago they used a potion containing arsenic to treat the spots, this was a very bad idea. Arsenic is poisonous.

Charlotte Figi, who was the inspiration for the popular medical cannabis strain called Charlotte's Web, had Dravet syndrome. She died this year, aged 13. 

I am told that you actually need some THC, rather than just CBD (cannabidiol), to be effective, but over time Charlotte’s commercial product contained less THC and I am told lost its effect.

Stiripentol, a positive allosteric modulator of GABAA receptors, is an approved therapy to treat Dravet Syndrome. 

Dravet syndrome is usually caused by the ion channel Nav1.1

You might wonder why does a sodium ion channel cause a defect in GABA signalling.

 

Delayed maturation of GABAergic signaling in the Scn1a and Scn1b mouse models of Dravet Syndrome

We found that GABAergic signaling remains immature in both DS models, with a depolarized reversal potential for GABAA-evoked currents compared to wildtype in the third postnatal week. Treatment of Scn1b−/− mice with bumetanide resulted in a delay in SUDEP onset compared to controls in a subset of mice, without prevention of seizure activity or amelioration of failure to thrive. We propose that delayed maturation of GABAergic signaling may contribute to epileptogenesis in SCN1B- and SCN1A-linked DS. Thus, targeting the polarity of GABAergic signaling in brain may be an effective therapeutic strategy to reduce SUDEP risk in DS.

 

SUDEP is Sudden Unexpected Death in Epilepsy and this is what is likely to occur in about 1 in 5 children with Dravet Syndrome. These deaths would appear to be, to some extent, preventable if you read the science and apply it.

This takes me to France where well-intentioned Autism Moms/Mamans are seeking to rein in 50 French doctors thought to be prescribing autism therapies off-label to 5,000 children.

Are these crazy therapies? or beneficial therapies? or perhaps a mixture of both?  For sure they are unorthodox therapies.

Olivia Cattan thinks French Moms/Mamans should be using behavioral methods (ABA, TEACCH etc) because they worked well for her young son.  Her charity, SOS Autisme, is trying to stop French doctors treating other people’s children with autism. 

The same thing happened a few years ago in the UK. A lone UK doctor was prescribing drugs to children with autism, word spread and other doctors reported him the medical regulator, who banned him from seeing patients with autism.

The US is the Wild West by comparison – anything goes.  A doctor can tweet "vaccines DO cause autism" and there are no consequences. Today, governments around the world are buying up future Covid-19 vaccines for their citizens and one factor in agreeing the price is whether the government indemnifies the producer for legal claims due to vaccine side effects. Rare side effects are possible even with a "good" vaccine.

I did ask Dr Frye about MAPS doctors getting into trouble with the authorities.  He told me the big issue is the occasional divorced spouse who objects to a child’s therapy.


France probes doctors prescribing antibiotics for autism

French prosecutors said Thursday that they had opened an inquiry into dozens of doctors prescribing antibiotics and other drugs as a purported treatment for autism in children, potentially endangering their health.

French prosecutors said Thursday that they had opened an inquiry into dozens of doctors prescribing antibiotics and other drugs as a purported treatment for autism in children, potentially endangering their health. The investigation comes after an alert by France's ANSM medicines watchdog that doctors were prescribing long-term courses of antibiotics and drugs against metal poisoning to autistic children. According to Olivia Cattan, who heads the help group SOS Autisme and has written a book on the practice, some 50 doctors in France are thought to be treating up to 5,000 children this way. Such prescriptions have been linked to controversial ideas from Nobel Medicine Prize laureate Luc Montagnier, honored in 2008 for his co-discovery of the virus that causes AIDS, but frequently dismissed by the medical community for his unconventional ideas in recent years.

The Paris prosecutor's office said its public health department has been entrusted with the probe into charges of "endangering the lives of others" and "offences related to research involving human beings." On Tuesday, the ANSM said it had referred the matter, flagged by Cattan, to prosecutors after collecting evidence including parents' testimony and prescription sheets. The watchdog said the children were prescribed antibiotics, anti-fungal, anti-parasitic or anti-viral drugs, as well as treatments for heavy metal ingestion that are normally reserved for use in case of poisoning. The ANSM "formally advises against these uses, for which these drugs have not shown to be effective and which put these children at risk, particularly with prolonged use." Effects can include digestive, cardiovascular and skin disorders, while misuse of antibiotics can lead to drug resistance that undermines the effectiveness of future treatments. The ANSM has also alerted French doctors' and pharmacists' associations. 

According to SOS Autisme:-

L’autisme n’est pas une déficience mentale, ce n’est pas une maladie, ce n’est pas une fatalité, et cela peut toucher tout le monde.

Aujourd’hui, grâce aux méthodes cognitives (ABA, Teach, Feuerstein, Pecs…). tous nos enfants peuvent progresser et devenir des êtres autonomes, des citoyens qui fondent une famille et qui travaillent.

 

Autism is not a mental disability, it is not a disease, it is not a destiny, and it can affect anyone.

Today, thanks to cognitive methods (ABA, TEACCH, Feuerstein, PECS ...). all our children can progress and become independent, people who start a family and who work.

 

The highlighted part in yellow would be great if this was true, but it is not.  Tell that to the Paris Prosecutor.

All these behavioral therapies can help, but go and look at autistic people born in the 1990s in the US, who had rich parents and who used ABA, TEACCH, PECS etc, for two decades.

Are they all now independent people who started a family and who hold down a meaningful job?  No.

Sadly, they are either still living at home with Mom and Dad, or they got packed off to live in a group home, or some other sheltered living accommodation. Life expectancy is short and parents are likely to outlive their child.

If you want to know autism reality to adulthood, go and talk to old hands with no vested interest like Catherine Lord, Bryna Siegel or even Manuel Casanova. 

 

Conclusion

There are many obstacles to treating and educating a child with severe autism and this is clearly reflected in the outcome in adulthood.  

Where you live can matter much more than how much money you have.

Yes, there are some crazy sounding autism therapies.

Yes, there are some people seeking to make a lot of money out of gullible parents.

Yes, there are labs overcharging for "special" diagnostic tests.

But, that is not the complete picture.

There are also some therapies that might look bizarre to a lay person, but if you read the science, they are very well founded.  They are experimental therapies.

The risks of not treating severe autism are huge; death due to seizures, drowning and accidents are very common and according to the Karolinska Institute such people have a life expectancy of under 40 years.   Too many continue to die in childhood. 

I am no fan of DAN doctors, but it looks like only one death has ever been associated with their treatment.  In 2005 a British boy was given intravenous chelation in a clinic near Pittsburgh; he went into cardiac arrest and died.

The French lady behind SOS Autisme is a big fan of ABA and I hope her son is fully functional when he reaches adulthood. Most children with severe autism become adults with severe autism, regardless of how much ABA therapy they receive, they are just more functional. Their life has no fairy tale ending.

For a transformative effect on outcome, you have to address the biological problems.  By all means, combine this with whatever educational therapy works for the child.   I am also a fan of ABA, but a realistic one; I continue to see its benefits. But, no amount of ABA could teach my son even basic mathematics, I know, I tried it to the age of 9.  Now he can do algebra and solve equations, sometimes better than his NT classmates. I am delighted to contradict SOS Autisme - autism is a mental disability and it is a disease, but it is treatable. 

Personalized therapy / precision medicine does not lend itself to clinical trials with thousands of participants, by definition you are treating a rare combination of dysfunctions. 

The important thing is that personalized therapy must be both safe and effective.

No progress without some ruffled feathers.

 




 

 

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.