January 3, 2014 Leave a comment
As it ended, 2013 turned out much better than I expected. I received a special present on Christmas Eve when, Itai Berger, Editor of Frontiers in Human Neuroscience, emailed me that my article on transcranial ultrasonography had been accepted and was available online in provisional format. See abstract below.
This publication was the result of ongoing collaborations with my Italian colleagues at the University of Firenze (Florence). Professors Ruggiero and Pacini are pushing the immunological research in autism, chronic fatigue syndrome (ME/CFS), and cancer through their detailed laboratory investigations of the vitamin D binding protein – GcMAF. It was our shared interest in GcMAF that brought us together on the ultrasound research. 2012 ended with the publication of the first article describing Nagalase and GcMAF in ASD. (title below).
One year later – to the day and after more than 10,000 article views – I was lecturing in Dubai at the 2nd International Conference on GcMAF Immunology. The conference was well attended with physicians and researchers fro many countries. Pediatricians and Psychiatrists from Dubai, Jordan, Turkey, Italy, India and the US shared their experiences with GcMAF therapy in ASD. It was very rewarding to hear their stories. They presented videos and collections of cases, all of which observed something similar to what i had already published: most children with autism respond vigorously to GcMAF and side-effects were minor and transient.
I consult with families from 37 different countries around the globe and I hear the same stories about GcMAF regardless of the child’s ethnicity or culture. That likely speaks to the immunological ties between immune dysfunction and autism. Below is one of the many extraordinary letters I received late in 2013.
Once upon a time my first born son was autistic.
He stopped developing properly around the age of 1 and lost the few words and skills he previously had, though I don’t believe he was up to par even then. From there he slipped away from us into his own world and it was as if he couldn’t even see or hear us. He didn’t know he had a name, that we had names, or that we were even there. He didn’t babble, he didn’t play with toys, he didn’t even look up at people when they entered the room. When we had kids over to play he would hide in a corner and cry. He was chronically ill with one sickness after another, always tired, sleeping 14 hours at night and if we woke him up from his nap before 3 hours he would scream hysterically sometimes for 2 hours. The first doctor told me he was just a boy and boys develop slower, the second doc said we were just bad parents, and the third finally gave us a diagnosis at 27 months – 8 months after I had begun to worry.
We tried everything; B-12 shots, ABA 20 hrs. a week, speech, OT, vitamin D, probiotics, and an extremely strict diet of no gluten, dairy, eggs, nuts, soy, fish, dyes, preservatives or anything artificial. These things did help a lot but even so it was an extremely difficult uphill battle of working months to gain a skill and if one person wasn’t consistent on the implantation of a goal he would regress immediately. There was a whole year that he woke up screaming every night for hours. Nothing I did helped and he couldn’t tell me what was wrong so I would resort to laying beside him and crying myself. He would wake up his baby brother who then also began screaming. It was a long year of screaming even from me! I once responded to one of his fits by having an all out screaming meltdown of my own, face down on the floor pounding the ground like a 2 year old. I was depressed, exhausted, and contemplated many times just ending it all…I have to be real because other parents need to know they are not alone in this. Besides the screaming he was always horribly constipated to the point of needing medical intervention, he had raging eczema head to toe, was allergic to literally everything; I knew my son was sick. I often told my husband, “some day 50 years from now the doctors will finally figure out that autism is a problem with the immune system but by then it will be too late for him.” I thought he would live with us his whole life and just continue to be a tired, sick, crying, itchy boy, who couldn’t get words out or look at us. Then my friend told me she found a doctor named Bradstreet who did believe it was immune related and was treating it! I had hope!
We started GCMAF and began seeing real progress after the level 7 dose. He seemed more energetic, cried less, and speech and eye contact were improving. Each week began to be amazingly better than the last and it felt like we were seeing actual recovery. Then after about a month he ended up in the hospital with a raging sinus infection of strep that led to an abscess behind his eye. This is a very rare complication but as I said, he had the immune system of a flea. He needed emergency surgery to save his eye but continued to battle the infection and a fever of 104 for 11 days until they resorted to surgery again, this time fully removing his right ethmoid sinus. During his hospital stay and for 3 weeks after while he was still on antibiotics we couldn’t do GCMAF. His regression was significant. His speech went way back to about 9 months before we started GCMAF, he could only get a few words out at a time with great difficulty and even I couldn’t tell what he meant. He actually said to me finally, “mommy. help me,” and I said, “with what baby?” He struggled to get out the following, “with the…words…not come….out… good.” I cried because I knew he felt trapped in his own body unable to do what he was trying to. When I told him the shots were going to help him be able to speak he was eager to get them and reminded me every week on Wednesdays.
When we started back up again and finally got the progress going he developed a rash which I now know was molluscum but at the time thought it could be related to GCMAF. We changed his dose from the level 12 once a week to level 5 twice a week and then we lost him. He went off into “autism-land” as I call it. Didn’t hear us, couldn’t focus, couldn’t even accomplish a single step direction and wandered around aimlessly. This dosage was working for other kids but not for him. We went back to level 12’s once a week and after 6 weeks of that he was in everyone’s mind effectively cured.
His speech and OT discharged him, and after 2 weeks of being in a typical kindergarten class with no aid, the school coordinator told me he didn’t even need any special accommodations. We increased his school day to be full day now from 8:30-3:30 and even though he isn’t even 5 yet, there are zero problems. Zero. No fits, no meltdowns, no non-compliance. His teacher told me he listens in class, follows the schedule with no extra prompting, plays with kids on the playground, holds his pencil properly (big one!), and even sits with friends asking them where they live and what they ate for snack. After school he is able to tell me what he did, describe details about movies or books they read, sing me songs he learned, and he still has energy to play and doesn’t melt down when we get home. He never previously had the skills of recalling events or asking/answering questions properly until this. He currently has no therapy and we see no autism in him whatsoever. He says what he wants when he wants fluently, uses slang terms and laughs at jokes! He has even developed a little bratty back-sass attitude which my husband and I correct but then turn to each other and cry happy tears because it’s SO normal!! He was actually able to tell me that he likes the shots because his sleep is better, he has more energy, and he can speak better. He also hasn’t gotten sick once since the hospital stay back in March. His bowels are no longer dependent on laxatives daily as they were for 2 years. It’s like a dark cloud has been lifted and my son has been freed from his internal prison. We have the son we never had but knew was in there somewhere dying to get out. I have no doubt he will live a normal life and accomplish anything he wants to from now on. I don’t know if he will need GCMAF permanently or not but even if he does I don’t care. I will never let him go back into that cave. I firmly believe God answered my prayers and healed my son and he used Dr. Bradstreet and GCMAF to do it. Our son is healed and so is our family.
Forever indebted and grateful beyond measure,
As a parent (and I am one with 2 boys, my own son and my step-son are both on the autism spectrum) these stories are powerful and touching. But as a scientist I am driven to understand the mechanisms behind these types of anecdotes. The story relates a child rapidly changing state from significant and non-verbal autism, to observed to be normal by parents, teachers and therapist over a mere few weeks. Autism has been felt to be a developmental and irreversible brain disorder. Clearly that is not always the case, as many stories of recovery are being published in the lay literature.
So how can this happen? Mechanistically, I think this must represent the presence of an interfering inhibitor to normal neurological functioning. Whatever this substance or effect is, it acts very much like local anesthesia blocking signals in specific parts of the brain. In at least the example described above, that effect is then rapidly dissipated and the brain essentially wakes up. This story is common and doctors at the conference in Dubai presented their own versions describing very similar events in their practices as well. But not all children respond to GcMAF and that speaks to various subtypes of the disorder, some of which are readily recovered while others seem much more entrenched in whatever autism represents at the brain level.
It appears a significant subset of autism is immunological driven and that would fit the observations noted from around the world regarding GcMAF as a therapy. The graphic below is from a review article: Gesundheit B, Rosenzweig JP, Naor D, Lerer B, Zachor DA, Procházka V, Melamed M, Kristt DA, Steinberg A, Shulman C, Hwang P, Koren G, Walfisch A, Passweg JR, Snowden JA, Tamouza R, Leboyer M, Farge-Bancel D, Ashwood P. Immunological and autoimmune considerations of Autism Spectrum Disorders. J Autoimmun. 2013 Aug;44:1-7. doi: 10.1016/j.jaut.2013.05.005. Epub 2013 Jul 15.
IN the graphic the authors depict the maternal immune system with its macrophages and other immune cells priming the response of microglial cells in the fetus. Microglial cells are derived from macrophages which migrate into the brain during fetal development. Those macrophages then undergo changes to become microglial cells. They, however, maintain many of the features of their original macrophage immunochemistry. Missing from the diagram is another intersect circle representing the postnatal environmental effects. But regardless of that limitation in the representation, the hypothesis they propose is chronic immune – inflammatory changes in the brain secondary to microglial swelling.
GcMAF as noted in my paper, stands for Gc protein macrophage activating factor. That name makes it sound like a pro-inflammatory molecule and as such based on the model above it would seem to be the last thing you would want to give to a child with autism. As it turns out, the argument for chronic inflammation in the brain of children with autism is not universally agreed upon and other researchers, particularly Prof Manuel Casanova, have the opinion there is no inflammation in the autism brain.
I had the pleasure of sitting with Prof Casanova at several autism-related think tanks where the immune system was being discussed. He took a decidedly differing view that there was no evidence of inflammation in the autism brain, but rather there was abnormal construction of the brain’s special electronics and at its smallest unit the minicolumn. Casanova explained he had dissected scores of brains in great detail and inflammation was not present. Instead the consistent finding was abnormal minicolumn construction. Below is an excerpt from a complex but insightful review we must consider.
How is it that both camps: the inflammatory and the minicolumn, can be so divided in their views of autism? First, I agree that autism is primarily influenced by epigenetic factors. In 2013 I participated in a review of these factors which is public access.
In this review we wrote: “The term epigenetics was first coined in the 1940s by British embryologist and geneticist Conrad Waddington, who described it as: “the interactions of genes with their environment, which bring the phenotype into being” . Our present knowledge enhances this earlier understanding, and epigenetics now evaluates the alteration of DNA transcription via variations in DNA methylation and histone modifications, but without alterations in the DNA sequence. These variants represent the epigenome, which in turn will be reflected in the transcriptome: that portion of the DNA which is being actively transcribed into RNA.” The key is the environment regulates DNA transcription (messaging) without changing the sequence (no mutations) of the DNA.
And most importantly this observation; that there was too much fluid around the brain of children with autism.
In the figure above I excerpted the images from Shen, et al., 2013 and added the arrows and notations of increased EAF.
In our paper on TUS we observed the same effect – increased fluid surrounding the brain. Below is a side-by-side comparison of fraternal twins from our paper in Frontiers in Human Neuroscience (2014).
Under normal conditions the fluid (hydrostatic) pressure of the subarachnoid space (the fluid surrounding the brain) is not sufficient to keep the space fully open at the point where the brain folds itself closely to the skull. In figure 13 from our paper, you can see the space of Twin A stays constant at 0.16 cm as the underlying brain compresses the arachnoid (meninges) of the brain, whereas with Twin B the space is compressed down to 0.01 cm. Now go back to the images from the Brain study of Shen, et al., 2013. If you study those images you will see that in the neurotypical child, the gyral summits (places where the brain folds up towards the overlying inside of the skull) come is very close proximity to the inner lining of the meninges and typically seem to be touching the membrane. In our higher magnification views we see the same effect (Twin B). However, we and Shen, et al., 2013 observe the same increased distance of fluid volume in the case of autism.
So what does this mean? At a recent MAPS conference I pulled Professor Theoharides aside to discuss my observations. “Theo”, as well al call him, is a brilliant Mast Cell researcher and you can pull up his publications at his website: www.mastcellmaster.com. I will insert a portion of one article, but realize Theo has extensively published on the immune and mast cell effects in ASD.
The graphic below is in my opinion a more complete understanding of the immune and epigenetic effects than the one from Geshundheit, et al., 2013.
This graphic gets us closer to what I think is really happening in autism, but it leaves out the potential role of the very much neglected meninges in the development of autism. Theo agreed this was an intriguing notion and one of my projects is to finish a review of this factor with Theo in early 2014. What I now theorize happens in autism is somewhat like happens in experimental models of multiple sclerosis – although obviously different in timing and specificity.
The meninges make the EAF which fills the subarachnoid space – that same EAF and subarachnoid space which is observed to be increased both both us, Bradstreet, et al., (2104), and Shen, et al., (2013). In the research above, the inflammatory changes in the subarachnoid space, what both Shen, et al., 2013 and we think is is happening, induce changes in the microglial cells of the cortex making them more appear more inflammatory and less ramified (supportive).
The cells are noted to be round and this is the way they look when they are inflammed.
In direct distinction, GcMAF treated microglial cells convert to the supportive ramified state. This means that the effect of GcMAF on microglial cells and macrophages is NOT inflammatory, but the opposite – anti-inflammatory.
In findings soon to be published, the images dramatic support this effect. I believe the shifting of macrophages and glial cells to anti-inflammatory states can explain why and how the mother’s story of her son’s recovery happened. To more fully understand this we need to understand the birectional role of TNF-alpha on memory and brain development.
TNF-alpha is one of the most potent pro-inflammatory mediators of the immune system. At proper concentrations it is required for development of memory and synaptogenesis. At pathological levels it destroys synaptic communication and is part of all neurodegnerative disease states including Alzheimer’s. New evidence points to the effects of TNF-alpha on NMDA receptor function.
In my clinical practice, I use MgThreonate routinely and it is nearly always helpful in autism. The mechanisms are speculative but it is both effective at NMDA-R restoration as noted above as well as a direct anti-inflammatory.
Tying these seemingly unrelated observations together gets me to where I think autism is taking our understanding.
1). Epigenetic, both prenatal and postnatal effects influence the priming of microglial cells and most assuredly mast cells as well.
2). Mast cells and macrophages contribute to inflammatory changes in the meninges.
3). The immune changes in the meninges opens the tight junctions in the capillaries and allows extra fluid to accumulate in the subarachnoid space.
4). The increased EAF also carries within it the inflammatory chemistry of the mast cells and macrophages.
5). This message also influences the microglial cells and the mast cells resident in the brain.
6). This disrupts minicolumn function and structure.
7). This process prevents the creation of proper harmonic communication in the electrical properties of the brain.
8). The end result is autistic symptoms.
Presumably GcMAF and Magnesium threonate work to restore both microglial cells and macrophages to the ramified supportive non-inflammatory state. The effect of mast cells in unknown. But with all of this I believe 2014 is going to bring some amazing breakthroughs for relieving the suffering of autism.
So Happy New Year – 2014