What is Autism? by James Jeffrey Bradstreet, MD, MD(H), FAAFP
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BIOMEDICAL
BY James JeffreY Bradstreet, md, md(H), faafP
W
hen I was asked to answer this question for The Autism File, it seemed like a straight shot. Anyone can find a standard definition of autism at their community library or on the Internet at countless sites, but that isn’t what you really want to know. I also know autism is not a simplistic or even homogeneous disorder. Rather, it represents a complex array of geneenvironment interactions that in turn create unique subtypes that may overlap in some ways while being very distinct in others. This demands a rigorous evaluation through a search of unique disease markers that can help lead us into a better understanding of each child’s individual needs. That all sounds rather intimidating to both doctors and parents – and not surprisingly so. Doctors are used to what is referred to as “usual and customary practice,” and what we are talking about is the attempt to profile a child’s specific and unique disorder. There is no usual autism treatment, and there is only one FDA-approved intervention for the agitation effects of autism (risperadone); beyond that there is nothing approved. As a result, most of you got about as far as the diagnosis when suddenly the resources and solutions being offered by the mainstream of medicine dried up. Perhaps you were referred for behavioral therapy to find a 2-year waiting list. But more than likely you were told to let
the school system handle your child’s needs. Occasionally that works fairly well, but, in general, school systems suffer from a serious lack of both financial and personnel resources, making it highly unlikely they could respond effectively to your child’s developmental needs without a lot of outside help – from you. However, we are finding ways to demystify at least some parts of the underlying medical problems, while finding they are frequently highly responsive to our medical, nutritional, and behavioral interventions. But the actual question really plaguing your heart, your mind, and your soul is this: what happened to my precious child? And after that question comes the next of a long series, which become wrapped in guilt, fears, sadness, and even panic. The second question has to be: what can I do to help my child? I know these questions too. Not just as a doctor, but as a father. I have stayed awake at night asking myself all of these countless questions – even the ones most people are afraid to talk about like: will he ever come back to me or is this all a hopeless waste of time and money? Two things have kept me focused throughout this journey with my son and thousands of other sons and daughters struggling to find their way back to wholeness. Are these great medical secrets I keep to myself? No. Really they have as much to do with any other aspect of life as
they do with autism. These are hope and persistence. A long time ago I read several books on success. It seemed logical enough. If you wanted to succeed you should learn from others who had actually done it. In one of those books was this quote from Dale Carnegie: “Most of the important things in the world have been accomplished by people who have kept on trying when there seemed to be no hope at all.” This is perfect. It merges together the key to success for any venture or quest you lay before it. That doesn’t mean you are guaranteed success – far from it. Most truly successful people fail over and over again. But it most assuredly is a guarantee you won’t succeed without these two on your side. On my desk is a solid bar of metal with this quote carved into it: “Never, Never, Never Give Up.” While that is not an exact quote from Winston Churchill, it is close enough. Most people give little thought anymore to one of England’s darkest hours. It was a time where people huddled in fear in underground subway tubes praying for safety and that they might just survive. It was time of dread and mortal consequences. Churchill’s words were not merely inspirational; they acknowledged a choice of survival lay before the English people. They needed to hear those words when they needed them the most.
Two things have kept me focused throughout this journey with my son and thousands of other sons and daughters struggling to find their way back to wholeness. Are these great medical secrets I keep to myself? No. Really they have as much to do with any other aspect of life as they do with autism. These are hope and persistence.
8 THE AUTISM FILE | www.autismfile.com | info@autismfile.com REPRINTED WITH PERMISSION © THE AUTISM FILE ISSUE 31 2009
Those are the same words you must carve into your psyche because, for most families, autism is like the London Blitz. Day after day of bad news is piled on top of more bad news. The bombs keep falling. The school fights you over the education plan, your insurer refuses to pay for your child’s medical care, your spouse feels neglected, your other children feel abandoned, your career (if you still have one) suffers, you cannot remember the last time you had fun, or you have no idea what sleep is because your little one always wakes up screeching at 1:00 AM. The Blitz just keeps coming day after day. When you reach this level of despair you empathize with the feelings of the war-shattered Londoners during those darkest hours of 1940-41. This gets me to my first useful definition of autism: autism is a war. It is a war being waged against your child and your family. Unless you fight back you are guaranteed more casualties and greater destruction. I had the opportunity to serve in the USAF early in my career. That whole military experience has served me well as I have taken on my son’s personal battle with autism and also the thousands of other children who have crossed my path. To some extent thinking militaristically helps you plan. We will talk more about this later. But autism is not just a metaphorical war within your family; it is an immunological battle taking place in the gut and brain of your child. When we set out to answer the questions about what has happened to your child we quickly find a large body of scientific evidence involving the abnormal regulation of the immune system. Unfortunately, we cannot examine the brain like we might a sore throat or a skin rash. It stays sealed away behind the armor-plate of the skull and inside the blood-brain barrier. This is why autism has been categorized, since its first observations 70 some years ago, as a behavioral disorder. We can see those manifestations of the illness – we cannot see the brain to assess its degree of inflammation or test it to see if toxins are present. So who are the friendlies and who are the enemies in this combat zone? Sadly it seems some of your child’s own
ISSUE 31 2009
defenders have defected and gone over to the enemy’s side. When immune cells lose their tolerance of the body’s own cells we call that autoimmunity. Researchers at Vanderbilt Medical School recently published direct evidence of the nature of the combat inside the brain1. In their landmark study of autism brain transcriptomics (the process of measuring what the DNA is making to learn what is really happening) they stated this: “… these expression patterns appear to be more associated with the late recovery phase of autoimmune brain disorders, than with the innate immune response characteristic of neurodegenerative diseases.” This is generally consistent with the brain studies of the Johns Hopkins group that showed very significant inflammatory brain disease at the time of autopsy from children with autism who drowned2. To build on this, researchers in Chicago found dramatically higher levels of the inflammatory immune marker TNFalpha in the spinal fluid than in the blood of children with autism3. This means the inflammatory response was greater inside the brain than outside the brain in the rest of the body. Almost 11 years ago a team in England found elevated levels of neopterin in the urine of children with autism4. Neopterin is produced when immune cells turn on – typically as in autoimmune disorders. We have observed a similar pattern and will be publishing this in the near future. This makes the autoimmune combat zone a likely critical feature of your child’s complex symptoms and problems. Inflammation in the brain would be expected to increase the risk of seizures, and in a study looking at magnetoencephalographic (MEG) patterns, over 80% of children with the regressive subtype had abnormal epileptiform (seizure-like activity on EEG) findings5. This autoimmune disorder would also be expected to be at least partially responsive to anti-inflammatory medications or interventions. While carefully controlled studies are lacking, various immune modifying agents have been discussed in the autism literature. These include intravenous infusion of human immunoglobulin derived antibodies (IVIG) 6, high dose steroids
On my desk is a solid bar of metal with this quote carved into it: “Never, Never, Never Give Up.”
as in Landau Kleffner Syndrome 7, spironolactone (a potassium-sparing diuretic with anti-inflammatory properties) 8, and pioglitazone (a diabetes drug with anti-inflammatory effects) 9. All of these diverse medications and therapeutic agents have one thing in common: they down-regulate inflammation and reduce the autoimmune response in the body. The fact that immune modifying agents are often effective, at least in open-label trials and from anecdotal observations of numerous physicians, supports the hypothesis that an underlying immune mechanism is contributing to autism symptoms. My belief, derived from the science we have today, is that most often autism represents the behavioral symptoms of a primary inflammatory or autoimmune brain disorder. But the brain, while the main symptom generator for the core autism complex of symptoms, is not the only target of this immune dysregulation. An immunological battle is being fought on at least two fronts: both the brain and the gastrointestinal tract are under attack. The pattern of gastrointestinal inflammation is distinct from both Crohn’s disease and ulcerative colitis (collectively, IBDs)10. Exactly what this means is, as of yet, unclear. Despite this, it is our observation that the inflammation seems to respond to similar treatments as the other IBDs. One of the weapons used by immune cells to target what they detect as an invader (which, as discussed, could be healthy brain cells) is the generation of free radicals. These are oxidizers (typically unstable molecules with unpaired electrons), which when present in excess is called oxidative stress. Free radicals are harmful to normal cells and can trigger a death mechanism inside cells. Numerous studies have demonstrated increased levels of oxidation in autism11. Dr. Ming and colleagues in New Jersey found increased urinary isoprostane (a marker
info@autismfile.com | www.autismfile.com | THE AUTISM FILE 9
REPRINTED WITH PERMISSION © THE AUTISM FILE
BIOMEDICAL
From left to right: 1. Dr. Bradstreet at the research laboratory. 2. Adriana’s team at the Science Fair award celebration: Adriana, Dr. Bradstreet, David Mancini (dad), Jacquie Mancini (mom), Alanna Apap, BCBA, and Andrea Soffici, paraprofessional. 3. Adriana and Dr. Bradstreet
of fatty acid – cell membrane oxidation) in autism cases12. We use this as a marker of both inflammation and oxidation since these two effects go hand in hand. Our own research in conjunction with Laboratoire Philippe Auguste in Paris, France confirms these observations, as well. Inflammation and oxidative stress have broad effects on the body and when left in place over extended time will create disruptions in how the brain forms, the ability of mitochondria (cell organelles) to produce energy, how food is digested, and how the body defends itself from infections. This would seem to be a battle on several fronts happening all at once, and that can truly be challenging and overwhelming for us as parents and doctors to understand and respond to. Unlike how penicillin treats strep throat, there are no magic bullets or perfect pills that can extinguish autism. Even good anti-inflammatories may need to be used in combination or with IVIG, as well as with other treatments to repair gut flora. The dysregulation of the immune system leaves the gate open for yeast and unhealthy bacteria to take over – often after a series of antibiotics for respiratory tract or ear infections. Over and over again we find evidence of harmful bacterial and yeast overgrowth (dysbiosis). This has been documented with sophisticated bacterial gene studies by the group headed by Sid Finegold13. Treatment of the yeast and clostridia bacteria typically results in significant gains, and both antifungals and anti-clostridia antibiotics are actively being evaluated in formal studies with our group in association with Dr. Doreen Granpeesheh’s team at the Center for Autism and Related Disorders and Dr. Finegold’s group at the LA Veterans Hospital and UCLA Medical Center. Imagine a combat zone where the generals (parents) deploy their troops (physicians, therapists, teachers, assistants, etc.) to defend against an allout assault from all sides. Now imagine one of them didn’t hear the inspirational speech about never giving up and decided the fight was just too hard and surrendered. No matter how strong the defense is to the right flank, if the left one collapses, the battle and, perhaps, the war will be lost. So this brings me to another critical definition: autism is a team effort. The ground we are all defending is the mind and health of a child. We do not have the luxury of quitting when we are tired or even when we are broke. The stakes are simply too high and the cost of losing unimaginable. This seems like a good place to introduce a hero in the autism war. If autism had a medal of honor this child and her team of supporters would absolutely be worthy of the award. You will get to know Adriana more in The Autism File, so I won’t detract from her and her family’s perspectives. Her issues are not that uncommon, but her response to immune therapy was dramatic and a cause for hope for all of us. This child had evidence of that autoimmune brain disorder reflected by autoantibodies to critical brain proteins. She had the inflammation and oxidative stress, and with the support and help of her parents, teachers, and therapists we took on this battle. Now her autism is gone due to the combined effects of IVIG and really good behavior therapy (ABA). These days I receive the most incredible emails from this little angel. I recently surprised Adriana when she won an award at her local school science fair. I drove the 90 minutes just to enjoy her recovery and successes. Later that night she wrote me, and I want to share a part of it here with you: “It’s hard to believe that you made that trip for me. I am glad that you did because unless we got to hang out together we wouldn’t know about each other. You are a good singer and dancer. I never knew that. Plus you are totally cool (I had to put that in – of course). Your kids are lucky. I know that I am not supposed to bug you with the emails (this is a General Mom instruction – not mine) but when I had autism I was not even able to share with you. Now I can, so please don’t get annoyed.” Isn’t that amazing? She has insights not only into who she is now, but where she has come from. Here is a soldier who can look to the battle won and truly appreciate
ISSUE 31 2009
She has insights not only into who she is now, but where she has come from. Here is a soldier who can look to the battle won and truly appreciate what has been restored back to her.
10 THE AUTISM FILE | www.autismfile.com | info@autismfile.com
REPRINTED WITH PERMISSION © THE AUTISM FILE
Find a doctor with an open mind, a listening ear, the experience and wisdom to guide the medical interventions, and one with a heartfelt desire to help your child.
what has been restored back to her. So do you think her emails bug me? Absolutely not! Instead they are like those words of Churchill inspiring me to press on so more children can share in this kind of success. Her parents built a combat-ready force to take on the battle of recovering this child. That team is discussed more in the article “Adriana: Coming Full Circle at Autism One” by Jacquie Mancini, General, Mom, and a winner, in this same issue of The Autism File. To summarize: what do we know? Autism is a war being fought on many fronts all at once. The battle is for your child’s mind, health, and future. Your child’s own immune system is dysregulated, and typically forming autoimmune reactions towards the gut and the brain. Immune activation creates oxidative stress, which in turn leads to impairment of normal body chemistry and weakening of mitochondria. Winning the battle requires persistence and hope. It also requires a knowledgeable team equipped with all the therapies required.
(educational plan and your child’s legal rights to an appropriate education) and advocate, advocate, advocate for your child. Find a doctor with an open mind, a listening ear, the experience and wisdom to guide the medical interventions, and one with a heartfelt desire to help your child. It isn’t easy, but it is important to your child’s future. It is unknown how much any child can recover. Most can become far healthier, experience less abdominal pain, and gain a better quality of life. Some can recover to the point where they fully integrate into life and go onto productive lives. Others will suffer with lifelong disabilities that will require someone else to be there for them. Regardless of the outcome, persistence gives you the best odds of winning. And you must remember the words of Winston Churchill: NEVER, NEVER, NEVER, NEVER GIVE UP (he actually did say it four times). References
Garbett K, Ebert PJ, Mitchell A, Lintas C, Manzi B, Mirnics K, Persico AM. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis. 2008 Jun;30(3):303-11. Epub 2008 Mar 10. 2 Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304. 3 Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007 Jun;36(6):361-5. 4 Messahel S, Pheasant AE, Pall H, AhmedChoudhury J, Sungum-Paliwal RS, Vostanis P. Urinary levels of neopterin and biopterin in autism. Neurosci Lett. 1998 Jan 23;241(1):1720. 5 Lewine JD, Andrews R, Chez M, Patil AA, Devinsky O, Smith M, Kanner A, Davis JT, Funke M, Jones G, Chong B, Provencal S, Weisend M, Lee RR, Orrison WW Jr. Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. Pediatrics. 1999 Sep;104(3 Pt 1):405-18. 6 Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996 Aug;26(4):439-52.
1 7
Dr. Bradstreet graduated from the University of South Florida College of Medicine and received his residency training from Wilford Hall USAF Medical Center. As a flight surgeon, he was involved in aerospace medicine research, and he has extensive experience and training in environmental medicine and toxicology. He is involved in autism-related outcome studies and environmental research with the University of Washington and UCLA and serves as a adjunct professor of child development and neuroscience at Southwest College of Naturopathic Medicine in Tempe, Arizona. Dr. Bradstreet is the founder and director of the International Child Development Resource Center (www.icdrc.org). His son, Matthew, is recovering from autism with the combined help of biomedical and behavioral interventions.
Mikati MA, Shamseddine AN. Management of Landau-Kleffner syndrome. Paediatr Drugs. 2005;7(6):377-89. Review. 8 Bradstreet JJ, Smith S, Granpeesheh D, ElDahr JM, Rossignol D. Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders. Med Hypotheses. 2007;68(5):979-87. Epub 2006 Dec 5. 9 Boris M, Kaiser CC, Goldblatt A, Elice MW, Edelson SM, Adams JB, Feinstein DL. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007 Jan 5;4:3. 10 Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006 Apr;173(12):126-34. Epub 2006 Feb 21. 11 Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci. 2004 Oct 8;75(21):2539-49. 12 Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):379-84. 13 Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol. 2004 Nov;70(11):6459-65.
Now, it’s time for you to put aside your fears, your doubts, and your feelings of helplessness and hopelessness and become the General in your own child’s battle to recover from autism. Get educated. Come to biomedical autism conferences (there is so much more to learn than what I could fit into one article). Learn about ABA and sensory integration therapies. Study the IEP rules
ISSUE 31 2009
REPRINTED WITH PERMISSION © THE AUTISM FILE
info@autismfile.com | www.autismfile.com | THE AUTISM FILE
11
BIOMEDICAL
BY James JeffreY Bradstreet, md, md(H), faafP
W
hen I was asked to answer this question for The Autism File, it seemed like a straight shot. Anyone can find a standard definition of autism at their community library or on the Internet at countless sites, but that isn’t what you really want to know. I also know autism is not a simplistic or even homogeneous disorder. Rather, it represents a complex array of geneenvironment interactions that in turn create unique subtypes that may overlap in some ways while being very distinct in others. This demands a rigorous evaluation through a search of unique disease markers that can help lead us into a better understanding of each child’s individual needs. That all sounds rather intimidating to both doctors and parents – and not surprisingly so. Doctors are used to what is referred to as “usual and customary practice,” and what we are talking about is the attempt to profile a child’s specific and unique disorder. There is no usual autism treatment, and there is only one FDA-approved intervention for the agitation effects of autism (risperadone); beyond that there is nothing approved. As a result, most of you got about as far as the diagnosis when suddenly the resources and solutions being offered by the mainstream of medicine dried up. Perhaps you were referred for behavioral therapy to find a 2-year waiting list. But more than likely you were told to let
the school system handle your child’s needs. Occasionally that works fairly well, but, in general, school systems suffer from a serious lack of both financial and personnel resources, making it highly unlikely they could respond effectively to your child’s developmental needs without a lot of outside help – from you. However, we are finding ways to demystify at least some parts of the underlying medical problems, while finding they are frequently highly responsive to our medical, nutritional, and behavioral interventions. But the actual question really plaguing your heart, your mind, and your soul is this: what happened to my precious child? And after that question comes the next of a long series, which become wrapped in guilt, fears, sadness, and even panic. The second question has to be: what can I do to help my child? I know these questions too. Not just as a doctor, but as a father. I have stayed awake at night asking myself all of these countless questions – even the ones most people are afraid to talk about like: will he ever come back to me or is this all a hopeless waste of time and money? Two things have kept me focused throughout this journey with my son and thousands of other sons and daughters struggling to find their way back to wholeness. Are these great medical secrets I keep to myself? No. Really they have as much to do with any other aspect of life as
they do with autism. These are hope and persistence. A long time ago I read several books on success. It seemed logical enough. If you wanted to succeed you should learn from others who had actually done it. In one of those books was this quote from Dale Carnegie: “Most of the important things in the world have been accomplished by people who have kept on trying when there seemed to be no hope at all.” This is perfect. It merges together the key to success for any venture or quest you lay before it. That doesn’t mean you are guaranteed success – far from it. Most truly successful people fail over and over again. But it most assuredly is a guarantee you won’t succeed without these two on your side. On my desk is a solid bar of metal with this quote carved into it: “Never, Never, Never Give Up.” While that is not an exact quote from Winston Churchill, it is close enough. Most people give little thought anymore to one of England’s darkest hours. It was a time where people huddled in fear in underground subway tubes praying for safety and that they might just survive. It was time of dread and mortal consequences. Churchill’s words were not merely inspirational; they acknowledged a choice of survival lay before the English people. They needed to hear those words when they needed them the most.
Two things have kept me focused throughout this journey with my son and thousands of other sons and daughters struggling to find their way back to wholeness. Are these great medical secrets I keep to myself? No. Really they have as much to do with any other aspect of life as they do with autism. These are hope and persistence.
8 THE AUTISM FILE | www.autismfile.com | info@autismfile.com REPRINTED WITH PERMISSION © THE AUTISM FILE ISSUE 31 2009
Those are the same words you must carve into your psyche because, for most families, autism is like the London Blitz. Day after day of bad news is piled on top of more bad news. The bombs keep falling. The school fights you over the education plan, your insurer refuses to pay for your child’s medical care, your spouse feels neglected, your other children feel abandoned, your career (if you still have one) suffers, you cannot remember the last time you had fun, or you have no idea what sleep is because your little one always wakes up screeching at 1:00 AM. The Blitz just keeps coming day after day. When you reach this level of despair you empathize with the feelings of the war-shattered Londoners during those darkest hours of 1940-41. This gets me to my first useful definition of autism: autism is a war. It is a war being waged against your child and your family. Unless you fight back you are guaranteed more casualties and greater destruction. I had the opportunity to serve in the USAF early in my career. That whole military experience has served me well as I have taken on my son’s personal battle with autism and also the thousands of other children who have crossed my path. To some extent thinking militaristically helps you plan. We will talk more about this later. But autism is not just a metaphorical war within your family; it is an immunological battle taking place in the gut and brain of your child. When we set out to answer the questions about what has happened to your child we quickly find a large body of scientific evidence involving the abnormal regulation of the immune system. Unfortunately, we cannot examine the brain like we might a sore throat or a skin rash. It stays sealed away behind the armor-plate of the skull and inside the blood-brain barrier. This is why autism has been categorized, since its first observations 70 some years ago, as a behavioral disorder. We can see those manifestations of the illness – we cannot see the brain to assess its degree of inflammation or test it to see if toxins are present. So who are the friendlies and who are the enemies in this combat zone? Sadly it seems some of your child’s own
ISSUE 31 2009
defenders have defected and gone over to the enemy’s side. When immune cells lose their tolerance of the body’s own cells we call that autoimmunity. Researchers at Vanderbilt Medical School recently published direct evidence of the nature of the combat inside the brain1. In their landmark study of autism brain transcriptomics (the process of measuring what the DNA is making to learn what is really happening) they stated this: “… these expression patterns appear to be more associated with the late recovery phase of autoimmune brain disorders, than with the innate immune response characteristic of neurodegenerative diseases.” This is generally consistent with the brain studies of the Johns Hopkins group that showed very significant inflammatory brain disease at the time of autopsy from children with autism who drowned2. To build on this, researchers in Chicago found dramatically higher levels of the inflammatory immune marker TNFalpha in the spinal fluid than in the blood of children with autism3. This means the inflammatory response was greater inside the brain than outside the brain in the rest of the body. Almost 11 years ago a team in England found elevated levels of neopterin in the urine of children with autism4. Neopterin is produced when immune cells turn on – typically as in autoimmune disorders. We have observed a similar pattern and will be publishing this in the near future. This makes the autoimmune combat zone a likely critical feature of your child’s complex symptoms and problems. Inflammation in the brain would be expected to increase the risk of seizures, and in a study looking at magnetoencephalographic (MEG) patterns, over 80% of children with the regressive subtype had abnormal epileptiform (seizure-like activity on EEG) findings5. This autoimmune disorder would also be expected to be at least partially responsive to anti-inflammatory medications or interventions. While carefully controlled studies are lacking, various immune modifying agents have been discussed in the autism literature. These include intravenous infusion of human immunoglobulin derived antibodies (IVIG) 6, high dose steroids
On my desk is a solid bar of metal with this quote carved into it: “Never, Never, Never Give Up.”
as in Landau Kleffner Syndrome 7, spironolactone (a potassium-sparing diuretic with anti-inflammatory properties) 8, and pioglitazone (a diabetes drug with anti-inflammatory effects) 9. All of these diverse medications and therapeutic agents have one thing in common: they down-regulate inflammation and reduce the autoimmune response in the body. The fact that immune modifying agents are often effective, at least in open-label trials and from anecdotal observations of numerous physicians, supports the hypothesis that an underlying immune mechanism is contributing to autism symptoms. My belief, derived from the science we have today, is that most often autism represents the behavioral symptoms of a primary inflammatory or autoimmune brain disorder. But the brain, while the main symptom generator for the core autism complex of symptoms, is not the only target of this immune dysregulation. An immunological battle is being fought on at least two fronts: both the brain and the gastrointestinal tract are under attack. The pattern of gastrointestinal inflammation is distinct from both Crohn’s disease and ulcerative colitis (collectively, IBDs)10. Exactly what this means is, as of yet, unclear. Despite this, it is our observation that the inflammation seems to respond to similar treatments as the other IBDs. One of the weapons used by immune cells to target what they detect as an invader (which, as discussed, could be healthy brain cells) is the generation of free radicals. These are oxidizers (typically unstable molecules with unpaired electrons), which when present in excess is called oxidative stress. Free radicals are harmful to normal cells and can trigger a death mechanism inside cells. Numerous studies have demonstrated increased levels of oxidation in autism11. Dr. Ming and colleagues in New Jersey found increased urinary isoprostane (a marker
info@autismfile.com | www.autismfile.com | THE AUTISM FILE 9
REPRINTED WITH PERMISSION © THE AUTISM FILE
BIOMEDICAL
From left to right: 1. Dr. Bradstreet at the research laboratory. 2. Adriana’s team at the Science Fair award celebration: Adriana, Dr. Bradstreet, David Mancini (dad), Jacquie Mancini (mom), Alanna Apap, BCBA, and Andrea Soffici, paraprofessional. 3. Adriana and Dr. Bradstreet
of fatty acid – cell membrane oxidation) in autism cases12. We use this as a marker of both inflammation and oxidation since these two effects go hand in hand. Our own research in conjunction with Laboratoire Philippe Auguste in Paris, France confirms these observations, as well. Inflammation and oxidative stress have broad effects on the body and when left in place over extended time will create disruptions in how the brain forms, the ability of mitochondria (cell organelles) to produce energy, how food is digested, and how the body defends itself from infections. This would seem to be a battle on several fronts happening all at once, and that can truly be challenging and overwhelming for us as parents and doctors to understand and respond to. Unlike how penicillin treats strep throat, there are no magic bullets or perfect pills that can extinguish autism. Even good anti-inflammatories may need to be used in combination or with IVIG, as well as with other treatments to repair gut flora. The dysregulation of the immune system leaves the gate open for yeast and unhealthy bacteria to take over – often after a series of antibiotics for respiratory tract or ear infections. Over and over again we find evidence of harmful bacterial and yeast overgrowth (dysbiosis). This has been documented with sophisticated bacterial gene studies by the group headed by Sid Finegold13. Treatment of the yeast and clostridia bacteria typically results in significant gains, and both antifungals and anti-clostridia antibiotics are actively being evaluated in formal studies with our group in association with Dr. Doreen Granpeesheh’s team at the Center for Autism and Related Disorders and Dr. Finegold’s group at the LA Veterans Hospital and UCLA Medical Center. Imagine a combat zone where the generals (parents) deploy their troops (physicians, therapists, teachers, assistants, etc.) to defend against an allout assault from all sides. Now imagine one of them didn’t hear the inspirational speech about never giving up and decided the fight was just too hard and surrendered. No matter how strong the defense is to the right flank, if the left one collapses, the battle and, perhaps, the war will be lost. So this brings me to another critical definition: autism is a team effort. The ground we are all defending is the mind and health of a child. We do not have the luxury of quitting when we are tired or even when we are broke. The stakes are simply too high and the cost of losing unimaginable. This seems like a good place to introduce a hero in the autism war. If autism had a medal of honor this child and her team of supporters would absolutely be worthy of the award. You will get to know Adriana more in The Autism File, so I won’t detract from her and her family’s perspectives. Her issues are not that uncommon, but her response to immune therapy was dramatic and a cause for hope for all of us. This child had evidence of that autoimmune brain disorder reflected by autoantibodies to critical brain proteins. She had the inflammation and oxidative stress, and with the support and help of her parents, teachers, and therapists we took on this battle. Now her autism is gone due to the combined effects of IVIG and really good behavior therapy (ABA). These days I receive the most incredible emails from this little angel. I recently surprised Adriana when she won an award at her local school science fair. I drove the 90 minutes just to enjoy her recovery and successes. Later that night she wrote me, and I want to share a part of it here with you: “It’s hard to believe that you made that trip for me. I am glad that you did because unless we got to hang out together we wouldn’t know about each other. You are a good singer and dancer. I never knew that. Plus you are totally cool (I had to put that in – of course). Your kids are lucky. I know that I am not supposed to bug you with the emails (this is a General Mom instruction – not mine) but when I had autism I was not even able to share with you. Now I can, so please don’t get annoyed.” Isn’t that amazing? She has insights not only into who she is now, but where she has come from. Here is a soldier who can look to the battle won and truly appreciate
ISSUE 31 2009
She has insights not only into who she is now, but where she has come from. Here is a soldier who can look to the battle won and truly appreciate what has been restored back to her.
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Find a doctor with an open mind, a listening ear, the experience and wisdom to guide the medical interventions, and one with a heartfelt desire to help your child.
what has been restored back to her. So do you think her emails bug me? Absolutely not! Instead they are like those words of Churchill inspiring me to press on so more children can share in this kind of success. Her parents built a combat-ready force to take on the battle of recovering this child. That team is discussed more in the article “Adriana: Coming Full Circle at Autism One” by Jacquie Mancini, General, Mom, and a winner, in this same issue of The Autism File. To summarize: what do we know? Autism is a war being fought on many fronts all at once. The battle is for your child’s mind, health, and future. Your child’s own immune system is dysregulated, and typically forming autoimmune reactions towards the gut and the brain. Immune activation creates oxidative stress, which in turn leads to impairment of normal body chemistry and weakening of mitochondria. Winning the battle requires persistence and hope. It also requires a knowledgeable team equipped with all the therapies required.
(educational plan and your child’s legal rights to an appropriate education) and advocate, advocate, advocate for your child. Find a doctor with an open mind, a listening ear, the experience and wisdom to guide the medical interventions, and one with a heartfelt desire to help your child. It isn’t easy, but it is important to your child’s future. It is unknown how much any child can recover. Most can become far healthier, experience less abdominal pain, and gain a better quality of life. Some can recover to the point where they fully integrate into life and go onto productive lives. Others will suffer with lifelong disabilities that will require someone else to be there for them. Regardless of the outcome, persistence gives you the best odds of winning. And you must remember the words of Winston Churchill: NEVER, NEVER, NEVER, NEVER GIVE UP (he actually did say it four times). References
Garbett K, Ebert PJ, Mitchell A, Lintas C, Manzi B, Mirnics K, Persico AM. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis. 2008 Jun;30(3):303-11. Epub 2008 Mar 10. 2 Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304. 3 Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007 Jun;36(6):361-5. 4 Messahel S, Pheasant AE, Pall H, AhmedChoudhury J, Sungum-Paliwal RS, Vostanis P. Urinary levels of neopterin and biopterin in autism. Neurosci Lett. 1998 Jan 23;241(1):1720. 5 Lewine JD, Andrews R, Chez M, Patil AA, Devinsky O, Smith M, Kanner A, Davis JT, Funke M, Jones G, Chong B, Provencal S, Weisend M, Lee RR, Orrison WW Jr. Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. Pediatrics. 1999 Sep;104(3 Pt 1):405-18. 6 Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996 Aug;26(4):439-52.
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Dr. Bradstreet graduated from the University of South Florida College of Medicine and received his residency training from Wilford Hall USAF Medical Center. As a flight surgeon, he was involved in aerospace medicine research, and he has extensive experience and training in environmental medicine and toxicology. He is involved in autism-related outcome studies and environmental research with the University of Washington and UCLA and serves as a adjunct professor of child development and neuroscience at Southwest College of Naturopathic Medicine in Tempe, Arizona. Dr. Bradstreet is the founder and director of the International Child Development Resource Center (www.icdrc.org). His son, Matthew, is recovering from autism with the combined help of biomedical and behavioral interventions.
Mikati MA, Shamseddine AN. Management of Landau-Kleffner syndrome. Paediatr Drugs. 2005;7(6):377-89. Review. 8 Bradstreet JJ, Smith S, Granpeesheh D, ElDahr JM, Rossignol D. Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders. Med Hypotheses. 2007;68(5):979-87. Epub 2006 Dec 5. 9 Boris M, Kaiser CC, Goldblatt A, Elice MW, Edelson SM, Adams JB, Feinstein DL. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007 Jan 5;4:3. 10 Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006 Apr;173(12):126-34. Epub 2006 Feb 21. 11 Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci. 2004 Oct 8;75(21):2539-49. 12 Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):379-84. 13 Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol. 2004 Nov;70(11):6459-65.
Now, it’s time for you to put aside your fears, your doubts, and your feelings of helplessness and hopelessness and become the General in your own child’s battle to recover from autism. Get educated. Come to biomedical autism conferences (there is so much more to learn than what I could fit into one article). Learn about ABA and sensory integration therapies. Study the IEP rules
ISSUE 31 2009
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