Login

Immune Dysfunction and Neuroinflammation in Autism

Feb 26

by James Neuenschwander on 26 February 2013 in , , , with 1 Comments

Parents of almost any child with an autism spectrum disorder (ASD) are aware that their children suffer from immune dysfunction.  Frequent ear infections, environmental and food allergies, asthma, seizures, unexplained skin rashes, and persistent intestinal yeast infections are a few of the more common signs of immune dysfunction.  In the past 40 years of research, 95% of articles examining immune dysregulation and ASD and 100% of articles examining oxidative stress and ASD showed positive associations.  Clearly, this is a fundamental issue in children with autism.

 

So, what are we talking about?  The immune system is designed to protect us against infections from the outside world, assist in repair of injury, and destroy any abnormal cells that are created.  In order to do this properly, the immune system must be able to discern self from non-self.   It is supposed to leave self alone and attack non-self (bacteria, viruses, fungus, parasites, etc.).  This is the process of immune tolerance—the immune system’s ability to know what to attack and what to leave alone.  When we lose immune tolerance, trouble ensues.  An allergy is a loss of immune tolerance to environmental factors—the immune system is attacking environmental factors as though they were infectious agents.  An autoimmune disorder is a loss of immune tolerance to self—the immune system starts attacking tissues of the body.  The third type of immunotolerance loss is more difficult to understand.  In this case, the immune system is responding to an infectious agent (whether it be an actual infection or a vaccine) in a way that is over-aggressive.  Many children on the autism spectrum exhibit signs of all three types of immune tolerance loss: they have allergies, they develop frequent infections, they over-react to vaccines/infections, and many have undiagnosed autoimmune disorders (such as autoimmune antibodies directed against specific brain proteins).

 

There have been multiple studies demonstrating an increase in inflammation markers and oxidative stress in ASD.  Markers such as TNFa, IL-6, and IL-17a have all been shown to be increased in children with ASD.  These are known as inflammatory cytokines—they act as chemical signals to turn on the inflammatory response. Oxidative stress markers such as 8OHdG (oxidized DNA marker), reduced glutathione (a compound that controls oxidation inside the cell), and lipid peroxides (oxidized membrane fats--usually from the brain) are frequently abnormal in children on the spectrum.  Even immune cell function has been found to be abnormal in ASD.  What does this mean?  These kids are on fire—their immune systems are hyper vigilant and over-react to everything.  The million-dollar question is: how does this affect the brain?

 

Neuroinflammation is the process of inflammation in the central nervous system (brain, spinal cord, and central nerves).  The brain should be protected from inflammation in the body by the blood brain barrier.  This barrier prevents most proteins in the blood from entering the brain.  The central nervous system is fed by cerebral spinal fluid (CSF) and not blood.  So, the activated immune cells and antibodies in the blood should never enter the brain.  There had been an argument that these inflammatory changes involved the body only and had nothing to do with the brain, because the blood brain barrier protected it.  Enter Dr. Vargas and her seminal study published in 2005 in which she examined the brains of children with ASD that had died in accidents.  She demonstrated definitively that there was neuroinflammation at play with these children.  She showed that the microglia were activated.  The brain is 10% neurons (thinking cells) and 90% support cells.  Microglia are these support cells.  Since the brain does not have an immune system, the microglia act like the immune system when they get activated.  The problem is that these cells are supposed to feed the neurons as well.  When they are activated, the neurons are not fed properly and trouble ensues.  Since then, there have been a number of studies that have shown elevated levels of inflammatory markers in the brains and CSF of children on the autism spectrum as well as confirmation of the glia cell activation that Dr Vargas identified.  In addition, there has been recent evidence that substances that impair the autoimmune process can improve autism symptoms and neuroinflammation.  Finally, there is evidence that this process of neuroinflammation can increase the levels of substances that directly damage the brain (neurotoxicity).  Two neurotoxins of interest are glutamate and neurotensin.  Glutamate is the most abundant neurotransmitter (compounds that nerves use to talk to each other) in the brain.  It stimulates the brain.  Too much glutamate has been associated with seizures and degenerative brain disorders.  Neurotensin is a compound released by mast cells that is toxic to neurons.  Both of these neurotoxins have been shown to be elevated in children on the spectrum.  Interestingly, the neurons of the speech centers in the brain appear to have the highest number of receptors for neurotensin leading to a theory that this might play a role in the speech issues children with ASD display.  Also of interest are the apparent association between mast cell activation and the tightness of the blood brain barrier.  Activating these mast cells will increase the permeability of the blood brain barrier and allow compounds to get into the brain that should not be there.  Again, trouble ensues.

 

Okay, all of this is pretty depressing.  What can we do about it?  One of the first issues is to understand the relationship between gut permeability and blood brain barrier permeability.  Although the blood brain barrier is much tighter the intestinal permeability, it is affected by similar processes.  There is also evidence that fixing gut permeability improves the integrity of the blood brain barrier.  Finally, much of the body’s immune function is in the small and large intestine.  This is why all of us biomedical docs are obsessed over gut function (at least I am).  If you don’t fix the gut, it makes everything else you do much more difficult (or even impossible).  How do you fix the gut?  Use the three R’s: remove, replace, rebuild.  Remove all of the bad stuff. This includes reactive foods (food sensitivity testing can help identify these), fermentative foods (sugars and simple carbs, even sweet fruits can be a problem), and foods that are genetically modified (they have been linked with bowel issues)—organic is best.  You also have to remove the bad organisms—excessive yeast or bacteria, pathogenic (disease causing) bacteria.  I normally will do an organic acid profile to identify excesses of compounds that are made by these organisms (i.e. too much tartaric acid is associated with an overgrowth of yeast).  You can also do a specialized stool test through one of the labs that specialize in this such as Genova, Doctor’s Data, or Great Plains.  Treatment can be herbal or medical but should be directed by the results of these tests.  These tests will also tell you if there are inadequate probiotics (good bacteria) and can give a clue about digestive enzymes.  Replace the bad with the good.  Add probiotics (almost all of us need them).  A good probiotic will contain a variety of organisms with at least 15 billion organisms guaranteed at expiration (this is important because you can lose up to 90% of the bacteria by the time the expiration date rolls around).  If you can’t afford them (or want to go natural), learn how to ferment foods—this is how we are supposed to get our healthy bacteria.  Finally, restore the intestinal permeability: supplements like glutamine, curcumin, and transfer factor have evidence that they improve permeability.

 

Wait a minute, what about the brain: are we talking neuroinflammation?  Fix the gut first.  For the brain, things get more complicated.  It is helpful to measure things if possible.  A number of specialty labs can measure 8OHdG, glutathione, lipid peroxide, Il-6, Il-17a, and TNFa levels.  Neurotensin levels can also be checked via a blood sample. Glutamate levels are inferred by measuring the ratio of kyenuric to quinolinic acid—a low ratio implies overproduction of glutamate.  The issue is always that we are measuring these things in the blood and the urine and not in the brain.  Frequently, we treat based on symptoms and suspicion.  There are a number of anti-inflammatory/anti-oxidant compounds that might help.  In the supplement world, there is evidence that curcumin can be helpful.  It appears to cross the blood brain barrier and improve inflammation.  The amino acid, l-theanine, can be used to lower high glutamate levels.  Omega 3 fatty acids play a critical role in managing inflammation (and repairing damaged membranes).  Finally, bioflavonoids like luteolin and quercetin can help stabilize mast cells and reduce the release of neurotensin and histamine.  Vitamins such as B6, methyl folate, and methyl B12 can assist in cellular detoxification.  The medications we use are all off label, meaning that they were approved for other conditions and not for neuroinflammation associated with ASD.  The first is low dose naltrexone (LDN).  I have used LDN for years to treat neuroinflammation in other disorders.  It appears to have the same benefit in ASD.  There have been studies demonstrating improvement in ASD symptoms using LDN.  LDN has to be prepared by a compounding pharmacy—the lowest commercial dose is 50mg, and we typically use 0.5-3.0 mg in kids.  The second medication is pioglitazone (Actos).  This is a diabetes medication that can decrease neuroinflammation.  It is controversial because of the negative effects pioglitazone has had in long term use with diabetics.  Corticosteroids (like prednisone or cortisone) have been used to reduce inflammation and have been shown to improve behaviors in a few small studies.  Because of significant side effects with long-term use, many of us are cautious in using these drugs.  Another approach is to use intravenous immunoglobulin (IVIG) therapy.  This involves monthly infusions of antibodies pooled from thousands of people’s plasma.  It can be very effective, particularly if the neuroinflammation is the result of an infectious agent such as strep (we call this PANDAS).  This approach is very controversial (and expensive).  Studies have shown some efficacy. Other drugs such as ibuprofen, spironolactone, low dose lithium, and pentoxifylline are also used, but have less evidence behind them.  Finally, if there is evidence of generalized excessive immune reactivity, I will use a process called LDA (low dose allergen) therapy to reduce this reactivity.  LDA is treatment in which extremely dilute solutions of allergens are injected into the skin once every two months to reduce immune overactivity.

 

At the end of the day, I start with a food sensitivity profile and a biochemical profile (I personally use the NutrEval from Genova, but there are other options) I clean up the gut, change the diet, and add probiotics.  If there is evidence of neuroinflammation, I then use trial and error to determine the best approach to this.  I usually use clinical progress to determine whether I am on the right path.  The tests can help guide the treatment, but much of this is done through direct observation and evaluation of improvement in symptoms.

 

 

About the Author
James Neuenschwander, MD is a graduate of the University of Michigan medical school. He is board certified in Emergency Medicine by the American Board of Physician Specialties. Much to his disillusionment, he discovered in medical school that medicine was not about healing people but was about controlling symptoms. He was exposed, first hand, to alternative healing methods—and this made him aware that there was an entire world of healing that he did not learn of in medical school. As a result of this experience, he was trained in herbal and homeopathic medicine through self-study and internship with master practitioners. He has obtained extensive training in acupuncture and completed a program for physicians at UCLA. He started an integrative/alternative medical practice in 1988. Dr. Neu is Board Certified by the American Board of Integrative and Holistic Medicine. In addition, he has spent countless hours attending workshops and training from the Autism Research Institute to become a level 2 practitioner for patients on the autism spectrum. He is a member of the American College for the Advancement of Medicine (ACAM) and has attended numerous conferences held each year to learn the about the latest research on alternative/complementary practices. He participated in extensive training in chelation therapy. He was one of the first physicians to take ACAM’s chelation course and passed their certification exam to be credentialed in chelation therapy. Dr. Neu is also a fellowship candidate of the Medical Association of Pediatrics Special Needs (MAPS), a group that provides extensive training and education in biomedical treatments for children with autism. Furthermore, he is a fellow of the American Academy of Anti-Aging Medicine and is currently attending the University of South Florida pursuing a Master's Degree in Integrative cancer therapies. 
James Neuenschwander, MD is a graduate of the University of Michigan medical school. He is board certified in Emergency Medicine by the American Board of Physician Specialties. Much to his disillusionment, he discovered in medical school that medicine was not about healing people but was about controlling symptoms. He was exposed, first hand, to alternative healing methods—and this made him aware that there was an entire world of healing that he did not learn of in medical school. As a result of this experience, he was trained in herbal and homeopathic medicine through self-study and internship with master practitioners. He has obtained extensive training in acupuncture and completed a program for physicians at UCLA. He started an integrative/alternative medical practice in 1988. Dr. Neu is Board Certified by the American Board of Integrative and Holistic Medicine. In addition, he has spent countless hours attending workshops and training from the Autism Research Institute to become a level 2 practitioner for patients on the autism spectrum. He is a member of the American College for the Advancement of Medicine (ACAM) and has attended numerous conferences held each year to learn the about the latest research on alternative/complementary practices. He participated in extensive training in chelation therapy. He was one of the first physicians to take ACAM’s chelation course and passed their certification exam to be credentialed in chelation therapy. Dr. Neu is also a fellowship candidate of the Medical Association of Pediatrics Special Needs (MAPS), a group that provides extensive training and education in biomedical treatments for children with autism. Furthermore, he is a fellow of the American Academy of Anti-Aging Medicine and is currently attending the University of South Florida pursuing a Master's Degree in Integrative cancer therapies. 

 

Rate this content

Post your comment

You cannot post comments until you have logged in. Login Here.

Comments

  • About neuroinflammation: Can i get your M.D. opinion on GcMAF therapy?

    Thank you.

    Posted by Serge Vaillancourt, 09/03/2013 1:02pm (2 years ago)

RSS feed for comments on this page | RSS feed for all comments

TOLL FREE 1-877-98AUTISM