If you are a parent of a child with autism, we hope to unfold what we know about the biology of autism, and if you are a clinician, we hope to share our experiences in diagnosing and treating the underlying pathophysiological mechanisms which manifest the neurobehavioral patterns we refer to as autism.
The foundation of good medical treatment requires a uniquely individualistic approach to the child or adult with symptoms of autism. Because the term autism refers to a collection of symptoms rather than a distinct genetic disorder like Down’s syndrome, many and varying factors will contribute to any one case presentation. That is a fancy way of saying,unless you look behind the symptoms and identify the biology of the person , you’ll be clueless as to what is really causing the behaviors.
I would like to comment here regarding the behavioral approach to autism before we start defining and treating biology. Behavioral therapist tell us that the individual with autism is demonstrating abnormal behaviors, which through proper conditioning and redirecting of that behavior, can learn to function more appropriately. This is an outgrowth of the behavioral theories of Skinner, which formed the foundation of the applied behavioral therapy of O. Ivar Lovaas. Behavioral therapy BT or ABA (which have many subtypes), can be quite successful in approximately 50% of children. The children are often left with significant residual autistic features, but have adapted a more successful approach to their environment. Behavioral therapy is clearly well tested over the last several decades and if it is reasonable and available , we recommend it with certain conditions. We do not believe ABA should be used to the exclusion of biological interventions. For example, a child with chronic seizures and autism still needs the seizures to be controlled. In a similar vein, our ABA therapists tell us the children receiving biological intervention generally respond faster and better to any of their interventions.
So, what about the biology of autism? What do we know, and what do these findings tell us about how we should proceed?
The paradigm of autism as a biological entity is still evolving. It has moved out of the primordial ooze and has even been seen to occasionally walk upright. It is considerably less hairy now than it was just a few years ago, but its final form remains uncertain. For me, the paradigm is shaping into another saga of the terrible consequences of a deranged immune system and subsequent persisting viral infections. The fact that we have an epidemic of autism is no longer in dispute. And how we arrived on the edge of the millennium with an epidemic of autism is becoming clearer. Typically, we think of epidemics as infectious diseases. That now appears to be the case with most autism spectrum disorders observed today. The history of our current autism dilemma is overflowing with controversy and dissension between medical experts. In many ways, we’re repeating the process endured during the discovery of HIV infections. We can certainly learn much from both the failings and successes of the medical community’s response to the AIDS epidemic as we move forward to understand this new one.
The label of autism is a deceptive one. It implies a similarity to the past labeling system and some degree of homogeneity. But the autism we see today is anything but that. What is being referred to as autism today, will likely go by a different name soon. Therefore what ensues here is a discussion of what the new names might be, and it may be somewhat different for each child. So I am reminded of the great comment by Samuel Johnson.
Great works are performed not by strength, but by perseverance.
Still today, the diagnostic criteria are controlled by the Diagnostic Statistical Manual, Fourth Edition, Revised (DSM-IV Rev). We hope here to replace that notion with a concept of defined biological problems. Autism was also traditionally thought of as a very rare disorder. We now have data provided by the State of California, and Federal Government sources which define autism as a disorder affecting approximately one in every 160 school-aged children. The most recent California data document a doubling in the past four years. But these numbers as shocking as they are, still underestimate autism from a boy’s perspective, approximately 1 in 80 boys has autism nationwide. Even more evidence comes from Cambridge University in England where a recent study of Cambridgeshire schools, revealed 1 in 50 boys has an autism spectrum disorder (ASD) in some areas. (In press Autism: International Journal of Research and Practice, Brief Report: Prevalence of Autism Spectrum Conditions in Children Aged 5 -11 Years in Cambridgeshire, UK. Fiona J. Scott, Simon Baron-Cohen, Patrick Bolton, and Carol Brayne. Autism Research Centre, University of Cambridge, Departments of Psychiatry and Experimental Psychology).
Note: Any attempt to review the published data would by necessity be reductionistic.
My hypothetical paradigm for autism looks like this: Autism begins with a wounding of the immune system, which may occur in the womb, but which unquestionably continues after birth (Thimerosal & environmental toxins), Which directly affect the developing brain and immune system of the child, Which leads to persistence of vaccine MV and perhaps other viruses, Further wounding the epithelium of the GI tract occurs as a result of the viral trigger autoimmune reaction to infected cells and programmed immune cells. The virus triggers autoimmune reactions in the gut and the brain. The persistence MV is a systemic infection (seizures, low white count, immune dysfunction etc) in a subset of children. Persistence of the MV or other factors as yet not identified, in turn depletes the body of the amino acid cysteine through renal wasting and poor absorption of sulfates in the gut, Cysteine controls the production of glutathione (a cofactor in numerous enzymatic pathways) and metallothionine (MT) which is perhaps best understood as the metal and mineral bank for the body, Loss of cysteine opens the door to heavy metal accumulation, since glutathione (GSH), MT and other sulfates are required for normal function of a myriad of enzyme detoxification and metal management systems.
The accumulated heavy metals are neurotoxic and immunotoxic. They also disrupt a wide array of activity within the body’s biochemistry, as is apparent in the inability to digest bread and milk proteins, or the ability to defend against heavy metals. The wound becomes self-perpetuating apart from intervention.
These biological disruptions interfere with normal brain function in a variety of ways. These include: impairment of normal neurotransmitter balance, structural and functional damage to neurons and other critical cells in the brain, abnormal blood supply regulation, and the generation of abnormal electrical rhythms (the worst of which are epileptiform and true seizures). This final aspect may be a significant key to the ultimate restoration of function for the brain.
Our approach therefore, begins with repair of normal function. Further mechanisms of restoration are required to overcome the broad level of toxic burden experienced by the children. These repair processes may include reduced glutathione intravenously, chelation of heavy metals, support of liver detoxification, removal of toxins from the environment and diet, antioxidative support, immune function support, and ultimately the removal of the persistent symptomatic viral infections when present. And again, unless brain function returns with biological healing, we take a careful look at ways to stimulate cognitive and functional aspects of the central nervous system.
An exciting field of research for us is neurofeedback. This technology uses external reinforcers linked to the EEG to teach the individual to retune brain electrical rhythms. While that sounds far fetched the science has reached validation through well controlled studies at major universities.
The consequences of the following three items have often been our primary focus in ASD treatment, but the core issues represent fertile ground for repairing autism biology.
These areas are: 1) Immunotoxicological Wounding, 2) Viral Persistence, and 3) Sulfur (Cysteine) Depletion resulting in Metallothione and Glutathione Disruption.
1. Immunotoxicological Wounding:
It is my impression that the typical regressed autistic presentation starts with combined immune and toxic provocations. Environmental agents like PCBs & insecticides along with the vaccine components (especially Thimerosal) are all potential toxins and none are likely acting alone. Somewhat surprisingly, the Institute of Medicine (IOM, Feb 20, 2002 Multiple Immunizations and Immune Dysfunction), recently admitted the evidence for the current vaccine program exposing the child to increased risk of various problems ranging from allergy to infection was significant, although their inconsistency between epidemiology and biology in the presentation makes it difficult to follow their thinking. They do not seem to feel the epidemiology is inconsistent with the biology.
My take of the literature is the vaccine schedule could cause a child to get sick from typical viruses and bacteria, while also be at great risk for asthma and allergy. So we may be trading a vaccine preventable disease , like polio – for perhaps an ear infection or asthma. On the surface that is a more than fair exchange. And infection exposes the child to other problems , recurrent antibiotic treatment is common in the children we see. Antibiotics in turn expose the child to yeast infection or yeast persistence and around we go. But the longer term effects of immune modification may be more serious.
So my thinking here is a child receives live viral vaccines after the immune system is primed to react in the wrong way and also concurrent with other vaccines (with many toxic substances including thimerosal) which further promote this immune weakening, thereby allowing the vaccine virus to have a wounded host to invade. This rationale comes from evidence that the vaccine schedule is going to direct a TH-2 shift in the child. What does that mean? Simply that the child will be less likely to defend against viruses, bacteria and yeast, and be more likely to develop allergies. The IOM did find weak evidence for allergy, but the literature would seem to me to be more than adequately convincing. We do know that MMR makes IgE switching more likely and IgE is the way to allergy. See below:
Infection of human B lymphocytes with MMR vaccine induces IgE class switching. Clin Immunol 2001 Sep;100(3):355-61
Imani F, Kehoe KE. Division of Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, Maryland 21224, USA. [email protected]
Circulating immunoglobulin E (IgE) is one of the characteristics of human allergic diseases including allergic asthma. We recently showed that infection of human B cells with rhinovirus or measles virus could lead to the initial steps of IgE class switching. Since many viral vaccines are live viruses, we speculated that live virus vaccines may also induce IgE class switching in human B cells. To examine this possibility, we selected the commonly used live attenuated measles mumps rubella (MMR) vaccine. Here, we show that infection of a human IgM(+) B cell line with MMR resulted in the expression of germline epsilon transcript. In addition, infection of freshly prepared human PBLs with this vaccine resulted in the expression of mature IgE mRNA transcript. Our data suggest that a potential side effect of vaccination with live attenuated viruses may be an increase in the expression of IgE.
The route of delivery bypasses the normal barrier mechanisms of the defense and immune systems (respiratory membranes), which introduces the virus to the body systemically before the immune response has been initiated. These issues are not addressed by the American Academy of Pediatrics position statement that a child’s immune system could naturally handle thousands of viral antigenic insults, because the immune system is now admittedly being altered and bypassed by the vaccine process itself.
But vaccines are complex and they contain aluminum and mercury and toxoids , any or more likely all of which could provoke an alteration in the immune system. Aluminum is actually deliberately placed in the vaccine to induce a TH-2 response. Then we have a host of toxic chemicals for our children to contend with. Edleson published his findings on this in 1998. Whether the toxins are present at greater levels than controls or whether the toxins are a result of other wounding to the child’s system (ie primary or secondary issues) is not determined at this time.
Autism: xenobiotic influences. Toxicol Ind Health 1998 Jul-Aug;14(4):553-63 Edelson SB, Cantor DS.
Environmental and Preventive Health Center of Atlanta, GA 30342, USA.
Excerpted: A proposed mechanism for the interaction of xenobiotic toxins with immune system dysfunction and continuous and/or progressive endogenous toxicity is presented as it relates to the development of behaviors found in the autistic spectrum.
The combined Immune Dysfunctions, can take several forms: Immunoglobulin (Antibodies) deficiency, such as IgA which is low in about 1/4th of the children (Gupta 1996). Subpopulations of Lymphocytes are abnormal (Gupta 1996, 1998, 1999 & 2000) also (Denney 1999), and (Warren and Singh 1990). The general consensus is that the immune system in children with autism is imbalanced in a TH-2 direction. Once again, TH-2 means the immune system prefers to make antibodies as opposed to cellular defenses. It also means an increased likelihood of allergy and autoimmunity. There is also an excess of Tumor Necrosis Factor-alpha, a chemical messenger which turns on inflammation and can destroy healthy cells, see:
Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression.
J Neuroimmunol 2001 Nov 1;120(1-2):170-9 Jyonouchi H, Sun S, Le H.
Department of Pediatrics, University of Minnesota, MMC 610 FUMC, 420 Delaware Street SE, Minneapolis, MN 55455, USA. [email protected]
In normal conditions, human gut mucosa is infiltrated with a large number of mononuclear cells. This is a reflection of the fact that human intestine is continuously subjected to a massive stimulation by luminal antigens. This state of “physiological” inflammation is a tightly controlled phenomenon, as several mucosal cells interact to generate and maintain an appropriate local immune response. Changes in cell type number and/or function, including the release of soluble mediators, have been associated with the development of chronic inflammatory diseases, such as Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease. Evidence also indicates that the type of inflammatory response occurring in the intestine of patients with CD differs from that in UC, and this probably reflects distinct pathways of immune activation. In CD mucosa, a Th1 response with high IL-12 and IFNgamma production prevails, while in UC a humoral immunity appears to be predominant. Despite this, CD and UC share downstream inflammatory events, characterised by high levels of inflammatory cytokines, free radicals, matrix-degrading enzymes (MMP)and growth factors.
Figure: The relationship of Cytokines to control of other cytokine pathways and MMP Autoimmunity is part of immune dysfunction in ASD and Dr Singh has been on the forefront of this investigation. Others have found autoimmunity in ASD as well. Autoantibodies to myelin basic protein (a constituent of brain insulation), has been reported in as many as 58% of ASD children (Warren 1993). Antibodies to myelin basic protein, as the pathological mechanism in autism, has been proposed by Singh, 2001-2 in various papers. See:
January 2002, part 2 ” Volume 109 ” Number 1 #702 Abnormal Measles Serology and Autoimmunity in Autistic Children Singh, VK & Courtney Nelson Immune factors such as autoimmunity may play a causal role in autism. We recently showed that many autistic children have autoantibodies to brain myelin basic protein (MBP) as well as elevated levels of measles virus antibodies. To extend this research further, we conducted a serological study of measles virus (MV), mumps virus (MuV), rubella virus (RV), cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), measles-mumps-rubella (MMR), diptheria-pertussis-tetanus (DPT), diptheria-tetanus (DT) and hepatitis B (Hep B) and studied correlations with MBP autoantibodies. Antibodies were assayed in sera of autistic children (n=125) and normal children (n=92) by ELISA or immunoblotting methods.
We found that autistic children have significantly (p=0.001) higher than normal levels of MV and MMR antibodies whereas the antibody levels of MuV, RV, CMV, HHV-6, DPT, DT or Hep B did not significantly differ between autistic and normal children. Immunoblotting analysis showed the presence of an unusual MMR antibody in 60% (75 of 125) of autistic children, but none of the 92 normal children had this antibody. Moreover, by using MMR blots and monoclonal antibodies, we found that the specific increase of MV antibodies or MMR antibodies was related to measles hemagglutinin antigen (MV-HA), but not to mumps or rubella viral proteins, of the MMR vaccine. In addition, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a causal association between MMR and brain autoimmunity in autism. Stemming from this evidence, we suggest that an ├Čatypical├« measles infection in the absence of a rash but with neurological symptoms might be etiologically linked to autoimmunity in autism. ICDRC reported to the Institute of Medicine in July of 2001, that 85% of 27 Indonesian children with ASD were positive for at least one autoimmune brain marker (Proceedings of IOM Vaccine Safety Committee Meeting, National Academies of Science, Bradstreet, et al, October 1, 2001).
In a paper presented by Dr Singh, our ongoing efforts to define the autoimmunity of autism and its relationship to the measles virus is apparent. He presented the paired spinal fluid studies at the ASM meeting in 2002, (see below).
Serological Detection of Measles Virus in Relation to Autoimmunity in Autism 102nd General Meeting of the American Society for Microbiology May 19-23, 2002, Salt Lake City, Utah, Presentation V-5
V.K. Singh, R.L. Jensen, J. J. Bradstreet Utah State University and the International Child Development Resource Center
Abstract: Autoimmunity to brain myelin protein (MBP) secondary to a measles infection may cause autistic regression in some children with this neurodevelopmental disorder. We hypothesized that measles-mumps-rubella (MMR) immunization is a source of measles infection; hence the serological link between MMR and MBP antibodies might exist in autistic children.
To test the hypothesis, we conducted a serological study of MBP, MMR and neuron-axon filament protein (NAFP) in serum and cerebral spinal fluid (CSF) of autistic children. Antibodies were assayed by immunoblotting with MBP, NAFP and MMR as antigens. We found that a significant number of autistic children had antibodies to MBP (up to 88% positive) and antibodies to MMR (up to 65% positive), but not to NAFP. Normal children did not harbor these antibodies. Moreover, the analysis of paired samples (serum and CSF) from 7 autistic children also revealed a high degree of serological association between MMR and MBP: 50% of CSF had MMR antibodies, 86% of CSF had MBP antibodies, 75% of sera had MMR antibodies and 100% of sera had MBP antibodies. Therefore, as indicated by paired analysis of serum and CSF samples, there is a strong correlation between MMR antibodies and MBP autoantibodies in autism. By using monoclonal antibodies, we characterized that the MMR antibodies are due to the measles subunit, but not due to mumps or rubella subunits, of the polyvalent vaccine. Furthermore, the MMR and MBP antibodies are not cross-reactive because the pre-incubation of MBP with MMR did not block the binding of MBP antibodies. In light of the new evidence presented here, we suggest that the MMR vaccine in some cases of autism might cause autoimmunity and it might do so by bringing on an atypical measles infection that does not produce a typical measles rash but manifests neurological symptoms upon immunization.
Singh went on to publish these in the Journal of Biomedical Science August 2002; 9:359-364. Additionally, research at Washington University Hospital, in St. Louis, demonstrated significant autoimmunity to blood vessel linings (endothelium). (See: Connolly AM, et al, Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999 May;134(5):607-13).
Drs Connolly and Bradstreet are working on defining the relationship of autoantibodies to various other brain proteins, as well as MBP in a population of children with autism as compared to neurological normal control children with incidental viral infections. The study is as yet incomplete and cannot therefore be discussed, but if it is consistent with Dr Singh’s findings, it would further establish a pattern of autoimmunity in autism and confirm those observations.
2. Viral Persistence
There is a considerable degree of overlapping between autoimmunity as discussed above and the GI autoimmunity now published in autism, see:
Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism.
Mol Psychiatry 2002;7(4):375-82 Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, Murch SH.
We have reported lymphocytic colitis in children with regressive autism, with epithelial damage prominent. We now compare duodenal biopsies in 25 children with regressive autism to 11 with coeliac disease, five with cerebral palsy and mental retardation and 18 histologically normal controls. Immunohistochemistry was performed for lymphocyte and epithelial lineage and functional markers. We determined the density of intraepithelial and lamina propria lymphocyte populations, and studied mucosal immunoglobulin and complement C1q localisation. Standard histopathology showed increased enterocyte and Paneth cell numbers in the autistic children. Immunohistochemistry demonstrated increased lymphocyte infiltration in both epithelium and lamina propria with upregulated crypt cell proliferation, compared to normal and cerebral palsy controls. Intraepithelial lymphocytes and lamina propria plasma cells were lower than in coeliac disease, but lamina propria T cell populations were higher and crypt proliferation similar. Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion.
Central to Dr Wakefield’s thinking in autism, is the persistence of measles virus (MV) in the GI tract of children. Persistence of Measles Virus is now published in both tissue biopsies from the ileum and in circulating immune cells (Uhlmann et al below). This is one of the likely triggers of MMP and TNF alpha as previously discussed. Other viruses speculated to be persistent in autism are CMV, EBV, and HHV-6. Because the lifecycle of these viruses is stealthy, it is difficult to prove they are causing problems. Measles has been the most readily documented persistent virus.
(See: Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000 Apr;45(4):723-9.) & (See also: Proc Natl Acad Sci U S A 1999 Oct 12;96(21):12102-7). The MV concept also fits well with Dr Singh’s work. But this received a new injection of momentum when the first of the following two papers from the Histopathology Group at Trinity College, Dublin, was published, and then again when the later was presented in July of 2002.
Potential viral pathogenic mechanism for new variant inflammatory bowel disease V Uhlmann*, C M Martin*, O Sheils, L Pilkington, I Silva, A Killalea, S B Murch, A J Wakefield, J J O’Leary
J Clin Pathol: Mol Pathol 2002;55:0,6 Aims: A new form of inflammatory bowel disease (ileocolonic lymphonodular hyperplasia) has been described in a cohort of children with developmental disorder. This study investigates the presence of persistent measles virus in the intestinal tissue of these patients (new variant inflammatory bowel disease) and a series of controls by molecular analysis.
Results: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal lymphonodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was identified within the follicular dendritic cells and some phocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,000 copies/ng total RNA.
Conclusions: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder.
Development of an ‘allelic discrimination’ type assay to differentiate between the strain origins of measles virus detected in intestinal tissue of children with ileocolonic lymphonodular hyperplasia and concomitant developmental disorder.
O.Sheils, P.Smyth. C Martin. J.J. O’Leary. Department of Histopathology, Trinity College Dublin, Ireland.
In a recent study, our group described the presence of measles virus RNA genes in a new form of inflammatory bowel disease with concomitant developmental disorder1. One of the many questions raised by this study asked if measles virus detected was wild or vaccine type in origin. The objective of this pilot study was to address this point.
Several conserved amino acid coding changes have been identified in measles virus strains in the Edmonston Vaccine lineage and it has been suggested these represent a vaccine ‘strain signature2. One such site (nucleic acid position 7901, amino acid position 211) displays a consistent A-G mutation in Edmonston derived vaccines compared with wild type strains. This site is located in the H gene region of the measles genome and is associated with cellular CD46 interaction. This single base mutation was used as the basis for the design of an allelic discrimination assay using TaqMan MGB probes (FAM labelled for wild type, and VIC labelled for Vaccine Type). The assay was run on an ABI 7000 sequence detection system using total RNA extracted from intestinal biopsies amplified with TaqMan one step RT-PCR kit.
Synthetic oligonucleotides representing wild and vaccine strains were designed using published sequences from the NCBI database, and used as controls in the assay system.
The assay identified wild type measles in three brain blocks from an SSPE patient, while 12 gut biopsies from affected children were deemed to have vaccine strain present. This pilot study further corroborates our previous findings of an association between the presence of measles virus and gut abnormalities in children with developmental disorder, and indicates the origins of the virus to be vaccine strain.
Based on these findings, we at ICDRC have undertaken to look for the MV and the immune findings of Singh in the CNS (brain , cerebral spinal fluid) of children with ASD. We will keep you posted as the results become available. Early observations are very consistent with the MV association in at least a subgroup of children.
To be fair to the published literature, epidemiologist have not been able to draw an association regarding MMR and ASD. Their studies have many intrinsic limitations and statistical problems. Ultimately, we do not give retrospective chart reviews the final say in medicine when molecular viral pathology and immunology can demonstrate clear distinctions between ASD and healthy individuals.
Gut disorders in autism are common.
Autoimmune Inflammatory Bowels Disease, a unique form of inflammatory bowel disease which is histopathologically (they way it appears under the microscope) distinct from Crohn’s Disease and Ulcerative Colitis, has been described in ASD. This is a furiously controversial issue at this time. It has evoked more emotional editorials than just about any issue in medicine. The reason revolves around the potential influence of the MMR vaccine in the cause of this disorder. For our purposes, it doesn’t immediately matter if MMR causes this disorder since, at the present-time there is no specific anti-measles anti-viral drug which could treat it. The treatment will therefore be aimed at symptom relief like any autoimmune disease. This is primarily the work of the Pediatric Inflammatory Bowel Disease Unit at the Royal Free Hospital in London and The Department of Pediatrics at the University of Tokyo. Although the team at Georgetown University Medical Center also replicated the work and doctors at Harvard are finding similar abnormalities as well. See: 1) Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. Pediatr. 2001 Mar;138(3):366-72. Furlano et al. 2) Measles virus and autism. Lancet. 2000 Aug 26;356(9231):772. 3) Enterocolitis in children with developmental disorders. Am J Gastroenterol. 2000 Sep;95(9):2285-95. 4)Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000 Apr;45(4):723-9. 5) Autism, viral infection and measles-mumps-rubella vaccination. Isr Med Assoc J. 1999 Nov;1(3):183-7. Review. 6) MMR vaccination and autism. Lancet. 1999 Sep11;354(9182):949-50. 7) Original report: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998 Feb 28;351(9103):637-41. The epidemiology, with all its reported weaknesses, does not exclude the detection of measles virus in the immune cells of children with autism. Upper Gastrointestinal Abnomalities: Reflux Esophagitis, Gastritis, Defective Secretin Activation, was originally described by Horvath and collegues at the University of Maryland, after a persistent mother, Victoria Beck, encouraged them to look after her child’s chronic diarrhea regardless of his autistic symptoms. It was a battle won. ASD children have common upper tract disorders. Dr. Horvath has observed a relationship between night awakings and reflux of acid. There is also an apparent association between crying, temper and disruptive behaviors and gastritis and other disorders in the GI tract. Added to the observations in the lower ileum and it’s no wonder ASD kids feel miserable and perform poorly. (See: J Pediatr. 1999 Nov;135(5):559-63. Gastrointestinal abnormalities in children with autistic disorder. Horvath K, et al & also the original observations in, J Assoc Acad Minor Phys. 1998;9(1):9-15. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. Horvath K, et al.)
3. Sulfur (Cysteine) Depletion, Metallothione and Glutathione Disruption
Phenol sulfotransferase (PST) Sulphur Metabolism Defects, the system that detoxifies many substances in the body have been documented to be deficient in children with autism through the research of Rosemary Waring and her colleagues. Sulphates in the blood help rid the body of waste products by making them water soluble and therefore easily excreted. Low levels of sulphate can lead to retention of toxins, which can lead to bio-chemical effects on the central nervous system.
In her study, 232 children with autism, matched with 86 control children, were found to have reduced levels of sulphate in blood , and to excrete higher levels of sulphate in urine, as compared with the control group. Loss of sulphate in urine may partly explain low blood sulphate levels, since once the process had started it would continue on a slow, but steady, downward spiral.
Sulphation capacity affects the gastro-intestinal tract. The mucins which line the gut are sulphated glycoproteins which rely on sulphation to maintain their structure. Reduced sulphation has been associated with inflammation,gut dysfunction, and increased permeability. (See also: Waring RH, Klovrza LV. J Nutri Enviro Med 2000; 10(1):25-32 Sulphation deficit in “low-functioning” autistic children: a pilot study.)
That is strikingly similar to what is reported in persistent HIV infection. I am not implying children with ASD have HIV. Rather, I am inferring that the defect in sulfur in ASD may be related to similar mechanism. Obviously HIV is a better studied persistent viral infection than MV in ASD.
We observe a low plasma cysteine (sulfur containing amino acid) level commonly in autism. Loss of cysteine, the rate limiting step in the production of Glutathione (GSH) and Metallothionine (MT) would result in increased oxidative stress, lowered immune function, neurotransmitter dysfunction, vagal nerve dysfunction, accumulation of heavy metals (especially lead and mercury) and viral persistence. In short, this step is likely the final blow in ASD and hence makes repairing this damage key to recovery. You may see the IOM presentation of Dr Bradstreet at the IOM website: http://www.iom.edu/IOM/IOMHome.nsf/Pages/Thimerosal+Agenda then click on Bradstreet Slides.
See also: Massive loss of sulfur in HIV infection. AIDS Res Hum Retroviruses 2000 Feb 10;16(3):203-9 Breitkreutz R, Holm S, Pittack N, Beichert M, Babylon A, Yodoi J, Droge W.
Skeletal muscle tissue from SIV-infected macaques was previously found to contain abnormally high sulfate and low glutathione levels indicative of an excessive cysteine catabolism. We now confirm the peripheral tissue as a site of massive cysteine catabolism in HIV infection and have determined the urinary loss of sulfur per time unit. The comparison of the sulfate concentrations of the arterial and venous blood from the lower extremities of 16 symptomatic HIV+ patients and 18 HIV- control subjects (study 1) revealed (1) that the peripheral tissue of HIV+ patients with or without highly active antiretroviral therapy (HAART) releases large amounts of sulfate and (2) that plasma sulfate, thioredoxin, and interleukin-6 levels are elevated in these patients. A complementary investigation of 64 asymptomatic HIV+ patients and 65 HIV- subjects (study 2) revealed increased plasma sulfate levels in the asymptomatic patients. The analysis of the daily urinary excretion of sulfate and urea of another group of 19 HIV+ patients and 22 healthy HIV- subjects (study 3) confirmed (1) that HIV+ patients experience a massive loss of sulfur and (2) that this loss is not ameliorated by HAART. The sulfur loss of asymptomatic patients was equivalent to a mean loss of about 10 g of cysteine per day. If extrapolated, this would correspond to an alarming negative balance of approximately 2 kg of cysteine per year under the assumption that the normal sulfate excretion equivalent to approximately 3 g of cysteine per day is balanced by a standard Western diet. The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool.
Consequences: Mercury: The issues are well discussed elsewhere, so I will only discuss the link to persistent viral infections and vaccines briefly with regard to how it links much of autism thinking together. It is clear that the type of findings Dr. Waring is describing in ASD (as mentioned above) would lead to an open door to heavy metal accumulation. In my personal discussions with her on the subject she believes the profile of the sulfur deficiency is exactly what you would see in a persistent viral infection like AIDS , except our kids do not have AIDS. Mercury and/or lead, depending on the child’s environment, are the most abundant metal toxins.
But then thimerosal (vaccine mercury preservative widely used until about 2000 when its used declined , but has not ceased) is a clearly toxic substance in its own right. It was regrettable that it was ever in childhood vaccines or in the anti-Rh given to Rh negative mothers. So a child had a dual threat (environmental and iatrogenic) at minimum, and depending on the mother’s and/or the child’s amalgam (mercury containing dental fillings) status may have a third risk for mercury exposure. Mercury has a number of ways to trigger immune dysfunction, and it directly causes brain toxicity, thereby making it a fair target of ASD research. A full discussion of that is available from Dr Jane El-Dahr, DAN! 2002 off the www.autism.com/ari website so I will not reiterate her discussion her. See also below:
Gluten and Casein: While there is growing evidence of a link between behaviors and bowel dysfunction and the proteins in bread and milk related foods, it is my impression that gluten and casein issues are secondary defects, rather than primary. In essence, the sulfation and detoxification problems we have described interfere with the enzyme required to digest these opioid (narcotic-like) portions of bread and milk. What exactly are these special food compounds? Embedded within all proteins are small segments of amino acids called peptides, meaning pieces of proteins. Normal digestion breaks big protein structures into small proteins and peptides, which are further cleaved into individual amino acids by peptidases (enzymes which cut away single amino acids one at a time). Eventually, this process leaves just amino acids which can then be transported into the body to by remanufactured by cells into human proteins. Within gluten, a bread protein and casein, a milk protein are scores of gliadomorphine or casomorphine peptides which are rich in proline, an amino acid which creates sharp bends in the molecule. Those sharp bends give these proteins their unique shape, but the shape requires a special enzyme called DPP-IV (dipeptidylpeptidase-IV).
As the names imply, casomorphine and glaidomorphine act like morphine, and work at opioid receptors in the brain. While this theory of autism is not terribly popular with mainstream pediatricians, the science behind it has never been discredited, and new evidence from Norway continues to confirm the presence of abnormal opioids and the benefits of removal of these proteins from the diet of children with autism symptoms. For years, we have been waiting for a controlled study of dietary changes in autism , finally we have one and the team in Norway is to be congratulated (see below).
A Randomized, Controlled Study of Dietary Interventions in Autistic Syndromes Nutritional Neuroscience, 2002 Vol. 5(4). Pp. 251-261. A.M. Knivsberg, K.L. Reichelt, T. Hoien and M. Nodland
Abstract: Impaired social interactions, communication and imaginative skills characterize autistic syndromes. In these syndromes urinary peptide abnormalities, derived from gluten, gliadin, and casein, are reported. They reflect processes with opioid effect. The aim of this single blind study was to evaluate effect of gluten and casein-free diet for children with autistic syndromes and urinary peptide abnormalities. A randomly selected group with 10 children in each group participated. Observations and tests were done before and after a period of one year. The development for the group of children on diet was significantly better than for the controls.
For a good discussion of opioid issues see: (Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O’Leary JJ, Murch SH., Aliment Pharmacol Ther 2002 Apr;16(4):663-7. Review article: The concept of entero-colonic encephalopathy, autism and opioid receptor ligands.)
CD 26 also known as DPP-IV, or dipeptidyl peptidase IV, this is a cell surface protein which has numerous functions in the body. First it is responsible for signaling immune cells known as lymphocytes to reproduce themselves. It is also the protein which serves as an enzyme to break down those opioids mentioned above. Its function is either impaired by toxins and interfering substances (Hg, PCBs, pesticides and other toxins), or it not being manufactured by cells in adequate amounts to do its job. (Jon Pangborn, paper presented at Oasis Conference, Portland Oregon, Dec 2000). (See also: Clin Sci (Colch) 2000 Aug;99(2):93-104. A guardian angel: the involvement of dipeptidyl peptidase IV in psychoneuroendocrine function, nutrition and immune defense. Hildebrandt M, Reutter W, Arck P, Rose M, Klapp BF.)
Seizures: This is a complex discussion and not without its unique controversies. Seizures are the result of neuronal membrane dysfunction. A huge list of variables may influence neuronal membrane activity. Nutritional deficiency, viral infections, low blood flow and etc, etc. It would easy to see how most of this list is the product of a more primary process of viral infection and gut dysfunction combined with dietary self-restrictions which produce deficiencies. For simplicity sake, let’s just look at the primary defects at this time. Jeffrey Lewine PhD documented these are often difficult to find with traditional EEG technology. He used Magnetoencephalography and found 82% of ASD children had seizures, (Pediatrics 1999 Sep;104(3 Pt 1):405-18). Despite the weakness with simple EEG, all observers have documented seizures in a significant number of children with autism. (Giovanardi Rossi P, 2000, found 38.3% and Tuchman, 1994, found 11% of boys and 24% of girls with ASD had seizures). Many of the symptoms we call autism can be explained by the high incidence of subclinical seizures found by Lewine and colleagues. But it is equally apparent to the physicians at ICDRC, that current or past viral infection in the CNS is a likely cause of seizures.
Purine Metabolism Disorders, Dr. Ted Page, (Biochim Biophys Acta 2000 Mar 17;1500(3):291-6), reported 1 in 5 children with autism had disorders of purine metabolism which created increased amounts of uric acid. Purines are part of the skeleton of DNA and RNA and the exact way in which this disorder may influence ASD symptoms is unknown. A few case reports from Page and Repligen Corp., as yet unpublished, indicate uridine may treat the symptoms of this disorder. Again, I suspect the purine disorder is generally resulting from other more primary issues. (Additional information on this can be found at “http://www.repligen.com” www.repligen.com)
Essential Fatty Acid Deficiency, these fatty substances are things like fish oil flax oil, pumpkin seed oil, borage, evening primrose oil and similar substances. We generally focus on the Omega 3 oils since it is rare to find Omega 6 deficiencies in autism. Dr. Andrew Stoll form Harvard’s McLean Hospital, has had a significant interest in one Omega 3, EPA and its role in behavioral disorders. Our experience agrees with Dr. Stoll, in that EPA is usually the ideal oil to supplement. Some children need balancing with all the Omegas, but that is less common. The French have just published their results which are in complete agreement with our observations, (See: Prostaglandins Leukot Essent Fatty Acids 2001 Jul;65(1):1-7. Plasma fatty acid levels in autistic children. Vancassel S, et al, from the Laboratoire de Nutrition et Securite Alimentaire.) The French study documents no decease in Omega 6 oils, only in Omega 3 oils. Another study showed decreased highly unsaturated fatty acids in a child with autism and the presence of Indole Acryloglycine, originally described by Paul Shattock and colleagues.
(See: Prostaglandins Leukot Essent Fatty Acids 2000 Jul-Aug;63(1-2):21-5. Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Bell JG, Sargent JR, Tocher DR, Dick JR.). The lack of fatty acids can be directly tied to dietary issues and gut dysfunction. Further, fatty acid deficiency would interfere with normal brain, red blood cell and blood vessel membranes which could cause serious abnormalities in oxygen delivery and brain cell functioning.
Serotonin Abnormalities: Serotonin is one of the key neurotransmitters which regulates mood and repetitive behaviors. Work on the tryptophan (the amino acid which serves as the base for serotonin) related neurotransmitter pathway suggests decreased function in serotonin function is an important area in autism. (See: Am J Psychiatry 2001 Jun;158(6):972-3. 5-HT(1D) function and repetitive behaviors.) Additionally, elevated whole blood serotonin is the most reproduced abnormality in the medical literature on autism. We have also confirmed these observations in our population of children with autism. (See this excellent review in: Paediatr Drugs 2000 Jan-Feb;2(1):67-81. Autism: current theories regarding its pathogenesis and implications for rational pharmacotherapy. Buitelaar JK, et al.) Also, (See: Psychiatry Res 1996 Nov 1;65(1):33-43. Serotonin and autism: biochemical and molecular biology features. Herault J, et al). Dopamine Pathway Abnormalities, have been documented by PET scan studies in ASD. This is a complex area of neurochemistry, but excess dopamine function is associated with hyperactivity, motor control abnormalities and repetitive/stereotypic disorders such as flapping. (See: Dev Med Child Neurol 1997 May;39(5):313-8, & Adv Neuroimmunol 1996;6(3):265-77 & Dev Med Child Neurol 1994 Aug;36(8):688-97). Also (Encephale 1989 Mar-Apr;15(2):255-62. [Disorders of catecholamine metabolism in infantile autism. Comparative study of 22 autistic children.] Ferrari P, et al. Dysbiosis: So much is written about this it is a whole talk in itself. Defined as a problem where abnormal bacteria (anerobes like Clostridia species), yeast and/or parasites become the dominant organisms in the gastrointestinal tract (Gut or GI, or Bowel are interchangeable terms with gastrointestinal tract). (Kidd 2000 re. ADHD), also see: (Zoppi G, Cinquetti M, Luciano A, Benini A, Muner A, Bertazzoni Minelli E Acta Paediatr 1998 Aug;87(8):836-4. The intestinal ecosystem in chronic functional constipation.) and (Sandler RH, et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000 Jul;15(7):429-35.) and (Shaw 1995). See the DAN! Protocol (Pangborn and Baker). Dr. Wakefield has also reported the presence of anergy (loss of immune recognition) to yeast/candida in autism. Also Dr Shaw’s work at “http://www.autism.com/shaw-yeast/interv.html”
Interestingly, Dr. Rimland’s parent rating scale of medications continues to find parents rate anti-fungals (yeast-fighters) very high on the scale of effective drugs for autism. No one has ever postulated an independent action of these anti-fungals apart from their intrinsic ability to inhibit yeast from growing. So we assume killing yeast aids the overall functioning of the child’s immune system and gut health. Furthering the notion, Dr Gupta independent of Dr Wakefield, identified immune disorders in autistic children which impair the child’s ability to deal with yeast as a pathogen (Dysregulated Immune system in children with autism: Beneficial effects of intravenous immune globulin on autistic characteristics. Gupta et al, 1996 Journal of Autism and Developmental Disorders.26: 439-452). Given the immune disorder and the overall observations of numerous parents and clinicians, aggressively dealing with both yeast and anerobic bacteria overgrowth, seems warranted in autism. We’ll present specific ways of dealing with these issues later.
In summary then, even this brief review of the biology of autism leads into some very complicated potential therapies. But our goal here is not to see how complicated we can make it , rather how we might focus our efforts on the most productive approaches for any given person with autism.