WITH NEW AND MORE PRECISE TOOLS and technology available to us now, the medical anatomy of “autism” is gaining definition after years of conflicting findings. Currently, EEG abnormalities,1 immune markers, and NeuroSPECT findings support the concept of a medical disease process occurring in these children’s brains. For example, it is generally recognized that an EEG finding of “slow” waves or “abnormal” brain wave activity is often consistent with the idea of an underlying and unknown encephalopathy/encephalitis.
In addition, ongoing work with the NeuroSPECT strengthens the connection of blood flow abnormalities and neurodysfunctional states, particularly in situations in which patients appear to have immune and/or possible viral etiologies. NeuroSPECT scans capture blood flow through specific areas of the brain. Blood flow correlates with function/activity.2, 3 As noted, NeuroSPECT scans on children with autism have shown a decrease in blood flow in the temporal and occipital areas, which is consistent with past reports of temporal lobe dysfunction in such children. Neurological models of the brain correlate right temporal lobe areas with social skills and left temporal lobe areas with speech and auditory processing, all of which are compromised in autistic children. It should also be noted that there is no good explanation for our finding of increased blood flow in the frontal lobes of a group of these children, which is more consistent with ADD and hyperactivity. Further research is required relative to this finding.
When monitoring the emerging body of evidence related to the immune system and its interactive messengers, interleukins and cytokines, it appears that a dysregulated immune system state—whether triggered by a virus, genetic disposition, or intrauterine, prenatal, or neonatal stress or trauma—may account for the cognitive processing and other deficits seen in some children with autism. This concept is supported by the lack of consistent neurological/anatomical abnormalities and metabolic abnormalities in these children. We now know that neuropolypeptides called cytokines can and do restrict brain blood flow under certain conditions. In these children, we may be looking at an immune system continually sending out signals to restrict brain blood flow. Whether this continues as an autoimmune reaction (whereby the immune system continues this pathway with no active reason to do so) or is due to the presence of a retroviral or other viral process is open to further research. However, the concept of an immune-related disease process in a large number of these children appears unquestionable at this point in time.
Many autistic children have major allergies or intolerances to many chemicals and foods. While occasionally these reactions may turn into urticaria or asthma, the effect in the majority of these children is the worsening of autistic-like behavior. Family history often reveals eczema, migraines (especially in mothers), hay fever, asthma, and histories of other disorders, which are often immune-mediated. These external symptoms may well prove to be signs of a hyper-reactive/stressed/dysfunctional immune system underlying the biochemistry of these children. Many anecdotal reports of successful therapies for autistic children (e.g., gammaglobulin, allergy-free diets) can most likely be explained through the concept of regulating a dysfunctional immune system and/or altering metabolic sensitivities and dysfunction.
Extensive clinical work over the last four to five years further supports the hypothesis that we are facing an immune-mediated disease state affecting the central nervous system (CNS) in these children. The literature is replete with articles connecting immune system abnormalities to autism, ADD, ADHD, CFS, and CFIDS. Here are several main examples:
Multiple researchers have shown an interaction of maternal antibodies with trophoblast or embryonic tissue antigens, and a cross-reaction with antigens found on lymphocytes.13, 14, 15, 16
Researchers have also shown a significant depression of CD4+ T helper cells and their suppresser-inducer subset17, 18 with an increased frequency of the null allele at the complement C4B locus19 in children with autism. As similar changes have been known to occur in other autoimmune diseases,20, 21 these researchers have postulated that immune activation of a T cell subpopulation may be important in the etiology of the disorder in some children with autism. Note: Many of the autistic children evaluated in studies and within my practice have shown very high CD4 and CD8 counts, low natural killer (NK) cells, or other “markers” consistent with immune dysfunction/dysregulation.
Abnormalities of cell adhesion molecules (NCAM)22 have been reported.
Antibodies to neurofilament axonal proteins (NFAP) have been noted in autistic children 23 and have been reported in neurotropic “slow virus” diseases (kuru and Creutzfeldt-Jakob disease) in adults.24 Other studies25, 26 have suggested an association of an infectious agent (slow virus) in the etiology of these diseases. This is considered indirect evidence that some cases of autism may also be associated with the concept of a slow virus.
Anti–central nervous system serum immunoglobin reactivity has been reported that was specifically directed against the cerebellum. 27
A small percentage of autistic children with demonstrable immunologic abnormalities have normalized their autistic symptoms with intravenous immunoglobulin treatment.28, 29 This result shows that immune abnormalities can cause autism in a subset of children and that acquired autism can be effectively treated.
Singh et al. hypothesized that autoimmunity secondary to a virus infection may best explain autism in some children.30 Congenital rubella virus 31 and congenital cytomegalovirus32 have been indirectly involved as causative factors in autism.
Given this support and much more from the medical research literature, the concept of immune dysregulation as a medical disease process in childhood neurocognitive dysfunction is an emerging reality. This concept could easily account for a significant portion of the increase of neurocognitive diagnoses over the last twenty to thirty years. Whether the etiology of this dysfunction is related to environmental factors (e.g., ozone layer depletion, local toxins, etc.), new retroviruses, or stealth, spongiform or other viruses (or altered viral responses), we now have a medical hypothesis that can facilitate the definition of clinical subgroups and lead to the treatment of these patients without first determining the exact/specific origin or etiology.
If an infectious etiology indeed exists, it may be as ordinary as the common cold or so rare that we have not yet developed the tools to identify or study it. Whether an ongoing agent is present, or the body simply remains in a dysfunctional state, it seems likely we are confronted with a phenomenon/illness that has multiple etiologies, multiple origins, and various clinical manifestations. At this point, they appear linked by an immune dysfunction or possible viral-mediated state. Genetic predisposition to this syndrome may have a great deal to do with why certain individuals suffer with these symptoms. However, we must begin to consider these apparently heterogeneous expressions as linked and potentially treatable through the common pathway of an immune dysfunctional/CNS dysregulated state. For example, in a study33 on chronic fatigue syndrome (CFS), Dr. Mena and I reported a significant diminution of blood flow in both the temporal and, to a lesser degree, the parietal lobes in children suffering from CFS and chronic fatigue immune dysfunction syndrome (CFIDS). These findings are similar to those previously noted in children with acquired autism.
The ASD medical disease hypothesis began to take form in the 1980s when multiple researchers found evidence that autoimmunity was a possible mechanism to explain autistic symptoms.37,38,39,40,41 Since these initial observations, the body of evidence has grown dramatically—witness this statement from Johns Hopkins Department of Neurology website (December 2009):
Current evidence suggests that neurobiological abnormalities in autism are associated with changes in cytoarchitectural and neuronal organization that may be determined by genetic, environmental, immunological, and toxic factors. Since neuroglia has central roles during brain development, cortical organization, neuronal function and immune responses, we hypothesize that neuroglia may contribute to the pathogenesis of autism in several ways:
Neuroglia may be dysfunctional during the process of neuronal organization and plasticity of cortical and subcortical structures, a change that may contribute to the neuropathological abnormalities observed in autism.
Neuroglia may react to extrinsic factors, such as systemic immune responses, toxins, or infections, and produce disturbances in the CNS microenvironment that facilitate the development of immune-mediated reactions.
Abnormal neuroglial activation may be present in autistic patients due to genetic susceptibility to inflammation, a change that can lead to abnormalities in neuronal-neuroglial interactions.
Neuroglial activation can trigger the development of cellular or humoral immune responses that lead to neuronal/neuroglial dysfunction.
1. Systemic immune responses may trigger abnormal pathogenic reactions in neuroglia.
Our experimental approaches include study of brain tissues obtained from patients with autism, determination of the profile of cytokines and chemokines and characterization of immune-mediated reactions in cortical and subcortical regions of autistic brains. Further understanding of the role of neuroglia and immune reactions in the neurobiology of autism may contribute to the design of therapeutic interventions that minimize the neurological and behavioral abnormalities that occur in this disease.
The cornerstone research was published in two journals (“Brain Inflammation Is a Sign of Autism,” Annals of Neurology, 15 November 2004; 01:18 and “Immunity, Neuroglia and Neuroinflammation in Autism,” Internet Review of Psychiatry, December 2005; 17[6]: 485–495). The study demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism, findings that support the view that neuroimmune abnormalities occur in the brains of autistic patients and may contribute to the diversity of the autistic phenotypes.
Here are multiple other studies that almost indisputably point to NIDS (or an immune-mediated encephalopathy) as playing a role in children and adults now labeled ASD:
Science reported in October 2009 that a relatively new retrovirus, XMRV, was identified in a higher-than-normal proportion of CFS patients, and also reported similar findings for people with autism, atypical multiple sclerosis, and fibromyalgia (“Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome,” Science Magazine New York, New York, Published Online, October 8, 2009).
In February 2009, the Journal of Neuroimmunology published a study concluding that ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD (“Elevated Immune Response in the Brain of Autistic Patients,” Journal of Neuroimmunology. 2009 Feb 15: 207 [1–2]: 111–6 Epub 2009 Jan).
These 2007 studies measured the presence of autoantibodies (directed against neural antigens) in ASD patients and explored the possible role of autoimmunity in the pathogenesis of ASD (“Brain-Specific Autoantibodies in the Plasma of Subjects with Autistic Spectrum Disorder,” Annals of the New York Academy of Science, 2007 Jun; 1107:92–103 and “Autoantibodies in Autism Spectrum Disorders,” Annals of the New York Academy of Science, 2007 Jun: 1107:79–91).
Changes in T cells (and T cell function)
CD4/CD8—increased/decreased
Low (and elevated) NK cells
B cells—increased/decreased
Increased DR+ T cells
Increased interleukin-2 receptors
Decreased mitogen response
Altered delayed hypersensitivity
Antibodies to serotonin receptors
Antibodies to neuro elements
Based on the evidence presented herein, I believe that developing a focus on the interrelationship of autism, ADD, ADHD, CFS, CFIDS, and other immune-modulated conditions is a key to helping groups of these children in ways never before possible. If we can address the physiologic part of the dysfunction in these children (irrespective of its specific etiology), educational therapy, counseling, study techniques, and most/all other current therapies have a far greater probability of success. In addition, research focused on developing and initiating new therapies for “autism” is likely to be useful in treating these other interrelated childhood disorders.
Years ago in medical school, we were taught that a certain number of pediatric patients were going to have febrile seizures. They were otherwise presumed to be healthy, and they would progress to develop correctly, and essentially outgrow their tendency to “febrile seizures.” Most seizures, even in later childhood, were considered idiopathic (from an unknown cause).
In the last few years, besides all the children now diagnosed as having “autism with seizures,” I began to meet parents of children presenting with one hundred or more seizures a month, sometimes one hundred a week. As any doctor will tell you—this many childhood seizures would ordinarily be diagnosed as a neurological (not psychiatric) disorder called epilepsy. Yet, to my surprise and dismay, these parents were distraught, as lost as parents of “autistic” children, for they were being told by the top pediatric neurologists in the country that their children’s seizures were idiopathic.
I knew there was an enlarging body of good, peer-reviewed evidence that a new family of higher-order herpes viruses, HHV-6, HHV-7, HHV-8 and more, were unlike the herpes simplex viruses so many of us were taught about in medical school. These viruses wanted to go to the brain, but unlike previous models, previous teaching, they smoldered at a low grade (below the radar—stealthily). Since I had never been told a virus living on my brain was good for me, besides the explanation for the neurodysfunction evolving in adults and then children, the idea of viruses was a perfect explanation for increased seizures. As noted below, the addition of the immune system itself attacking the brain completed a picture, compatible with medical school teaching, of what we were told were “irritable foci.” When they fire off inappropriately the brain could then fire off inappropriately at large, creating a seizure!
In preparing to give a talk to these parents I was floored, then dismayed, that in peer-reviewed medical journals talking about seizures, the literature was not only full of neuroimmune, chemokines, cytokines, but by the literature at least 25 to perhaps as many as 40 percent of these children had evidence for herpes viruses in their brain, particularly the temporal lobes. The concept of the temporal lobes, herpes viruses, and seizure foci has been strengthened over the years by repeatedly confirmed findings on autopsies in children and adults. As noted above, we know HHV-6 and related viruses go to the brain. A very disturbing finding in the literature was the fact that latent (30 percent) and active (12 percent) forms of HHV-6 were found in supposedly “normal” pediatric brains on autopsy. The article stongly supported the idea that “the glial tropism and anatomical location of HHV-6 may have important implications into the pathogenesis of disease.” How can we tell so many parents their children’s seizures are idiopathic and accept missing so many likely reasons and pathogens? Again, by a system not willing to put any “marker” value on elevated titers, with the fallacies of PCR probes (which will be positive sometimes, but not consistently), short of brain biopsies, how do we verify, prove what should be clinically obvious to many by now?
In using NeuroSPECT for many years now, it has become obvious that “scattered” areas of dysfunction, vasculitis with either increased or decreassd flow, was occurring in areas that could not be correlated to existing tracks or pathways in the brain. The findings over many years now are only consistent with the idea of a virus scattered living in/irritating the brain, and/or the immune system attacking those or other scattered areas of the brain.
Case note: A ten-year-old old girl, presenting with epilepsy and autism, had NK cells of 2.8 percent, a sedimentation rate of one. With those findings alone, irrespective of other parts of her history, the likelihood she was in a neuroimmune state, had a stressed immune system, and an overwhelming probability of viral activation was clinically a sure thing. Whatever the original reason, or insult, this said there was something medically going on that I was likely familiar with, and I could likely try to help this patient. I am pleased to say, over a year later, with The Goldberg Approach (see chapter 7) seizures are almost nonexistent, negative medications are lower or removed, and she is beginning to blossom educationally and physically, as she never could before.
Reviewing the seizure literature, it turned out there were many articles supporting the potential role for herpes-related viruses, including a number on the likely role of HHV-6b in epilepsy, limbic encephalitis, myocarditis, encephalitis, febrile seizures, and MS.
Clinical Note: As a general pediatrician, before subspecializing, I had be come aware that newly identified HHV-6, the common cause of roseola in children, was possibly connected to febrile seizures.
Many articles supported these ideas, these connections, but it was becoming obvious, even for university-based pediatric neurologists, this was a direction they were not pursuing. It is worth noting that often the articles refer to the lack of conventional inflammatory changes, which is to me completely supportive of the idea of neuroimmunity being presented in this book.
With the literature validating that many febrile seizures are occurring without the previous concept of a rapid rise in temperature, understanding that many of these are not benign anymore, that many are forerunners to true epilepsy, potentially lifelong seizure disorders, mean therapy and prevention need to come to the forefront, not just watchful waiting; these “idiopathic” seizures are perhaps no longer really benign.
Along with the multiple articles or various roles of the immune system and chemokine and cytokine abnormalities related to seizures came a very interesting finding. In the “epilepsy and seizure” literature articles showed a direct linkage of the concept of peripheral inflammation mediating or leading to altered CNS excitability.35 36 It was shown that in a mouse or rat given a chemical causing GI inflammation, an increased susceptibility to seizures “strongly correlated with the severity and progression of intestinal inflammation.” If we’re not looking at proper dietary controls, if we’re giving impure supplements or agents that may be allergenic to a child, how much harm will be done? Worse, does the recognition of GI inflammation leading to brain inflammation confirm another likely cause, besides just viral, for the disproportionately large increase in seizures in “autistic” children?
This area needs a full pediatric investigation immediately. Inadvertently, many parents may be being asked to do things that are not only not helping, but may be contributing to increased long-term dysfunction and morbidity. While frustrated (to say the least) by the failure of current research ers to recognize that autism in the past had essentially no association with seizures; now when 35–40 percent of children with “autism” are prone to seizures, how much longer is it going to take to realize there is no relationship between what is happening now, and whatever we thought this was in the past?
Within the seizure literature, they are already looking at creative ways to reduce inflammation and block or prevent the attacks on the brain, I continue to believe that within this medical specialty, stepping back, looking at the bigger picture of that child and his or her general health, immunity, and brain could be a big step forward.
From a disorder being called “autism” in the 1940s and 1950s with no connection of note to seizures in those children presenting then, to the routine statement that 35–40 percent of these children today may develop seizures, is one very large additional finding that should clearly demonstrate this is not Dr. Kanner’s autism.
Over the years, consistent with the medical world documenting a significant increase in thyroid disorders in adults and children, growth disorders in children, and other pituitary/endocrine disorders in general, came the recognition and understanding that the findings on NeuroSPECT, the neuroimmune-mediated shutdown of blood flow and function going on in the temporal lobes of the brain could begin to explain some of the enlarging endocrine dysfunction that was occuring. In particular, this could explain the increasing number of cases pediatric endocrinologists were seeing and calling “atypical.” More than a decade ago, I had some very interesting discussion with top pediatric endocrinologists regarding mutual patients that were having “baffling” growth issues. Pituitary markings/ findings might make sense if they thought of the general “pituitaryhypothalamic” system as not broken, but dysfunctional—thankfully this was logical to them.
To a pediatrician, always aware of growth and development in a child, aware of expected markers or ways to detect dysfunction, it became obvious that not only were there real issues for children from GH (growth hormone) dysfunction, but as I would frequently advice a parent whose child was being evaluated but who we knew had NIDS, neuroimmune issues, that just a “static” test of growth hormone function would often be normal, when a stressed or dynamic one would be abnormal. This becomes logical in terms of a system that is not broken, but is dysfunctional.
Over the years the idea of autoimmune, dysfunctional, but not broken was illustrated by the classical teaching of thyroiditis and its ability to result in increased and/or decreased function, depending upon the disease process, and activity levels. That was not the teaching for much of what we called pituitary disorders, but now the neuroimmune connection may begin to explain a lot of what has certainly been perplexing to pediatric patients and their endocrinologists.