THE NIDS MEDICAL ADVISORY BOARD PRESENTS:

A DRAFT PROPOSAL OF ITS NEURO-IMMUNOLOGY HYPOTHESIS STATEMENT CONCERNING AUTISM

Clinical Hypothesis - Immune "Dysfunction / Dysregulation" - A Reason for Childhood Neuro-Cognitive Dysfunction:

Autism, as classically defined, is a devastating disorder that often robs children of their ability to communicate and thrive in society. It is characterized by primary alterations in social interactions and receptive/expressive language, and is often accompanied by symptoms including ritualistic behaviors and a lack of imaginative play. Additionally, many "autistic" children exhibit a craving for sensory (vestibular) stimulation that often manifests itself in self-stimulatory behaviors (e.g., spinning and hand-flapping).

By definition, autism has an early onset before 30 months of age (which has now been extended to 36 months under the DSM-IV guidelines), while disorders appearing later in life have been thought to be symptomatically and medically different from "autistic" conditions. However, publications over the last 13 years have cast some doubt on this assumption, and it has been noted in the literature that there is no firm evidence that similar or identical syndromes might not develop in older children.

From an epidemiological standpoint, autism has migrated from a rare disorder to one that is now ten (10) to twenty (20) times more likely to be diagnosed. Ten years ago, "autism" occurred in 1-3 per 10,000 births. Now, current estimates suggest an incidence rate of 20 ñ 40 per 10,000 births. In fact, "cluster groups" throughout the world are currently being analyzed due to even higher incidence rates. It is also worth noting that other neuro-cognitive conditions such as "quiet" ADHD and "mixed" ADHD have received a renewed focus and attention among children and adolescents due to their perceived increase in incidence rates. Although a portion of these increases can likely be attributed to better and earlier recognition by the medical community and parents, the NIDS Board believes that this increase must prompt a change in how we approach these children. Specifically, we must begin to consider that these are not congenital, brain-damaged conditions but instead are medical disease processes acquired early in life.

In accordance with this premise, recent discussions have focused on the differentiation between "congenital autism" (including "classic" Kanner autism) and another form related to neurologic and medical disorders such as tuberous sclerosis, phenylketonuria, congenital rubella, and Downís syndrome. However, a third form has emerged which is being referred to as "acquired or regressive autism" (perhaps the largest sub-group of these children). For purposes of this hypothesis statement, "acquired autism" is a condition in which the child develops normally for the first 12 to 18 months of life and then regresses into the increasingly wide spectrum of "autistic" disorders.

These children challenge the previous belief that 70% to 80% of autistic children are mentally retarded. They crawl, sit up, walk, and usually attain "normal" motor milestones on schedule. Until the age of symptom onset, they are affectionate and appear to have above average intelligence. Children with acquired autism may begin to develop some speech but then, without warning, cease to progress, and begin to regress. Suddenly, these children become withdrawn. They vacillate between being quiet and hyperactive. Often self-stimulatory behaviors (i.e. arm flapping, rocking, spinning, or head banging) may develop. Over time, some manifest symptoms that are both similar and atypical of children previously diagnosed as having congenital autism. The authors propose that many of these children with acquired autism fall into the medical category of N.I.D.S. (Neuro-Immune Dysfunction Syndromes), and need to be viewed as suffering from an auto-immune medical illness that is potentially treatable.

The Past:

Unfortunately, without the tools or the technology to accurately investigate the human brain, the label of "autism" evolved as a set of symptoms in a young, dysfunctional child. In its most severe form ("classic autism"), effective speech was absent and clinicians often saw symptoms of repetitive, highly unusual, aggressive and sometimes self-injurious behavior. Those afflicted had extremely abnormal ways of relating to people, objects, or events. Parents noticed that something was "not right," often within the first three to six months of life. These children typically did not smile and often resisted affection.

Most researchers and clinicians did not look for "medical" answers to autism because they believed it was a disorder that was medically untreatable. Without the technology to understand these children, pediatricians and pediatric psychologists accepted the concepts of poor parenting, childhood psychosis/schizophrenia and classified "autism" as a psychological and/or developmental disorder. Treatment was typically delivered by psychologists and psychiatrists.

Eventually, it became well documented that known medical disorders such as tuberous sclerosis, PKU, congenital rubella, and others could cause autism. However, to date, these remain rare disorders and a small sub-group of autism. Given that researchers are just now beginning to understand the medical origins and implications of the potential therapies for these children, autism is still treated primarily by psychologists and educators (with mixed results).

Past Medical Research:

A review of the existing medical literature relative to autism research reveals evidence of an emerging medical disease process in these children. For instance, research indicates that autism can follow infectious disorders affecting the central nervous system including encephalitis.^,,, Multiple studies have focused on various anatomic locations of suspected dysfunction.^,,, It is important to note that emphasis is often put on the medial temporal lobe. Pertinent to this new "model" of dysfunction, are the multiple published reports of autistic symptoms developing in association with encephalitis in children. (Ref: 1981 DeLong, 1986, Gillberg, 1989,) Most of these reports site injury to the temporal lobes as part of their findings. This is consistent with the areas of decreased function identified on NeuroSPECT scans initially by Dr. Ismael Mena from the NIDS Board and now by Dr. Bruce Miller and Dr. Fred Mishkin, both of who have clinical research in progress.

New research techniques are increasing the rates at which Herpes Simplex Virus (HSV) sequences are being identified in temporal lobe tissues^, (i.e., locales likely to be substrates for various aspects of autism). In 1975, an article was published in Cortex describing a syndrome similar to autism in adult psychiatry. The condition involves the loss of emotional significance of objects, the inability to adapt in social settings, the loss of recognition of the significance of persons, and the absence of sustained purposeful activity after temporal lobe damage.

The literature also comments on the cognitive and behavioral deficits caused by temporal lobe damage in Herpes encephalitis. There are many reports, particularly in the British literature, suggesting a connection to coxsackie/enteroviruses, while in the United States it has been suggested that many cases may be linked to the Herpes family of viruses (i.e., EBV, HHV6, HHV7, CMV, etc.).^,,,, Neither theory has been conclusively proven, nor has the evidence for a contagious disorder been conclusive (although some have inferred it based upon incidents related to epidemic outbreaks^,) However, HSV in humans has long been known to prefer temporal lobe and limbic sites. One theory focuses on the olfactory nerves as a possible route for infection, but oral cavities may also provide entry. In 1996, OíMeara et al postulated that: "Inoculation of murine tooth pulp with HSV selectively infected the mandibular division of the trigeminal nerve and caused encephalitis predominantly affecting the temporal cortex and limbic system, a pattern of disease similar to human HSE [herpes simplex encephalitis]...."

While other studies have also implicated the temporal lobes in the pathogenesis of autism,^, a direct association between temporal lobe pathology and autism has not yet been proven conclusively. In fact, research has found a variety of lesions in the "autistic" brain, particularly in the cerebellum. These variable findings may be due to the heterogeneity (differences) in the possible etiologies or time/duration effects within this syndrome.

Although Herpes virus has a predilection for the temporal lobes, the course of autism does not suggest an acute infection with traditional Herpes viruses. However, delayed temporal lobe development early in life may produce different symptoms from those arising from deterioration or destruction of previously normal lobes.

In summary, although not conclusive, past research further strengthens the linkage of the temporal lobe and "autistic" symptoms. Boucher and Warrington noted similarities between behavioral deficits reported in animals with hippocampal lesions and autistic behavior. Medial temporal lobe damage on pneumoencephalograms was reported in a subset of autistic children. Damasio and Mauer proposed that "the syndrome results from dysfunction in a system of bilateral neural structures that includes the ring of mesolimbic cortex located in the mesial frontal and temporal lobes, the neostriatum, and the anterior and medial nuclear groups of the thalamus. At least two other studies have also implicated the temporal lobes in the pathogenesis of autism.^,

The Present:

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, immune markers, and NeuroSPECT findings support the concept of a medical disease process occurring in these childrenís 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, recent work with the NeuroSPECT strengthens the connection of blood flow abnormalities and neuro-dysfunctional 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.^, As noted, NeuroSPECT scans on children with autism have shown a decrease in blood flow in the temporal and parietal 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 dysfunction, 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.

Also, the Board has been 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, intrauterine, prenatal, 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 neuro-polypeptides 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 "auto-immune" reaction (whereby the immune system continues this pathway with no active reason to do so) or is due to the presence of a retro-viral 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.

Futhermore, 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.

Examples of autismís probable connection to immune dysfunctional states are:

Extensive clinical work over the last four to five years further supports the Boardís 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. Among the main examples are:

1. Multiple researchers have found evidence that autoimmunity is a possible mechanism to explain autistic symptoms.^,,,,
2. An increased incidence of two or more miscarriages and infertility as well as pre-eclampsia and bleeding during pregnancy have been shown to occur in mothers of autistic children. There are also multiple studies in the obstetrical literature connecting these events to immune autoantibody production.
3. Studies have been done comparing the maternal antibodies of mothers with their autistic children, suggesting an association of abnormal maternal immunity with autism. Antibodies reactive with lymphocytes of fathers of autistic children have also been found.
4. Multiple researchers have shown an interaction of maternal antibodies with trophoblast or embryonic tissue antigens, and a cross-reaction with antigens found on lymphocytes.^,,,
5. Researchers have also shown a significant depression of CD4+ T helper cells and their suppresser-inducer subset^, with an increased frequency of the null allele at the complement C4B locus in children with autism. As similar changes have been known to occur in other autoimmune diseases,^, 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 by the Board have shown very high CD4 and CD8 counts, low natural killer (NK) cells, or other "markers" consistent with immune dysfunction/ dysregulation).
6. Abnormalities of Cell Adhesion Molecules (NCAM) have been reported.
7. Antibodies to neurofilament axonal proteins (NFAP) have been noted in autistic children ^56a and have been reported in neurotropic slow virus diseases (Kuru and Creutzfeld-Jacob disease) in adults. Other studies^, 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."
8. Anti-central nervous system serum immunoglobin reactivity has been reported that was specifically directed against the cerebellum. ^56a
9. A small percentage of autistic children with demonstrable immunologic abnormalities have normalized their autistic symptoms with intravenous immunoglobulin treatment. ^{59a 59b} This result shows that immune abnormalities can cause autism in a subset of children and that "acquired autism" can be effectively treated.
10. Singh et al. hypothesized that autoimmunity secondary to a virus infection may best explain autism in some children. Congenital rubella virus and congenital cytomegalovirus have been indirectly involved as causative factors in autism.

Given this support from the medical research literature, the concept of immune dysregulation as a medical disease process in childhood neuro-cognitive dysfunction is an emerging reality. This concept could easily account for a portion of the increase of neuro-cognitive diagnoses over the last ten years. Whether the etiology of this dysfunction is related to environmental factors (e.g., ozone layer depletion, local toxins, etc.), new retro-viruses, stealth, spongiform or other viruses (or altered viral responses), we now have a medical hypothesis that can facilitate the definition of clinical sub-groups and lead to the treatment of these patients without first determining the 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 either 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 recent study on Chronic Fatigue Syndrome (CFS), two NIDS Board members 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.

Based on the evidence presented herein, the NIDS Board believes that developing a focus on the inter-relationship 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 are likely to be useful in treating these other inter-related childhood disorders.

The Future:

As outlined, we have witnessed the evolution of what is now being recognized and accepted at the National Institutes of Health (NIH), the Centers for Disease Control (CDC), and academic institutions world-wide as a "neuro-immune" epiphenomena. Studies are now confirming the concept of physiologic immune-mediated diseases underlying an abnormal physiologic state for these patients. This, in turn, creates both physical and neuro-cognitive deficits and dysfunction, usually of long-term duration.

The NIDS Board believes that many of the characteristics ascribed to autistic (and "quiet" ADHD) children overlap with the multiple complaints of adults afflicted with components of CFS/CFIDS and adult "ADHD". As previously noted, all of these groups have reports of various immune abnormalities including T-cell changes reflected, for example, by increased or decreased CD4/CD8 cells, increased / decreased NK and B cells, and altered viral titers. It is this common denominator of immune alterations that gives hope for potential new therapies in the near future for these children.

However, while this hypothesis now has support in the literature, there are many important questions to be answered. How many "autistic" children have evidence of or are linked to an immune-dysfunctional state or a conclusive viral etiology? Can these children be viewed and treated differently than the "classic autistic" child of 20 to 30 years ago? Is their prognosis for recovery significantly better than the "classic autistic" children from the past?

It is time to recognize that these children are likely suffering from a medical disease process and need our clinical and research efforts now! Current treatments need to be modified and adjusted to account for this finding. The symptoms of the "quiet" ADD child (who is likely connected to this phenomenon) is not consistent with the past training or processes used to "explain" and address the "hyper" ADD child. It seems likely that the cognitive defects described in adults and children with CFIDS may be thought of as milder, later-onset form of "autism", as they are similar in symptomatology and possible etiologies. The continued exploration of an immune-dysfunctional epiphenomena, and the potential etiologies linked to it, is a door we must walk through if we expect to change the future of this generation of children!

It is the proposed mission of this Board to accelerate the integration of the above clinical and research findings to facilitate the employment of new (and perhaps some older) immune-modulating therapies in the treatment of "acquired autism", ADD/ADHD and CFS/CFIDS. We believe that by helping to "regulate" or "normalize" the immune system, we can restore health to these children. Through our unique acceleration of clinical knowledge and academic research, there is a chance to recognize and treat this disease process while these children are still young and while there is still time to effectively help their cognitive development.

NIDS Medical Board Members