The Autism Society Event and Education Recordings Archive

To effectively manage the ever-increasing number of children with autism, the need of the hour is evidence- based approach towards newer therapeutic techniques. Emerging concepts associating autism and inflammation suggest that "bodily symptoms could be the manifestations of signaling and metabolic derangements that may have widespread effects integrally related to what we now call autism." They also imply that treatment targets could be identified in any of the pathways that underlie tissue inflammation.

Presented here is our in-vivo experience in a novel biomedical approach towards autism that involves integrating traditional medicine and advanced scientific knowledge and targeting "chronic inflammation" as the common denominator. The biological and molecular basis of this therapeutic hypothesis and the outcome of a five-year prospective clinical study are discussed.

Molecular Basis of Chronic Disease

Autism is clearly heterogeneous. Instead of studying it through a symptom-by-symptom approach, autistic behaviour could be better understood by studying the underlying intermediary biological processes. The underlying macromolecular computing system of RNA protein- and protein-to-protein interactions appear to be the result of fine-grained information, encoded and accumulated over evolutionary time. Regulatory complexity and dysregulation in neural gene expression have a major influence on cognitive, emotional and synaptic functions.

A large body of evidence now links the molecular pathways of cellular stress response to the onset of chronic inflammation associated with chronic diseases. A human cell in resting homeostasis contains precise “molecular order” composed of millions of RNA-protein interactions located in “acceptable” regions of shape and space. When the trigger of stress exceeds the “robustness” limits of cellular networks, “molecular disorder” gradually ensues, disturbing the homeostasis. As the stress vector impacts the molecular machineries in its path, Disorder Associated Molecular Patterns (DAMPs) appear in the microenvironment. The cellular sensors recognize these DAMPs and initiate pathways of inflammation to respond to the increased levels of molecular disorder. When this reparative inflammation process fails to reach its endpoint, molecular damage and disorder begin to accumulate. “The wrong macromolecules at the wrong place, at the wrong time generate chronic inflammation, tissue degeneration and chronic disease.”

Autism as a Model of Inflammation-Associated Chronic Disease

Endoscopically Reflux oesophagitis, gastritis, duodenitis, reduced motility and constipation have been documented. Many have reported altered mucosal immunity and atypical immune responses to certain dietary components. An animal model of inflammatory bowel disease with activation of areas of brain implicated in autism has been reported. The identification of oxidative stress, vasculitis, neuro-inflammation and potential hypo-perfusion direct our attention towards systemic mechanisms underlying brain changes in autism. Implication of mast cells in gut–blood–brain barrier disruption [BBB] suggest that symptoms of autism could be intensified by chronic inflammatory molecules generated in the GI tract.

On a molecular basis, a recent genomic study of gene expression from twins divergent in their autistic phenotype, the majority of differentially expressed genes relevant to neural development closely mapped to a network centered on TNFα and other inflammatory genes. This study lends molecular support to the neural inflammation study on autism. A recent study has shown that inflammatory complement proteins are expressed in neurons resulting in nearby synaptic pruning. Circulating inflammatory cytokines gradually break down the BBB, introducing permeability to cytokines and inflammatory factors.

Unrestricted by boundaries between the body and brain, the consequences of inflammatory factors in the destabilization and loss of synaptic connections can be significant. A recent neuro-imaging study to evaluate motor execution in autism has demonstrated "decreased connectivity" lending "functional significance" to these underlying molecular events. Several studies indicate and emphasize the influence of specialized neuronal pools of limbic and mirror neuron systems in empathy, processing and communication skills. Thus, in autism, inflammation and decreased connectivity could hamper simultaneous and complex coordination between functional areas of the brain, resulting in impaired social and communication skills.

Our hypothesis proposes that dietary or environmental triggers affecting the gut microbiome produce systemic inflammatory cytokines on a chronic basis. This downstream inflammation could signal upstream molecular unrest, ultimately affecting synaptic connectivity in susceptible individuals. We postulate that autism may function under a “two-hit’ onset mechanism, where a "permissive genetic landscape" must interact with a series of environmentally destabilized dominoes, such as those described above.

Based on such evidence-based hypothesis, we deviate from the "hard-wired" concept that possibly paints an untreatable stigma to autism. We propose that by "effectively treating the downstream inflammatory pathology, we could initiate reestablishment of upstream molecular order." Molecular order restored could activate the dormant neuronal pools, improve connectivity and restore functional integration.

“Integrated therapy” is the treatment protocol we conceptualized and standardized towards this goal. Integrated therapy is "therapeutic integration of chosen traditional Indian treatment methods applied in synergy with disease-based research of mainstream medicine."

Synergy of Integrated Therapy with Molecular Mechanisms

• The components of integrated therapy are medicines and techniques derived from the traditional Indian medical systems of Yoga, Ayurveda and Siddha.
• These ancient medical techniques practiced for centuries postulate that the "state of health" is a balance of bio-energetic forces called Vata–Pitta and Kapha.
• These ancient therapeutic systems are built on the hypothesis that inefficient elimination of bodily toxins imbalance the bio-energetic forces, resulting in chronic ailments.
• Their corrective therapeutic concept is toxin elimination – rejuvenation and regeneration.
• We found this therapeutic concept of the traditional Indian medical systems in complete synergy with the present-day technological understanding of chronic disease as cellular stress, molecular disorder, cytokines and signal triggers between body and brain.

Methodology of Integrated Therapy

Patient selection

The admission of patients is based on standard tests (DSM-IV guidelines), and the patient pool represents a spectrum of severity observed in autistic patients in general. The Childhood Autism Rating Scale (CARS) and M-CHAT are the standard assessment tools used. The children range in age from 3 to 14 years. Their racial origin is Asian. The patient pool consists of 15 individuals on different follow-up periods and who have been on this therapy since 2004.

Therapeutic protocol

• The prescribed diet is a simple, natural and easily assimilated "Sathvik Diet" practiced by the science Yoga. Animal proteins, wheat and milk products are strictly avoided, except buttermilk and ghee.

• Herbal medications, certified by the Ayurvedic (including Siddha) pharmacopia of India are administered. They are oral formulations, administered daily and absorbed through lingual route.
• Yoga technique is a combinatorial approach. Progressively from passive manipulation, these children improve to execute and maintain yogasanas through command.
• Ayurvedic oleation therapies with medicated oils are done once in 4 months for consecutive 14 days. Therapy techniques are varied in cyclic manner.

Ethical & safety guidelines

• A well-informed consent is obtained from parents.
• The therapy techniques and medicines are chosen by evidence-based risk-benefit ratio, proven over centuries in their clinical science.
• On a one-to-one basis, qualified professionals document therapy on paper and video.
• Clinical safety is further ensured by evaluating pretreatment EEG and periodic monitoring of biochemical parameters to assess renal, hepatic and hematological functions.

Controls

We follow each patient, from the time of admission through their recovery (or lack of it). Thus, each participant in the study will serve as his/her own control.

Discussion on the benefits obtained and results

• The immediate benefit observed is alleviation of painful gastrointestinal symptoms, like constipation, hyperacidity and Gastro Esophageal Reflux Disease [GERD].
• The reduction in GERD improves the sleep pattern and hence the daytime behavior. Reduced GERD- induced respiratory infections lessen the need for antibiotics and reduce damage to intestinal microflora.
• Yogasanas improve somato-sensory perception and sensory-motor coordination. Together with the oleation therapies of ayurveda, the intestinal function improves significantly.
• Endocrine regulation is seen in the form of improved menstrual flow cycles in the female individuals.
• Improved eye gaze is evident within the initial 2-3 weeks of therapy. It precedes improvement in response, attention and reduction of hyperactivity. Subsequent to the development of eye contact, we observe measurable genesis in body language and speech development.
• With every cycle of ayurvedic oleation therapy, there is improvement in the emotional behavior and the development of empathy.Concurrently, we notice the development of learning by imitation and meaningful communication.
• Improvement is influenced by the age of induction into therapy, duration of follow-up and compliance with the details.
• In our five-year clinical experience, we identified parental compliance to be proportional to the trust in therapy. We also found matrimonial issues, family pressure, inputs from the Internet, normal school inclusion, subsequent pregnancies and siblings as variables that can make or break positive outcomes.
• Willful or accidental default in medicine or dietary regime "influenced by the above-listed variables" resulted in temporary return of symptoms. Such events helped us understand the therapeutic role played by components of therapy in a better way.
• Eye Contact, Play, Communication, Empathy and Generalization are the behavior domains in ascending order of evolution, chosen to assess and quantify behavior and cognitive improvement.
• Out of 15 children in different periods of follow-up, optimum generalization ability is obtained in four individuals on continuous therapy and follow-up for more than 30 months.
• These four children are successfully studying in normal school and can read, write and speak in two languages. We aim to replicate it on the children who follow.

Conclusion

• The focus of integrated therapy is to normalize GI tract inflammation. In our five-year clinical study, along with significant alleviation of painful GI tract symptoms, we found improved functional connectivity indicated by quantifiable improvements in behavior and cognition.
• In the absence of a reliable bio-marker, the observed improvements in behavior and cognition domains are the only non-invasive indicators of restoration of molecular order and integration of the upstream neuronal pools.
• Consistent replication of observed phenotypic data on individuals thus treated lends validity to this biomedical approach towards autism. This clinical outcome also supports the hypothesis that chronic inflammation could indeed be the common denominator for connectivity and processing abnormalities resulting in autism.
• With this preliminary clinical outcome, we contemplate generating carefully characterized full-genome expression profiling data to validate our biomedical approach and to study the involvement of the intestinal flora in the inflammation-related etiology of autism.
• We propose to examine the gastrointestinal metagenomic analysis of intestinal flora, blood-gene expression and non-coding RNA (ncRNA) expression profiles on lymphoblasts in a series of before and after comparison-based molecular studies.
• This might generate direct evidence in favor of a causal relationship between systemic inflammation and autism, generate diagnostic determinants for definition of this variant of autism, and define a link between diagnostics and treatment by this and any future treatment technique.

Contribution of the Session to the Best Practice and Advances in the Field of Autism

In the research on treatment of autism, this endeavor aims to create a positive platform where biomedical treatment targets could be effectively used to achieve functional connectivity and independent existence.