Everybody has suffered from some type of inflammatory condition. Inflammation is a common symptom reflecting that something harmful is happening to your body. Contrary to popular belief inflammation is not restricted to infections but, rather, it is a reaction against anything that irritates the body or causes some type of damage to it. In this regard inflammation is a generic response stemming from the body’s innate immune system.
During the inflammatory process blood vessels at the site of injury dilate thus allowing blood to pool or dwell for a longer period of time at the site of injury and for some of its contents to pass into the tissue. This makes the site of inflammation red, swollen, and painful. Under the microscope inflammation can readily be seen by the engorgement of vessels and by some red blood cells becoming closely apposed to the vessel wall. Plasma permeates the blood vessel walls and goes into the injured tissue causing edema and, depending on the stage of the reaction, having different types of white blood cells enter the injured tissue.
Many people have long been proponents that autism is the result of an inflammatory reaction in the brain. For many years my good friend Andy Zimmerman at Hopkins used to be one of its proponents and based his research directly on this assertion. Andy used to draw cerebrospinal fluid (CSF: the liquid that bathes the brain) from lumbar punctures and study its contents for the presence of markers for inflammation. This liquid usually has a very low concentration of proteins and in cases of inflammation this concentration rises significantly. Least to say Andy’s studies were perennially negative: CSF pressure, concentration of proteins, and presence of white blood cells were always within normal limits. Andy’s results made sense as autistic individuals do not have the clinical signs of either meningitis or encephalitis. Furthermore, evidence of an active inflammatory response in these individuals would point towards an ongoing deteriorating process, one probably leading to profound cognitive impairment, severe central nervous symptoms, and death. This is not consistent with the natural history of autism.
This was the natural state of things until a study, also from Hopkins, was published in 2005 (Vargas et al. 2005). The first author was Diana Vargas but the senior team member was also another good friend Carlos Pardo. The study used different techniques to show evidence that some of the cells that participate in the brain’s innate inflammatory response (i.e., astrocytes and microglia) were pathologically increased in autism. All of the techniques employed by the authors, e.g., histology, immunocytochemistry, fluorescent microscopy, and blots quantitating concentration of proteins, were in agreement. There was little in denying that the authors observed gliosis in the brains of autistic individuals. Note gliosis according to Wikipedia: “is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar” (https://en.wikipedia.org/wiki/Gliosis).
Although the findings in the Vargas et al (2005) study were real, they probably reflected significant differences between the autistic and control populations used in the study. Most autistic individuals died suffering from lack of oxygen and, in many cases, after resuscitation and survival for a certain period of time. I have always said that the pathology described in the Vargas study was that of ischemia-reperfusion injury (lack of oxygen caused by slow or absent blood flow followed by reperfusion of oxygen rich blood) and in essence the findings reflected how the patients died rather than a core finding of the condition.
The robust gliosis reported in the Vargas et al. (2005) study would have meant that the patients would have died eventually from the inflammation or have had a monumental expression of symptoms before they died. Despite the nonsensical nature of the findings, the Vargas article was received with much fanfare in autism news circles. According to Google Scholar the article has received 1193 citations in the medical literature making it a classic.
It must be said that the Vargas’ article created, unknowing to the authors, a lot of damage to autism research. It derailed a lot of research into a cul-de-sac of doubtful findings. Furthermore, it was taken up as the emblem of a certain faction within autism circles that called for anti-oxidant therapy and simultaneously helped propelled a commercial market for this type of therapy. Ever since this article, others have reported similar findings in the literature. Those written based on postmortem material were directed by people having no neuropathological training, wasting precious tissue, using inadequate techniques, and reporting worthless findings.
Now the Hopkins group has published a follow up to their original study (Pardo et al., 2017). In it the researchers studies blood and cerebrospinal fluid from 104 participants with autism and 54 typically developing controls to determine potential mediators of an inflammatory response. In the following paragraphs I will provide the authors’ own results and conclusions:
As compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism. Some modulators of immune function (e.g., EGF and soluble CD40 ligand) were increased in the autism group; however, no evidence of group differences in traditional; markers of active inflammation (e.g., IL-6, TNFa, IL-1b) were observed in the serum…”.
“These longitudinal observations fail to provide support for the hypothesized role of disturbances in the expression of circulating cytokines and chemokines as an indicator of systemic inflammation in autism.”
I think this article, although very important, will never reach the level of citations as the Vargas et al. (2005) manuscript. People will likely consider their own theories blindly to the available data.
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57(1):67-81, 2005.
Pardo CA, Farmer CA, Thurm A, Shebl FM, Illieva J, Karla S, Swedo s. Serum and cerebrospinal fluid immune mediators in children with autistic disorder. Molecular Autism, published 5 January 2017. Open access DOI:10.1186/s13229-016-011507
This is very interesting.I had looked off an on for years for a specific connection between autism and meningitis,with little success.I had acute meningitis with pneumonia as an older infant.My mother always told me,I suffered my first autistic regression as a result.My first of many,triggered by acute infection or illness,She told me the differences in my behavior were striking before and after the illness.My mother may or may not have been decades ahead of her time,as it has only been in recent years,researchers and clinicians have been able to detect autism in infants.
It is likely most forms of autism have some degree of neuroinflammation,but it may only be in regressive autism,where the inflammation is more profound,more obvious and levels of markers like cytokines and chemokines are more abnormal.Most regressive autism is likely due to underlying immune,or metabolic,disorders.
Roger, I agree that multiple autistic behaviors are likely of non-progressive inflammations and further that “increases” in action potential velocity “differentials dyscoordinate their integration at downstream neurons”. (Newton, JR 1999)
The recent large gene-imaging studies together strongly suggest
regional structure/volume abnormalities for multiple diagnoses.
thanks for deflating the hype around another autism cure fad.
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Events of large epistatic SNP combinations and environments strongly influence “increased” brain regional volume, and other “differentials”, in multiple psychiatric diagnoses. see (Newton, Joe Ray 1999)
A huge problem is the lack of established biological markers for optimum diagnosis of all psychiatrics.
Unfortunately there is a pay wall on the Vargas paper and DOI:10.1186/s13229-016-011507 was not found so I can’t comment .