Sometime in the nineteenth century a German physician by the name of Rudolph Virchow described the different symptoms that constituted an inflammatory response. Thus, we would call a knee as being inflamed, if according to Virchow, it was swollen, red, tender and felt warm to the touch. The genius of Virchow was not in the description of symptoms but in predicting that the disparate symptoms of inflammation would entail a large number of interacting mechanisms.
We now know that the body responds to a noxious stimulus in a stereotyped manner by mobilizing specialized cells to the injured site. Chemical signals released by the injured tissue dilate blood vessels which thus engorged provide for redness and a feeling of warmth. Leakage of fluid from the dilated vessels into adjacent tissue provides for swelling. Expansion of the swollen tissue provides for stretched nerve endings which along with other released chemicals are perceived as pain. This knee jerk response is called innate because it happens in response to any injury. Adaptive immunity on the other hand is specific to individual pathogens.
A few years ago an article popularized the notion that there was an “inflammatory” response in the brains of autistic individuals. The subject population was derived from an autopsy series wherein autistic individuals as compared to neurotypicals had an increased number of non-neuronal supporting cells that usually carry housekeeping functions within the brain (i.e., astrocytes and microglia). Unfortunately, partisan groups soon hijacked the article as proof of exposure to a toxic element or viral infection. The fact that the study came from the Neuropathology Laboratory at Johns Hopkins seemed to add credence to the report. While the findings described in the article are real, the nature of this so-called inflammatory reaction deserves further attention.
First of all, the article did a disservice by calling their findings an inflammatory reaction. Contrary to Virchow’s classical description of inflammation, the presence of a vascular response in the brains of autistic individuals has never been proven. A number of studies using either postmortem tissue or samples of the liquid that bathes the brain (cerebrospinal fluid) have never shown leakage of vascular elements. The number of cells and amount of protein in cerebrospinal fluid of autistic individuals is normal. After voicing some concerns about both the findings and applied nomenclature some of the more sophisticated researchers relabeled their findings as “neuroinflammation” rather than inflammation. In this regard they meant to emphasize an increase in the supportive cellular elements of the brain in spite of an absent vascular component.
In a recent international meeting held in Barcelona I was able to partake in dialogue with Sue Swedo from the NIMH. Sue was in the process of collecting data for one of her massive studies on autism. One of the components of her study was made in association with the authors of the previously mentioned Johns Hopkins study. Sue’s intent was to investigate the putative presence of inflammatory elements within the cerebrospinal fluid of autistic individuals. According to Sue, after breaking the blind, nothing has been found. The negative findings make sense for the following reasons:
1) A diagnosis of autism does not include the presence of fever, muscle/joint pains, or somnolescence that would be indicative of systemic inflammation.
2) Postmortem examination has never revealed the presence of engorged vessels or the recruitment of white blood cells, rather, findings are indicative of an intact blood brain barrier.
3) There is no evidence of an adaptive response to specific pathogens. Immunocytochemical studies have failed to identify T- and B- cell lymphocyte infiltration or the deposition of immunoglobulin/complement proteins in brain tissue of autistic individuals.
4) The negative findings also make sense from the standpoint of the natural history of autism. Autistic patients, in many cases, get better with time. By contrast, the presence of an ongoing inflammatory response in adult individuals would suggest a clinical deteriorating course for the patient.
If the postmortem findings of the Hopkins study are real, how can we make sense of them? A survey of available postmortem tissue collected by the Autism Tissue Program (ATP) helps explain the findings. As of July 2007 the ATP had collected brains of 35 autistic patients. Eleven of these patients drowned, 1 stated no cause of death, and 23 died of diverse causes including seizures, circulatory failure, sepsis, anoxic encephalopathy, and acute respiratory distress. Of the eleven drowning victims 3 had missing medical records and autopsy findings, 2 received CPR and survived for an undetermined amount of time. It thus appears that the vast majority of postmortem tissue available for research came from patients that suffered from some type of insult that deprived them of oxygen (anoxia or hypoxia) during life or in the hours before death. In some cases, anoxic patients were resuscitated and survived for undetermined periods of time before being declared dead (e.g., near drowning victims).
Tissue that is anoxic and then reperfused exhibits its own pathology (hypoxia-reperfusion injury). After re-establishing circulation fresh blood on a hypoxic site procreates a gigantic free radical reaction. These active chemicals (free radicals) target long carbon-carbon chains having double bonds. A special type of cell (oligodendrocyte) that provides for the insulation of neuronal cell projections is preferentially affected. Injury under these conditions occurs preferentially, but not exclusively, within the white matter. This is the type of injury reported in the Hopkins’ article. One has to wonder how much of the findings relate to how the patients died rather than to autism.
I do believe that patients with autism are selectively vulnerable to inflammatory responses and can be stressed by increasing their oxidative load. I will write a blog in this regard sometime in the future. In the meanwhile I do believe that we have to take with a grain of salt much of the available literature.
Casanova MF. The Neuropathology of Autism. Brain Pathol 17(4):422-433, 2007.