By Rudy J. Castellani MD, Professor of Pathology and Neuroscience, West Virginia University and Rockefeller Neuroscience Institute
I am a neuropathologist. In my practice, I diagnose diseases of the nervous system. In living patients, this may involve interpretation of brain tissue samples that could fit on the head of a pin. I also diagnose nervous system diseases involving entire human brains, often at the request of forensic pathologists charged with the task of determining cause and manner of death. The examination may assist criminal investigations by characterizing patterns of homicidal abuse, for example, or by identifying unexpected natural disease processes. To be sure, neuropathology can be a powerful diagnostic tool. Unfortunately, such a powerful tool also risks exploitation. If the neuropathologist strays from uncompromising adherence to objective analysis, entire lines of scientific inquiry may become “fruit of the poisonous tree.”
Causal theory surrounding chronic traumatic encephalopathy (CTE) is especially problematic in this regard. The role of repetitive subconcussive head trauma in the appearance of interpretive microscopic phenomena decades later is unknown and unknowable. Neither cause nor effect is defined in that equation. The truth is that CTE is little more than a curiosity of immunohistochemistry. CTE in the absence of sport or traumatic brain injury is well described in scientific literature, if largely unreported in the media. Seminal index cases in both boxing and football, jarringly misinterpreted, add to the confused mosaic, while rare and tragic high profile suicides, along with intense media exposure, lend a metaphysical quality to CTE, and false beliefs within broader society that are impossible to decontaminate. Suicide notes describing the struggle with a fictitious disease process are sobering reminders about the danger of mixing advocacy campaigns with mischaracterized and misunderstood science.
The social realm of “CTE awareness” may present a greater challenge than the problem of pseudoscience in CTE research (i.e., research efforts with pre-ordained conclusions).The acknowledgment in a semi-public forum that questions of causation remain unanswered leads quickly to ad hominem attack from CTE theorists. This has created a second CTE-specific cultural phenomenon, where a majority of genuine experts are dismayed and appalled by the scientific over-reach, but remain silent.
As someone who has studied many thousands of human brains and thousands of immunohistochemical stains for tau protein, I should break the silence by pointing out that a report suggesting putative CTE in 99% of NFL athletes (JAMA 2017;318:360-370) is neither surprising nor concerning. One might argue the obvious, that such studies lack a denominator, but that misses the point. The real problem is the mockery such reports make of the diagnostic process.
Current methodology involves whole brain screening: a fishing expedition for something that accumulates in everyone with age, and then the perception of a pattern within that accumulation. This pattern, which is inherently subjective and “preliminary” according to those who described it, has an unknown error rate among observers, no lower limit for diagnosis, no requirement for discernible trauma, no requirement for neurological signs during life, and no requirement for secondary review by independent experts blinded to sport history. The simple fact is that the NFL cohort has better cardiovascular health, less cancer, a lower suicide rate, and a lower mortality rate than men in the general population (Am J Cardiol 2012;109:889 — 896). If 99% of this cohort also has “CTE”, what exactly are neuropathologists diagnosing besides a marker of superior occupational health?
It is also a matter of concern that the above described exercise in postmortem diagnosis legitimizes pure ipse dixit interpretation (Some of the diagnostic challenges are reviewed in: J Alzheimers Dis 2019;67:447-467). The pressure from families pursuing damages from third parties, the multitude of biases on the part of interpreters, the permissiveness in criteria, and the autopsy setting in which there are no patient consequences for misdiagnosis, risk findings of personal preferences rather than genuine disease. One Mayo Clinic study actually used the word “adjudicate” in reference to the CTE diagnosis (Acta Neuropathol 2015; 130: 877—889). The reader should be under no illusions. Many deceased individuals are diagnosed with CTE, and will be known in posterity as having had CTE, not because they had a distinct neurodegenerative disease caused by sport (they did not), but because someone said so. That should give any judge cause for concern in CTE-concussion litigation.
In short, CTE theory as we know it today is fruit of the poisonous tree: rooted in misinterpretation of anecdotal cases, and sustained by pseudoscience. Sadly, it does not end there. The linking of CTE theory with known neurodegenerative diseases (such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis) and with suicidality, as promoted by advocacy-based media campaigns, has managed to infect the psyche of countless men with a disease they do not have, sometimes with tragic results. As recently noted in an article signed by 61 neuroscientists, “…individuals with potentially treatable conditions, such as depression or post-traumatic stress disorder, might make decisions on their future on the basis of a misplaced belief that their symptoms inevitably herald an untreatable, degenerative brain disease culminating in dementia.” (Lancet Neurol. 2019 Mar;18(3):231-233).
CTE theory as we know it today is a template for science fiction of historic proportions, as the narrative pursued in litigation is both scientifically bankrupt and causing measurable harm to society. The appeal here is to recognize that the typical civil complaint claiming CTE is, by definition, devoid of scientific causation. Claims to the contrary are rooted in something other than empirical observation and evidence-based medicine, and need to be challenged.