In Reply: Recommendation to Create New Neuropathologic Guidelines for the Postmortem Diagnosis of Chronic Traumatic Encephalopathy.

Abstract

To the Editor: Omalu and Hammers1 have misinterpreted several comments from our previous correspondence2 that was written in reply to their original Letter.3 These remarks require clarification. The definition that we quoted of traumatic encephalopathy syndrome (TES) was published in the National Institute of Neurological Disorders and Stroke (NINDS) Consensus statement4 that uses the term as the clinical correlate of the pathological entity chronic traumatic encephalopathy (CTE). Although there are many post-traumatic cerebral pathologies, TES is now accepted as the definition outlined by the NINDS Consensus statement.4 We believe that conflating this definition with other conditions will only confuse, not consolidate, the research efforts and clinical applications. The NINDS Consensus definition of TES requires a “history of substantial exposure to repetitive impacts to the head” to be present.4 Omalu and Hammers' disagreement is with the NINDS Consensus definition and not with our response; the focus of their critique should be directed toward the NINDS Consensus definition authors.4 Omalu and Hammers1 briefly described case examples, such as “a patient with post-traumatic encephalopathy with bilateral frontal lobe encephalomalacia but no tauopathy or CTE” after a single traumatic event, and suggest that this should be classified as TES. However, current best practices suggest that cognitive impairment in this individual would be conceptualized under the existing Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosis of major or mild neurocognitive disorder due to traumatic brain injury,5 depending on its severity. Of note, major neurocognitive disorder is the current term for “dementia.”5 We do not understand the utility of labeling this hypothetical patient as having TES given that it would not add additional information regarding their clinical presentation beyond the current classification system. The NINDS/NIBIB Consensus statement defining the neuropathological criteria for CTE states that “clusters of p-tau-immunoreactive astrocytes in the white matter of the frontal and temporal cortex, basal ganglia, and lateral or medial brainstem were considered consistent with aging-related tau astrogliopathy (ARTAG)6-9 and not specific features of CTE”10 and that “additional structures, notably brainstem, [with] abnormal subcortical tau pathology is a supportive feature of CTE.”10 Omalu and Hammers' disagreement regarding these neuropathological criteria is with the NINDS/NIBIB Consensus statement to which we referred, and they should direct the focus of their critique to the Consensus authors,10 not us. Omalu and Hammers stated “In their letter, Zuckerman et al2 get the established principles of CTE wrong. CTE is not defined by Aβ deposition but is a primary tauopathy and is defined and diagnosed by the presence or absence of tau deposition and inclusions.”1 Our letter did not state that Aβ was part of the CTE definition, but rather, considered Aβ as a hallmark characteristic of neurodegeneration in other conditions and noted that Aβ may occur normally, as can hyperphosphorylated tau, and that it is the anatomic distribution of p-tau that is specific to CTE. We consider that the figure presented by Omalu and Hammers1 to be problematic for a variety of reasons, several of which are discussed in our initial correspondence.2 For example, they describe postconcussion syndrome (more aptly termed persisting symptoms after concussion) as TES, yet persistent postconcussion symptoms in the absence of cerebral histopathological abnormality is not TES and can often be treated effectively with a variety of targeted interventions.11,12 Similarly, Omalu and Hammers listed dementia (separate to CTE) as TES; yet, this is patently absurd because there are a multitude of etiological causes of dementia (eg, Alzheimer disease, frontotemporal dementia, progressive supranuclear palsy, vascular dementia, etc.) that are not TES, irrespective of a history of traumatic brain injury.