Reply: Is Pathology Always the Diagnostic Gold Standard in Neurodegeneration?

We read with interest Dr. Espay's viewpoint regarding the place of pathology in defining disease.1 He describes a fascinating case challenging how we ultimately classify disease—a patient with a progressive dystonia-ataxia syndrome and a supranuclear gaze palsy who fulfilled pathological diagnostic criteria for PSP, but was shown to harbor a variant in the TGM6 gene that they postulate ultimately led to the tau pathology.2 Medicine, and the way in which we come to a medical diagnosis, is ever evolving. As a neurologist one typically starts by localizing the clinical problem, and then considers pathologies known to affect this area. The available paraclinical tests, antibodies and genetic analyses are ever growing. Which of these gets the ultimate say on the diagnosis is subject to revision as knowledge expands. Our case demonstrated clear clinical-pathological correlation over a decade of follow-up.3 The right sided chorea correlated with pathological findings in the STN. The Wallerian degeneration and atrophy of the left > right corticospinal tract correlated with the eventual development of right hemiplegia. Both clinical presentation and pathology are relevant to nosology. Dr Espay asks: could an autoantibody have caused or contributed to the visualized tau deposition in a man with aPL antibodies and thrombocytopenia? Indeed, given the chorea and antiphospholipid (aPL) antibodies without an obvious alternate cause, we elected to treat empirically with pulsed IV steroids, IVIG and methotrexate. The aPL antibodies and thrombocytopenia normalized but there was ongoing neurological progression, making a causal relationship unlikely. Furthermore, at autopsy there was no microangiopathy that might have been expected had there been a causal relationship and we know that aPL antibodies are common in the general population.4 Anti-IgLON5 related tauopathy is a fascinating disorder that makes us think about correlations between neuroinflammation, neurodegeneration and genetics. This condition has an expanding clinical phenotype, and emerging pathological correlates and genetic associations. As testing for this antibody was not available when treating our patient, we cannot refute that this antibody or another as-yet-unknown antibody potentially existed. There are different pathological distributions of tau between PSP-PNLA and anti-IgLON5 cases,5 both the pathology and its distribution are worthy of consideration. Furthermore, sequencing of the MAPT gene did not reveal any pathological mutations. However, he was found to have the MAPT H1/H1 genotype, a known and common genetic risk factor for PSP pathology. Reporting novel clinical presentations with pathological findings on autopsy remains worthwhile. Consider how we classify dementias, one could group dementias based on site of lesion, histopathology, clinical features, or etiology—reliance on one alone would cause error but an integrated nosology brings both clinical and experimental benefits.6 As our understanding of disease pathways evolves, so our nosology will have to also. We thank Dr Espay for his thoughtful comments. 1.Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. RS: 1A, 1B. MM: 1A, 1B. BJ: 1B. KJ: 1B. RE: 1B. BSE: 1B. LAE: 1B. GK-F: 1A, 1B. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report. Ethics committee review was not indicated for this case report, but the authors adhered to the Declaration of Helsinki throughout the process. Written consent was obtained from the patient for the purposes of case report preparation. All authors have read and complied with the Journal's Ethical Publication Guidelines. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

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