In Reply We appreciate the interest and comments of Palma et al regarding our recent review about the onset of synucleinopathies.1 The review was based on epidemiological evidence. Notably, there have not been sufficient epidemiologic data that examine some of the early manifestations or symptoms for some aspects of synucleinopathies. As an example, the prospective study performed by the Autonomic Disorders Consortium on the natural history of pure autonomic failure was based on 100 patients.2 Although the sample size is large for a pure autonomic failure study, it is a relatively small number when compared with larger population-based epidemiology cohorts. Likewise, orthostatic hypotension is one of the most important signs of dysautonomia in synucleinopathies. We agree with Palma et al regarding the importance that orthostatic hypotension may have in the diagnosis and prognosis of an evolving synucleinopathy. Unfortunately, there are not enough epidemiological studies on orthostatic hypotension. Thus, we did not include orthostatic hypotension in our model. We agree that smell sense is relatively preserved in multiple-system atrophy compared with other synucleinopathies, but the epidemiological evidence on anosmia are scant given the difficulties of studying anosmia in larger populations other than using smell sense tests prospectively and systematically.
Savica R, Boeve BF, Mielke MM. Orthostatic Hypotension as a Prodromal Marker of α-Synucleinopathies—Reply. JAMA Neurol. 2018;75(9):1155. doi:10.1001/jamaneurol.2018.2251
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