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Essential Tremor versus “ET-plus”: A Detailed Postmortem Study of Cerebellar Pathology

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Abstract

Essential tremor (ET) is among the most prevalent movement disorders, and by some accounts, the most common form of cerebellar degeneration. Over the past 15 years, we have carefully documented a large number of postmortem changes within the cerebellum; these cerebellar changes differ significantly between ET and controls. A recent Consensus Classification of tremor proposed that ET patients with other neurological signs aside from action tremor (e.g., parkinsonism, ataxia, cognitive changes, dystonia) should be segregated off as “ET-plus”. This diagnostic concept has raised considerable controversy and its validity is not yet established. Indeed, “ET-plus” has not been distinguished from ET based on differences in genetics, pathology or prognosis. Here we determine whether ET cases differ from "ET-plus" cases in underlying pathological changes in the postmortem brain. We examined postmortem brains from 50 ET cases (24 ET and 26 ET-plus), using a set of 14 quantitative metrics of cerebellar pathology determined by histologic and immunohistochemical methods. These metrics reflect changes across the Purkinje cell (PC) body (PC counts, empty baskets, heterotopias), PC dendrites (swellings), PC axon (torpedoes and associated axonal changes), basket cell axonal hypertrophy and climbing fiber-PC dendrite synaptic changes. ET and ET-plus were similar with respect to 13 of 14 cerebellar pathologic metrics (p > 0.05). Only one metric, the linear density of thickened PC axon profiles, differed between these groups (ET = 0.529 ± 0.397, ET-plus = 0.777 ± 0.477, p = 0.013), although after correcting for multiple comparisons, there were no differences. If ET-plus were indeed a different entity, then the underlying pathological basis should be distinct from that of ET. This study demonstrated there were no pathological differences in cerebellar cortex between ET versus ET-plus cases. These data do not support the notion that ET and ET-plus represent distinct clinical-pathological entities.

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Acknowledgments

This work was supported by the National Institutes of Health (NINDS R01 NS088257).

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Authors and Affiliations

  1. Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA

    John T. Gionco, Whitney G. Hartstone, Regina T. Martuscello & Phyllis L. Faust

  2. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Sheng-Han Kuo

  3. Department of Neurology, University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas, TX, 75390-9020, USA

    Elan D. Louis

Authors
  1. John T. Gionco
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  2. Whitney G. Hartstone
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  3. Regina T. Martuscello
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  4. Sheng-Han Kuo
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  5. Phyllis L. Faust
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  6. Elan D. Louis
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Contributions

The following is a list of all authors and their contributions in the project and the preparation of the manuscript. These include but are not restricted to: (1) research project: A. conception, B. organization, C. execution; (2) statistical analysis: A. design, B. execution, C. review and critique; and (3) manuscript: A. writing of the first draft, B. review and critique.

Mr. Gionco: 1B, 1C, 2B, 2C, 3A, 3B.

Ms. Hartstone: 1C, 3B.

Dr. Martuscello: 1C, 3B.

Dr. Kuo: 1A, 1B, 3B.

Dr. Faust: 1A, 1B, 1C, 2A, 2C, 3B.

Dr. Louis: 1A, 1B, 2A, 2B, 2C, 3B.

Corresponding author

Correspondence to Elan D. Louis.

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Gionco, J.T., Hartstone, W.G., Martuscello, R.T. et al. Essential Tremor versus “ET-plus”: A Detailed Postmortem Study of Cerebellar Pathology. Cerebellum 20, 904–912 (2021). https://doi.org/10.1007/s12311-021-01263-6

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