Abstract
Although the number of postmortem studies in essential tremor (ET) has grown in recent years, clinical-pathological correlations remain limited. We are unaware of a study that has assessed whether the pathological changes in ET, if asymmetric, lateralize to the cerebellar hemisphere that is ipsilateral to the arm with more severe action tremor, as one would predict if the lesions were tremor producing. We compared postmortem changes in the right vs. left cerebellar hemispheres in ET and examined how these correlated with asymmetry of tremor on neurological examination. Action tremor in each arm was quantified using a reliable and valid clinical rating scale. Cases were divided into three clinical groups: tremor more severe on right, tremor more severe on left, and tremor symmetric. Calbindin D28k immunohistochemistry was performed on 100 μm vibrotome sections from a standard tissue block of both right and left neocerebellums to quantify Purkinje cell linear density, torpedo counts, and a group of previously described changes in Purkinje cell axonal shape (thickened axonal profiles) and connectivity (axon recurrent collaterals, axonal branching, terminal axonal sprouting, arciform axons, extent of recurrent collateral plexus). ET cases were divided into three postmortem groups: findings greatest on right, findings greatest on left, and findings symmetric. In 18 (72.0 %) of 25 ET cases, clinical and pathological features were concordant (i.e., both clinically and pathologically right-predominant (one case), both clinically and pathologically left-predominant (five cases), or both clinically and pathologically symmetric (12 cases), p = 0.007). In the remaining seven (28.0 %) ET cases, clinical and pathological data were not concordant, and in none were they completely discordant (i.e., tremor was more severe on the right, and postmortem cerebellar changes were paradoxically more severe on the left or vice versa). Among the seven ET cases with >20 % side-to-side difference in tremor severity, six cases (85.7 %) had the expected pathological asymmetry, with quantified postmortem cerebellar changes more marked ipsilateral to the more clinically affected side. We also created continuous measures of asymmetry. For the entire sample, there was a positive correlation between the clinical asymmetry index and the pathological asymmetry index = 0.52, p = 0.01 (i.e., the right-left difference in clinical asymmetry was correlated with the right-left difference in postmortem changes). For the seven ET cases with clear clinical asymmetry, the correlation was even more robust (r = 0.78, p = 0.039). Clinical-pathological correlations are important in terms of understanding the significance of observed pathological changes. The correlation between clinical laterality or symmetry of tremor and pathological changes in the majority of ET cases provides additional evidence that the pathological changes in the cerebellum in ET are of patho-mechanistic importance.
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Acknowledgments
Dr. Vonsattel has received funding from the NINDS #R01 NS39422 (co-investigator), Dr. Faust has received funding from the NINDS #R21 NS077094 (principle investigator) and NINDS #R01 NS39422 (co-investigator), Dr. Louis has received research support from the National Institutes of Health: NINDS #R01 NS042859 (principal investigator), NINDS #R01 NS39422 (principal investigator), NINDS #R01 NS085136 (principal investigator), NINDS #T32 NS07153-24 (principal investigator), NINDS #R01 NS073872 (principal investigator), NINDS #R21 NS077094 (co-investigator), NINDS #R01 NS36630 (co-investigator), NIEHS P30 ES09089 (co-investigator), and CTSA grant number UL1 RR024156. He has also received support from the Parkinson’s Disease Foundation, the Arlene Bronstein Essential Tremor Research Fund (Columbia University), and the Claire O’Neil Essential Tremor Research Fund (Columbia University).
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Louis, E.D., Lee, M., Cortés, E. et al. Matching Asymmetry of Tremor with Asymmetry of Postmortem Cerebellar Hemispheric Changes in Essential Tremor. Cerebellum 13, 462–470 (2014). https://doi.org/10.1007/s12311-014-0560-9
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DOI: https://doi.org/10.1007/s12311-014-0560-9