Emerging Pathogenesis of Essential Tremor

Science Editorials and Reviews—Edited by David Riley, MD

October 16, 2008

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By Holly Shill, MD

This editorial was developed for AAN.com, which is publishing expert opinions on a variety of hot topics in neurology.

Author Disclosure

Over the last two years investigators have begun to elucidate the neuropathological findings in the essential tremor (ET) brain.1, 2 Prior studies had not detected specific changes in ET, but a recent larger series by Louis et al., in which detailed neuropathological assessment was performed, has led to a proposal that ET is a variant of Lewy body disease with postural and kinetic tremor, rather than parkinsonism and dementia.3 Lewy bodies were detected in the brainstems of six of ten cases in this study and demonstrated a distribution restricted to the locus ceruleus (LC). A larger series of 33 brains studied by the same group2 found a somewhat lower percentage (24%) of patients having Lewy bodies. These findings stimulated additional studies of the neuropathological findings in ET.

Essential tremor (ET) is one of the most common neurological conditions, particularly in the elderly, with more than 10% of people over age 70 reporting a tremor. Despite being slowly progressive and primarily monosymptomatic, nearly everyone with tremor reports some degree of disability. Therefore, it is somewhat surprising that there has never been a therapy specifically developed and approved for ET, nor (until recently) has there been substantial investigation into the condition’s underlying pathophysiology.

Divergent Findings

In our series of 24 subjects1 we were unable to confirm the findings of the studies cited above. We found a similar frequency of Lewy bodies in our ET patients and controls. We also found substantial pathology in the LC, primarily pigmentary depletion. However, the two data sets provide persuasive evidence that the locus ceruleus is involved in the pathogenesis of ET.

The issue of whether ET may be a variant of Lewy body disease is still uncertain. It is my opinion that Lewy bodies are primarily a feature of Parkinson’s disease and Lewy body dementia , and that the higher proportions seen in series by Louis et al. might reflect a recruiting bias or a difference in subject classification. Our study was drawn primarily from a community-based sampling of brain donors, many of whom were not substantially symptomatic with ET, whereas the ET Centralized Brain Repository actively seeks donors nationally and thereby may bias toward a population of ET patients whose symptoms are more progressive and severe, and may, indeed, be developing PD clinically. Patients with "incidental" Lewy bodies have been shown to have reduced levels of tyrosine hydroxylase (the rate-limiting step in dopamine metabolism) in the striatum, a finding that supports the contention that this pathological group does indeed have subclinical dopamine deficiency. It can thus be argued that, had they lived longer, they likely would have manifested features of parkinsonism.4

ET-Related Cerebellar Degeneration

Another primary pathology seen with ET is cerebellar degeneration. Purkinje cell neurons are both qualitatively and quantitatively reduced in a subset of ET patients, particularly those lacking locus ceruleus pathology. Also seen are Bergmann’s gliosis and cerebellar torpedoes, unique fusiform swellings of Purkinje cell axons within the granular layer that are a marker of neuronal death and axonal loss. How much of ET is attributable to cerebellar degeneration is still questionable, but combined studies suggest a frequency as high as 75% of cases. Involvement of the dentate nucleus was seen in several subjects in both of the larger series. Whether this might represent another type of cerebellar degeneration is not clear. Additionally, it is entirely possible that there may be several types of cerebellar degeneration in ET, as is true of the hereditary spinocerebellar ataxia.

Where to From Here?

  • An important step in research will be to determine how often the locus ceruleus is affected or whether it might be a bystander of the cerebellar processes.
  • Further study of Lewy bodies in ET is important to determine whether the relationship between PD and ET is real. Larger pathological series will help with this, and patient recruitment remains a priority.
  • Genetic evaluation of patients with pathologically confirmed cerebellar degeneration is of interest, since the hereditary component in most ET is well known.
  • If specific biochemical or enzymatic alterations are found, these may be amenable to pharmacological manipulation. Currently, most drugs to treat ET are only modestly effective and fraught with side effects.
  • Clinical correlation of the pathological findings is of great importance, particularly if we get more subtype-specific therapies. As it stands, we have no way of differentiating these pathological subtypes in living individuals.

The future of treating ET will look something like this: a patient is referred for tremor and is found to have specific abnormalities on clinical examination or by simple testing. This, in turn, allows the clinician to differentiate the subtype to which the patient belongs. The most subtype-specific treatment, which produces substantial efficacy with minimal side effects, is then selected. ET is now converted from an often disabling condition to one that fully deserves the name "benign" essential tremor.

References

  1. Shill HA, Adler CH, Sabbagh MN, et al. Pathologic findings in prospectively ascertained essential tremor subjects. Neurology 2008;70:1452-1455.
  2. Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130:3297-3307.
  3. Louis ED, Vonsattel JP, Honig LS, Ross GW, Lyons KE, Pahwa R. Neuropathologic findings in essential tremor. Neurology 2006;66:1756-1759.
  4. Beach TG, Adler CH, Sue LI, et al. Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol 2007;115(4),445-451.

Read more information on essential tremor on the NINDS Disorders page.

Author Disclosure

Dr. Shill has received personal compensation from Teva Neuroscience, Boehringer-Ingelheim, and Allergan for consulting or speaking within the past 24 months. In addition, within the past five years she has received research support from the following: Chelsea Therapeutics, Inc., Schering-Plough Research Institute, Sun Health Research Institute, the US Department of Defense, Boehringer-Ingelheim, Parkinson Study Group, the National Institutes of Health, Cephalon, H. Lundbeck A/S, Arizona Biomedical Research Commission, Arizona Parkinson Disease Center, Barrow Neurological Foundation, Merck KgaA, and Kyowa Pharmaceutical, Inc.