Background: Recent postmortem studies have demonstrated pathological changes, including Purkinje cell loss, in the cerebellum in essential tremor (ET). Toxic exposures that compromise cerebellar tissue could lower the threshold for developing ET. Ethanol is a well-established cerebellar toxin, resulting in Purkinje cell loss.
Objective: To test whether higher baseline ethanol consumption is a risk factor for the subsequent development of incident ET.
Methods: Lifetime ethanol consumption was assessed at baseline (1994–1995) in a prospective, population-based study in central Spain of 3285 elderly participants, 76 of whom developed incident ET by follow-up (1997–1998).
Results: In a Cox proportional hazards model adjusting for cigarette pack-years, depressive symptoms and community, the baseline number of drink-years was marginally associated with a higher risk of incident ET (relative risk, RR = 1.003, p = 0.059). In an adjusted Cox model, the highest baseline drink-year quartile doubled the risk of incident ET (RR = 2.29, p = 0.018), while other quartiles were associated with more modest elevations in risk (RR3rd quartile = 1.82 (p = 0.10), RR2nd quartile = 1.75 (p = 0.10), RR1st quartile = 1.43 (p = 0.34) vs non-drinkers (RR = 1.00)). With each higher drink-year quartile, the risk of incident ET increased an average of 23% (p = 0.01, test for trend).
Conclusions: Higher levels of chronic ethanol consumption increased the risk of developing ET. Ethanol is often used for symptomatic relief; studies should explore whether higher consumption levels are a continued source of underlying cerebellar neurotoxicity in patients who already manifest this disease.
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Essential tremor (ET) is one of the most common neurological disorders.1 The underlying disease mechanisms are not clear; however, evidence from clinical and neuroimaging studies implicates a disorder of the cerebellum.2 3 Recent postmortem studies demonstrate pathological changes in the ET cerebellum, including swellings of Purkinje cell axons and Purkinje cell loss.4–6 With this understanding, one would expect that exposures that compromise cerebellar tissue might predispose to ET or lower the threshold for developing ET. Ethanol is a well-established cerebellar toxin.7–9 We hypothesised that a higher baseline ethanol consumption would be a risk factor for the subsequent development of incident ET.
The Neurological Disorders in Central Spain (NEDICES) is a population-based survey of major age-associated conditions of older people (⩾65 years) from three communities in Spain (Las Margaritas, Lista and Arévalo).10 Detailed accounts of the study population and survey methods have been reported.10–12 Signed informed consent was obtained upon enrolment.
As documented,10 the baseline in-person evaluation (1994–1995) included a questionnaire (demographic, medical, lifestyle information). Data on smoking were collected; prior results suggest that smoking may decrease the risk of incident ET.12 Hence, a priori, cigarette pack-years were a major potential confounder of interest. A general neurological examination included assessments of action tremor and the motor portion of the Unified Parkinson’s Disease Rating Scale (UPDRS).13 Diagnostic criteria for ET have been described.10
As detailed elsewhere, the follow-up evaluation (1997–1998) was similar to the baseline evaluation, and the diagnostic approach to ET was identical.10
Follow-up data were available on 3942 of 5278 baseline participants (online figure). We excluded 657 participants with incomplete data on ethanol consumption, leaving 3285 participants. These remaining 3285 participants were similar to the original 5278 participants in mean (SD) baseline age (73.5 (6.6) vs 74.3 (7.0) years), gender (56.8% vs 57.3% women) and education (12.7% vs 12.1% illiterate).
There were 76 incident ET cases, including 40 who had in-person baseline examinations and did not have ET on those examinations and 36 who did not have in-person baseline examinations. Baseline handwriting samples of these 36 were reviewed by a senior neurologist (EDL), and none had tremor that was in the ET range (all had Bain and Findley14 handwriting tremor scores ⩽1, which are within the range of normal).15 Furthermore, each of the 36 cases was reinterviewed during the follow-up evaluation to establish that the onset of their tremor had been after the baseline assessment.
In statistical analyses (SPSS version 16.0, SPSS, Chicago, Illinois), baseline pack-years = packs of cigarettes smoked/day×years smoked. One drink-year = one drink of ethanol (one 360 ml can of beer or one 120 ml glass of wine or 30 ml of liquor) per day/year. We used Cox proportional hazards models to estimate the relative risk (RR) of incident ET, beginning with an unadjusted model, and then included covariates associated with both baseline ethanol consumption and incident ET in univariate analyses.
The 3285 participants included 1838 (56.0%) who were ethanol drinkers (>0 drink-years) at baseline. These differed from non-drinkers in several respects (eg, age, table 1). The mean (SD) follow-up was 3.3 (0.8) years (range = 0.1 to 6.6 years). The 76 incident ET cases differed from 3209 controls by baseline depressive symptoms and cigarette pack-years (table 1).
The median number of baseline drink-years was 57% higher (26.3 vs 16.8) in incident ET cases versus controls, although this difference did not achieve statistical significance (table 1). In analyses that stratified by cigarette pack-year tertile, the number of drink-years within each stratum was higher in incident ET cases than controls, although this difference only reached significance in the highest cigarette pack-year tertile (p = 0.035, table 1).
In an unadjusted Cox proportional hazards model, the baseline number of drink-years was not associated with risk of incident ET (RR = 1.001, 95% CI 0.998 to 1.004, p = 0.52). There were a number of obvious confounding factors (esp. cigarette smoking). In a Cox model that adjusted for cigarette pack-years, depressive symptoms and community, baseline number of drink-years were marginally associated with higher risk of incident ET (RR = 1.003, 95% CI 1.000 to 1.006, p = 0.059, that is, for every 10 unit increase in drink years, the risk of ET increased 3%). Adding an additional covariate, use of an antidepressant medication, to the model did not change the results (RR = 1.003, 95% CI 1.000 to 1.006, p = 0.055).
In a Cox proportional hazards model that adjusted for cigarette pack-years, depressive symptoms and community, the highest baseline drink-year quartile was associated with a doubling of risk of incident ET (RR = 2.29, 95% CI 1.15 to 4.54, p = 0.018, table 2). With each advancing quartile, the risk of incident ET increased (table 2), and a test for trend indicated that with each higher drink-year quartile, the risk of incident ET increased on average by 23% (RR = 1.23, 95% CI 1.05 to 1.43, p = 0.01).
ET cases included 40 who had had an in-person baseline examination and 36 who did not. When we included in the adjusted Cox proportional hazards analysis a covariate indicating the type of baseline evaluation, the results did not change (RR in highest quartile vs non-drinkers = 2.29, 95% CI 1.15 to 4.54, p = 0.018).
The highest quartile of baseline ethanol consumption was associated with substantially higher risk of developing incident ET, while other quartiles were associated with more modest elevations in risk. There was a dose–response effect; with each advancing higher drink-year quartile, the risk of developing incident ET increased an average of 23%.
One interpretation of these data is that ethanol, a known cerebellar toxin, lowers the threshold for developing ET, which seems to be a disorder involving the cerebellum. Ethanol is a well-established cerebellar toxin, and a variety of noxious changes have been demonstrated, including reductions in Purkinje cell number and density, regression of Purkinje cell dendritic arbors, and loss of synapses.7–9 16 Although the effects are most pronounced in the cerebellar vermis, they are not restricted to that cerebellar region, and gross atrophy of cerebellar hemispheres has been demonstrated in many studies.17 18 The long-term intake of moderate doses of daily ethanol in humans has been shown to result in significant Purkinje cell loss.19 Recent postmortem studies of ET have indicated that there are cerebellar changes including Purkinje cell axonal swellings, Purkinje cell loss and possibly gliosis in excess of that seen in age-matched control brains.4–6 In some brains, more extensive cerebellar degeneration is evident, including changes in the dendate nucleus.20 A two-hit model has been proposed for a variety of diseases of the central nervous system, with the basic concept being that an initial exposure/injury to a distinct neuronal population can produce permanent and cumulative neurotoxicity and enhance vulnerability to a second set of insults involving that same neuronal population.21–24
One possibility is that the 76 NEDICES participants who developed incident ET between the baseline and follow-up evaluations had preclinical ET at baseline (ie, enough tremor for them to notice but not enough for a diagnosis of ET), and they were self-medicating with ethanol (ie, they were drinking more ethanol in order to lessen this tremor). We think this is unlikely. First, when asked at baseline whether their arms or legs shook, they answered “no,” indicating that they did not notice tremor. Second, each of the 76 had an in-person neurological assessment or a detailed assessment of handwriting, and each was found to have negligible if any tremor. Finally, the assessment of baseline handwriting samples in 36 incident ET cases indicated that a baseline tremor of 1 rather than 0 was not associated with more ethanol consumption (χ2 = 10.27 (p = 0.25) for baseline handwriting tremor score vs baseline drink-year quartile), indicating that even this negligible amount of tremor did not have as a correlate greater consumption of ethanol.
NEDICES participants in the highest quartile of ethanol consumption were consuming on average 3 to 4 standard drinks per day; this amount is consistent with prior clinical definitions of heavy ethanol consumption (⩾3 standard drinks/day in women and ⩾4 in men)25 and commensurate with chronic ethanol intake levels shown to be associated with Purkinje cell degeneration in humans.19
This study had several limitations. The findings may be generalised only to ET cases age ⩾65 years. Also, our mean follow-up time was modest, and a longer follow-up would likely have resulted in more incident ET cases and greater study power.
Our findings have possible clinical implications. We observed that the highest levels of chronic ethanol consumption seemed to increase the risk of developing ET. The mechanism, though not established, could involve cumulative cerebellar neurotoxicity. By implication, it is conceivable that chronic ethanol use, while symptomatically beneficial for patients, could be a continued source of underlying cerebellar neurotoxicity and, therefore, be a continued contributor to the progression of the disease. If this were the case, then patients would need to be cautioned about the potential deleterious effects of high levels of ethanol on their underlying disease. Future studies should explore these issues.
The authors gratefully acknowledge the help of the other members of the NEDICES Study Group: S Vega, JM Morales, R Gabriel, A Portera-Sánchez, A Berbel, A Martínez-Salio, J Díaz-Guzmán, J Olazarán, J Pardo, J Porta-Etessam, F Pérez del Molino, J Rivera-Navarro, M Alonso, C Gómez, C Saiz, G Fernández, P Rodríguez and F Sánchez-Sánchez. Finally, we also wish to express our sincere thanks to J de Pedro-Cuesta, MJ Medrano and J Almazán, and the municipal authorities, family doctors, nurses and the populations of Getafe, Lista and Arévalo county.
Review history and Supplementary material
An additional figure is published online only at http://jnnp.bmj.com/content/vol80/issue5
Funding: NEDICES was supported by the Spanish Health Research Agency and the Spanish Office of Science and Technology. Dr Louis is supported by NIH R01 NS042859, R01 NS039422, and ES P03 09089 from the National Institutes of Health, Bethesda, Maryland.
Competing interests: None.
Ethics approval: Ethics approval was provided by University Hospital “12 de Octubre.”
Patient consent: Obtained.
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