Essential Tremor: Not So Benign?

Abstract & Commentary

By Claire Henchcliffe, MD, DPhil, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University; Dr. Henchcliffe reports no financial relationship to this field of study.

Synopsis: In a population-based study of the elderly in central Spain, individuals with essential tremor beginning after age 65 had a two-fold increased likelihood of incident dementia when compared with controls without essential tremor.

Source: Bermejo-Pareja F, et al. Risk of incident dementia in essential tremor: a population-based study. Mov Disord 2007;22:1573-1580.

The nedices (neurological disorders in central Spain) survey is a population-based study of age-associated conditions affecting individuals age 65 and older in three communities in central Spain. Baseline evaluations, including a screening question for essential tremor (ET), were completed from 1994 to 1995; those with baseline dementia (based upon Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV criteria) were excluded. ET was diagnosed in 206/3891 individuals (204 by direct examination). Those with ET were older than those without (74.6 ± 6.7 versus 73.1 ± 6.3 years, p=0.003), and depressive symptoms were more commonly associated with ET (43.5% versus 25.8%, p<0.001), but there was no significant difference by gender, smoking, alcohol consumption, heart disease, hypertension, diabetes, or stroke. Follow-up occurred at a mean of 3.2 years; 16/206 (7.8%) ET cases had developed dementia, compared with 145/3685 (3.9%) controls. Dementia followed ET diagnosis by a mean time period of 10.5 years (range, 2.5-53 years). Ninety-seven ET cases had a younger onset, with tremor beginning before they were age 65. Of these, only two (2.1%) developed dementia, compared with 14/109 (12.8%) older-onset ET cases (p=0.004). Adjusted Cox models were applied to account for differences between groups in age and educational level, or age, educational level, alcohol, stroke, hypertension, and depression. Relative risk (RR) for dementia was 1.84-1.98 (depending on adjustments applied, p=0.01-0.04) in older onset ET versus controls. In younger-onset ET, adjusted RR did not reach significance. Possible or probable Alzheimer's disease (AD) accounted for the majority of incident dementia (71.4%), and older-onset ET was associated with an adjusted RR for AD incidence of 2.04-2.13.

Commentary

Cognitive deficits have been reported in association with ET. While these are usually mild, and can include memory or frontal executive function, they have been little-studied to date and their true impact and significance is unclear. The authors have previously demonstrated the association of ET with prevalent dementia, and this community-based study using the same NEDICES database extends those findings. As they acknowledge, despite careful record review and direct examination in the majority of ET cases, their study design has a number of inherent problems. This includes the presence of confounding factors that are difficult to adjust for, the (low) likelihood of misdiagnosis, and the possibility of patients developing an unrelated neurodegenerative process. A small proportion of ET patients have been reported to develop Parkinson's disease; therefore, could synuclein pathology be a contributing factor to development of dementia in the older-onset ET cases? Extrapolating from independent studies, the number of individuals expected to develop Parkinson's disease in this time period would simply not account for the increased dementia risk observed. As a result, an alternative explanation needs to be examined. It is becoming evident that the true spectrum of ET likely involves features other than tremor, such as ataxia, and the present study underscores likely involvement of regions outside of the cerebellum in at least a subset of cases. The association of ET with dementia, particularly given its potential impact on quality of life, will require further study. We need to determine who is at risk to provide adequate counseling and treatment for our ET patients.