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November 26, 2002; 59 (10) Brief Communications

Olfactory dysfunction in essential tremor

A deficit unrelated to disease duration or severity

Elan D. Louis, Steven M. Bromley, Eva C. Jurewicz, Dryden Watner
First published November 26, 2002, DOI: https://doi.org/10.1212/01.WNL.0000033798.85208.F2
Elan D. Louis
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Eva C. Jurewicz
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Dryden Watner
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Citation
Olfactory dysfunction in essential tremor
A deficit unrelated to disease duration or severity
Elan D. Louis, Steven M. Bromley, Eva C. Jurewicz, Dryden Watner
Neurology Nov 2002, 59 (10) 1631-1633; DOI: 10.1212/01.WNL.0000033798.85208.F2

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Abstract

Because olfactory dysfunction is a feature of neurodegenerative diseases, the authors hypothesized that it would be present in essential tremor. Thirty-seven cases and control subjects underwent the University of Pennsylvania Smell Identification Test. Mean score was lower in cases than in control subjects (29.0 ± 6.1 vs 31.9 ± 4.6, p = 0.02) and was not correlated with tremor severity or duration.

Essential tremor (ET) increases in severity with age and disease duration. On 1H-MRSI, there is a reduction in cerebellar N-acetylaspartate to creatine (NAA/tCR), which is a marker of neuronal damage or loss,1 as well as an acceleration in the age-associated decline in cerebellar NAA/tCR,1 supporting the view that ET may be a neurodegenerative disease.

Olfactory dysfunction is present and marked in several neurodegenerative diseases, including PD, AD, and the parkinsonism-dementia complex of Guam.2 In contrast, olfactory dysfunction in patients with ALS and progressive supranuclear palsy is of lesser average magnitude. We compared smell recognition in a group of ET cases and matched control subjects, determined whether this difference was explained by confounding variables, and determined whether an olfactory deficit in cases was associated with tremor duration or severity.

Methods.

We enrolled 37 ET cases and 37 control subjects. Cases were identified from patients billed at our center in the last three years. Those with PD, dementia, or other neurologic disorders were excluded. Potential control subjects were selected from the New York, New Jersey, and Connecticut area by random digit dialing and were frequency matched to cases on age, sex, and ethnicity. Cases and control subjects were screened for cognitive impairment using the 10-minute Telephone Interview for Cognitive Status.3 Individuals with cognitive impairment (score <30 of 41) were excluded. Because cigarette smoking causes olfactory dysfunction,4 we excluded current (within 1 year) cigarette smokers.

Data were collected on disease duration and smoking habits. A limitation of this study is that we did not assess second-hand smoke exposure, which could lead to olfactory dysfunction. Odor identification testing was performed with the University of Pennsylvania Smell Identification Test (UPSIT, Sensonics Inc., Haddon Heights, NJ).2,4⇓ The UPSIT was administered by a tester who released 40 standardized microencapsulated stimuli and placed them under the subjects’ nares. The UPSIT is highly reliable2,4⇓ and sensitive to a variety of olfactory deficits. The score ranges from 0 to 40 (normal). Scores may be converted to age- and sex-specific normative percentiles.4

A videotaped neurologic examination was reviewed by a researcher (E.L.) blinded to UPSIT scores, and a total tremor score (0–36)5 was assigned based on a 0 to 3 rating of action tremor during 12 activities. ET diagnostic criteria were moderate amplitude tremor during ≥3 activities or head tremor.5 No subjects had PD on videotape.

Based on UPSIT data on individuals >65 years old,2,4⇓ and assuming alpha =0.05 and power =80%, we needed 37 subjects per group to detect a 10% difference between cases and controls.

χ2 And Student’s t-test were used. When analyzing UPSIT scores, nonparametric tests (Mann–Whitney U, Spearman’s r) were used or scores were transformed (log[41 − UPSIT]). For some analyses, subjects were stratified into five olfactory groups (normosmia, mild microsmia, moderate microsmia, severe microsmia, and anosmia) as described elsewhere.4 To compare differences between cases and control subjects in UPSIT scores while adjusting for potential confounders (age, sex, past cigarette smoker [yes/no], cigarette pack years) an analysis of covariance (ANACOVA) was performed. Analyses were performed in SPSS (Version 9.0, Chicago, IL)

Results.

Cases and control subjects were similar in age, sex, ethnicity, and education (table 1). None had acute or chronic rhinitis or sinusitis. Mean tremor duration in cases was 18.9 years; 23 (62.2%) had ET for >10 years.

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Table 1 Characteristics of 37 cases and 37 control subjects

We examined potential confounding variables among control subjects. The UPSIT score was negatively correlated with age (r = −0.56, p < 0.001) but was similar in men and women (31.4 ± 5.1 vs 32.4 ± 4.1, z = 0.38, p = 0.70), and in those who did and did not have a past history of cigarette smoking (32.5 ± 4.1 vs 31.5 ± 5.0, z = 0.43, p = 0.68). It was similar in ET patients who were vs ET patients who were not currently taking medication for their tremor (28.1 ± 4.4 vs 29.3 ± 6.7, z = 1.27, p = 0.22).

UPSIT scores ranged from 10 to 39 (UPSIT percentile = 5% to 83%, table 2). The mean UPSIT score was lower in cases than in control subjects (29.0 ± 6.1 vs 31.9 ± 4.6, z = 2.25, p = 0.02). The mean UPSIT percentile was 11.5% lower in cases than in control subjects (35.5% ± 20.2% vs 47.0% ± 20.3%, z = 2.49, p = 0.01). Subjects were stratified into five olfactory diagnostic groups, and cases and control subjects differed (table 3, χ2 = 13.2, p = 0.01); 18.9% of cases vs 40.5% of control subjects were normosmic (χ2 = 4.14, p = 0.04, see table 3), and 27% of cases vs 2.7% of control subjects had severe microsmia or anosmia (χ2 = 8.65, p = 0.003, see table 3).

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Table 2 UPSIT scores in ET vs PD

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Table 3 Olfactory diagnosis by neurologic diagnosis

In an ANACOVA that included diagnostic group (case vs control) and several covariates (age, sex, past cigarette smoker [yes/no], cigarette pack years), the transformed UPSIT score differed by diagnostic group (F = 5.68, p = 0.02) and age (F = 17.93, p < 0.001) but not by other covariates.

In cases, there was no correlation between UPSIT score and total tremor score (r = −0.07, p = 0.68) or disease duration (r = 0.11, p = 0.53). Total tremor score in cases was stratified into quartiles, and there was no difference in mean UPSIT score between cases in the lowest vs the highest quartile (25.0 ± 10.0 vs 28.0 ± 5.2, z = 0.52, p = 0.60). Disease duration was stratified into quartiles, and there was no difference in mean UPSIT score between the lowest vs the highest quartile (28.7 ± 6.3 vs 31.0 ± 4.0, z = 1.11, p = 0.31). Ten cases had disease of short duration (<5 years). Their mean UPSIT percentile was 35.7%, and in eight of these, the UPSIT percentile was <50%.

Discussion.

A mild olfactory deficit was present in ET cases compared with matched control subjects. As in PD, the deficit is unrelated to disease duration and severity and seems to be present early in the disease.2

In a previous study,6 lower mean UPSIT scores in ET cases (36.3) did not differ (p = 0.19) from those of control subjects (37.2),6 although with 16 subjects per group, the study power, which was not reported, may not have been adequate. Also, their cases were younger than ours (mean age 50.6 years). Age-related deficits in olfactory dysfunction are well documented.4 A normal age-related deficit in olfaction in our older population of ET patients may have unmasked an underlying disease-related deficit.

The role of the UPSIT in distinguishing ET cases from PD requires further study. Although the mean UPSIT score is lower in PD, there is also overlap between ET cases and similarly aged patients with PD (see table 2). Better differentiation between the two groups could occur in certain age groups or differently in men and women. A larger data set is needed to address these issues.

The basis for the olfactory deficit in ET is not clear. Cerebellar pathology could be responsible. Cerebellar involvement in ET is apparent in fMRI studies.7 Study results also suggest that the cerebellum plays a role in human olfaction. In a fMRI study, odorants induced significant activation of the posterior and the lateral portions of the cerebellar hemispheres.8 Tumors in and around the cerebellum are reported to cause olfactory dysfunction.9 In the animal literature, the staggerer mutant mouse, with a reduction in cerebellar size and abnormal connections among Purkinje cells and parallel and climbing fibers, exhibits olfactory deficits.10 Alternatively, there may be involvement of the olfactory pathways in ET, as has been hypothesized in other neurologic disorders of late life such as PD.2 Regardless of the basis of the olfactory disorder associated with ET, its presence provides a similarity between this disease and other neurodegenerative disorders.

Acknowledgments

Supported by grants R01 NS39422 and RR00645 (General Clinical Research Center) from the National Institutes of Health, Bethesda, MD.

  • Received May 14, 2002.
  • Accepted August 1, 2002.

References

  1. ↵
    Louis ED, Shungu D, Chan S, Mao X, Jurewicz EC, Watner D. Metabolic abnormality in essential tremor: a 1H magnetic resonance spectroscopic imaging study. Neurology . 2002; 58 (suppl 3): A253.Abstract.
    OpenUrl
  2. ↵
    Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology . 1988; 38: 1237–1244.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Brandt J, Spencer M, Folstein M. The telephone interview for cognitive status. Neuropsychi Neuropsychol Beh Neurol . 1988; 1: 111–117.
  4. ↵
    Doty RL. The Smell Identification Test Administration Manual. Haddon Heights, NJ: Sensonics, 1995.
  5. ↵
    Louis ED, Ford B, Frucht S, Barnes LF, Tang M-X, Ottman R. Risk of tremor and impairment from tremor in relatives of patients with essential tremor: a community-based family study. Ann Neurol . 2001; 49: 761–769.
    OpenUrlCrossRefPubMed
  6. ↵
    Busenbark KL, Huber SJ, Greer G, Pahwa R, Koller WC. Olfactory dysfunction in essential tremor. Neurology . 1992; 42: 1631–1632.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Bucher SF, Seelos KC, Dodel RC, Reiser M, Oertel WH. Activation mapping in essential tremor with functional magnetic resonance imaging. Ann Neurol . 1997; 41: 32–40.
    OpenUrlCrossRefPubMed
  8. ↵
    Sobel N, Prabhakaran V, Hartley CA. Odorant-induced and sniff-induced activation of the cerebellum of the human. J Neurosci . 1998; 18: 8990–9001.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Tucker BR. Report of a case of tumor of the ponto-cerebellar angle on the left side of the brain with bilateral loss of smell and disturbance of taste. Old Domin J Med Surg . 1991; 13: 327–334.
  10. ↵
    Diess B, Baudoin B. Hyposmia for butanol and vanillin in mutant staggerer mice. Physiol Behav . 1997; 61: 209–213.
    OpenUrlCrossRefPubMed

Disputes & Debates: Rapid online correspondence

  • Olfactory dysfunction in essential tremor: A deficit unrelated to disease duration or severity
    • Christopher Hawkes, Oldchurch Hospital Romford UKchrishawkes@msn.com
    • Mussadiq Shah and Leslie Findley
    Submitted April 09, 2003
  • Reply to Letter to the Editor
    • Elan D Louis, College of Physicians and Surgeons Columbia University New York NYedl2@columbia.edu
    • Steven M Bromley, Eva C Jurewicz and Dryden Watner
    Submitted April 09, 2003
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