RESEARCH ARTICLE
CLINICAL PRACTICE
Intention Tremor of the Legs in Essential Tremor: Prevalence and Clinical Correlates Meir Kestenbaum, MD,1 Monika Michalec, MPH,2 Qiping Yu, PhD,1 Seth L. Pullman, MD,1 Elan D. Louis, MD, MSc1,2,3,4,*
Abstract: The aim of this study was to estimate the prevalence and assess the clinical correlates of intention tremor in the legs in essential tremor (ET) patients. The cerebellar features of ET are of growing interest to clinical neurologists. Arm tremor has an intentional component in many ET patients. Intention tremor in the legs, however, has never been systematically evaluated. One hundred twenty-eight ET patients were enrolled in a clinical-epidemiological study at Columbia University (New York, NY). A videotaped neurological examination included 10 toe-to-target movements with each foot. Videotapes were independently reviewed by two movement disorder neurologists who noted the presence versus absence of intentional leg tremor. Two patients underwent quantitative computerized tremor analysis to study the physiological characteristics of the tremor. Thirty-five patients (27.3%) had intentional leg tremor; in 21, tremor was unilateral and in 14 it was bilateral. The 35 patients with intentional leg tremor did not differ from the remaining 93 in their clinical characteristics. Analyses comparing the 14 patients with bilateral intentional leg tremor to the 93 with no intentional leg tremor showed trends toward longer disease duration and moresevere intentional arm tremor in the former. Tremor analysis showed a 3-fold increase in average tremor amplitude from movement onset to the point just before touching the target. Our data suggest that intentional leg tremor, another cerebellar feature, is common in ET patients. The tremor may be associated with longer disease duration and more-severe intentional arm tremor, but these preliminary trends need to be assessed in larger study samples.
Essential tremor (ET), the most common tremor disorder,1,2 is characterized by kinetic and postural tremors, affecting mainly the arms and hands. Current clinical, neuroimaging, and postmortem data indicate cerebellar involvement in ET.3–6 The identification and characterization of additional cerebellar features on neurological examination provides further evidence to support this. With this in mind, the cerebellar features of ET are of growing interest to clinical neurologists. Interestingly, the kinetic arm tremor in ET often has an intentional component. Intention tremor is defined as tremor that increases in amplitude as the target is approached during visually guided movements.7–11 Intention tremor in the arms occurs in 44% to 58% of ET patients.10,11 Intention tremor is not limited to the arms, and it occurs in the head in approximately 10% of ET patients.12 Some forms of tremor in ET are limited to specific
body regions (i.e., in ET, rest tremor occurs in the arms, but is not observed in the legs),13 so we posed the clinical question of whether intention tremor of the legs was a feature of ET. To our knowledge, this has never been assessed formally, and we could find no published data that addressed this question. The aims of this study were to (1) estimate the prevalence of intention tremor in the legs in ET patients and (2) assess its clinical correlates.
Patients and Methods Study Participants and Diagnoses As described previously, ET patients were enrolled in an ongoing clinical-epidemiological study of ET at Columbia University
1
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA; 2GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA; 3Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA; 4Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
* Correspondence to: Dr. Elan D. Louis, Department of Neurology, College of Physicians and Surgeons, Columbia University, 710 West 168th Street, New York, NY 10032-3784, USA; E-mail: [email protected]
Keywords: essential tremor, clinical, intention tremor, cerebellum. Relevant disclosures and conflicts of interest are listed at the end of this article. Received 28 July 2014; revised 11 September 2014; accepted 14 September 2014. Published online 23 October 2014 in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/mdc3.12099
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© 2014 International Parkinson and Movement Disorder Society doi:10.1002/mdc3.12099
RESEARCH ARTICLE
Kestenbaum et al.
(New York, NY), which began in 2000.14 All provided written informed consent approved by the Columbia University Internal Review Board. After a thorough assessment of both questionnaire-derived data and a videotaped neurological examination, ET diagnoses were confirmed by a senior movement disorder neurologist (E.D.L.) based on reliable and validated diagnostic criteria (moderate or greater amplitude kinetic tremor during at least three activities or a head tremor in the absence of Parkinson’s disease [PD], dystonia, or another known cause, e.g., thyroid disease, medications, or Wilson’s disease).2 As described previously,15 assessment of leg tremor by videotaped neurological examination, began in August 2007. For the current analyses, we selected the 128 patients who had had a digitized videotaped neurological examination after that date. There were also 74 age- and gender-matched controls enrolled in the same study during the same time period who had a digitized videotaped neurological examination; data on intention tremor in the legs in these controls were used as a comparison point.
Study Evaluation Cases underwent a comprehensive tremor questionnaire. During the questionnaire, age of onset and duration of tremor symptoms were assessed, as well as complaints of leg tremor (“Do you often have an uncontrollable tremor in your leg?”) and family history of tremor (first- and second-degree relatives). Reported frequency of falls in the last year was assessed (“How many falls have you had in the past year?”). The videotaped neurological examination included detailed assessments of postural, kinetic, and intention tremor in the arms. The severity of postural and kinetic tremor in the arms (total tremor score: range = 0–36) was based on the 0 to 3 ratings of six tasks with each arm. As in previous studies,10 intention tremor (i.e., tremor that occurs with goal-directed movement [finger-nose-finger movement] and worsens when approaching the target) was rated as 0 (absent), 0.5 (probable), and 1 (definite); severity of intention tremor (two arms combined) was therefore graded from 0 to 2. Presence of head and voice tremor was assessed during the videotaped neurological examination. The study began in 2000; however, assessment of leg tremor during the videotaped neurological examination did not begin until August 2007. Starting at that point, the videotaped neurological examination included an assessment of postural tremor of the legs, as previously described,15 as well as 10 repetitive toeto-target movements with each foot. Patients were examined while seated and asked to remove their shoes and socks, although a few preferred to keep their socks on. They were asked to raise their foot from the ground to reach the target (a tongue blade) and touch it with their big toe. The tongue blade was placed at least 16 inches from the ground level (see Videos 1 and 2). The videotapes were reviewed independently by two movement disorder neurologists (M.K. and E.D.L.), who noted the presence versus absence of intention tremor in the legs (i.e., tremor that worsened terminally as the patient’s foot was in
close proximity to the target). The more junior of the two neurologists (M.K.) was trained by the more senior neurologist (E.D.L.) to conservatively mark the presence of intention tremor in the legs. In the case of disagreements between the neurologists, the videotapes were coreviewed until a consensus was reached. There were 37 instances in which the junior neurologist marked the presence of intention tremor of the legs, but on further assessment by the senior neurologist, the tremor was deemed to be no more than kinetic tremor. There were no other sources of disagreement between the two neurologists. A 9-m walk was assessed by asking the patient to walk that distance.16 This task was performed twice and the average time was calculated. Two subjects with intention tremor of the legs (1 male and 1 female, both with intention tremor of the arms as well) were selected to undergo computerized quantitative tremor analysis using an ultralight piezoresistive miniature accelerometer (25 g; weight, 1.2 g) with linear sensitivities of approximately 4.5 mV/g in the biological tremor range (0–25 Hz). The accelerometer was attached to the distal phalanx of the great toe. Movement signals were obtained while performing a targeting task with the foot, moving from the floor to a pressure sensitive target cue 80 cm in height. The tremor acquisition setup allowed for relatively unrestrained activity of the leg and foot throughout testing, approximating the clinical state. Six 10-second trials were obtained per patient. Data from the more affected foot were used in the calculations of averages. Total testing time was approximately 1 hour. Two channels recorded the accelerometric and target sensor signals. Recordings were digitized at 700 Hz with a 16-bit A/D board, smoothed, and processed. Displacement (tremor amplitude) was derived offline by double integration of accelerometric data after filtering out low-frequency voluntary movements (less than 2 Hz) and averaging. Displacement data were calculated from 0.5-second epochs taken from 100 ms after movement onset and 100 ms before reaching the target sensor. Tremor frequencies were calculated from accelerometry using a fast Fourier transform (FFT) to generate auto spectra.
Statistical Analyses Statistical analyses were performed using SPSS software (version 21.0; SPSS, Inc., Chicago, IL). Differences between groups were evaluated using Student’s t and chi-square tests. Ninetyfive percent confidence intervals (CIs) were calculated.
Results Thirty-five (27.3%) of 128 ET patients had intention tremor in the legs (95% CI = 20.3–35.7); by comparison, only 2 (2.7%) of 74 age- and gender-matched controls had such tremor (chisquare test = 19.0; P < 0.001). In 21 (16.4%) of 128 ET patients, tremor was unilateral (in 9 affecting the right leg and in 12 affecting the left leg) and in 14 (10.9%) of 128 it was bilateral. Four (3.1%) ET patients had postural tremor of the MOVEMENT DISORDERS CLINICAL PRACTICE
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RESEARCH ARTICLE
Intention Tremor in Legs in Essential Tremor
TABLE 1 Demographic and clinical characteristics of 128 ET patients P Value
Demographics/Characteristics
Total Patients
Intention Tremor of the Legs
No Intention Tremor of the Legs
No. of ET patients Age, years Female gender Duration of symptoms, years Family history of tremor Severity of action tremor in the arms, total tremor score Severity of intention tremor in the arms Presence of head tremor on examination Presence of voice tremor on examination Complaint of leg tremor by history Reported frequency of falls in the last year 9-m walk, seconds
128 71.5 12.9 66 (51.6) 32.5 18.9 85 (66.4) 20.4 6.1
35 70.5 12.5 15 (42.9) 35.1 19.6 24 (68.6) 19.9 5.3
93 71.8 13.1 51 (54.8) 31.5 18.6 61 (65.6) 20.6 6.4
0.61* 0.23* 0.36* 0.75** 0.56*
0.9 0.7 55 (43.6) 35 (27.8) 16 (12.5) 1.0 3.2 9.6 4.1
1.0 0.65 14 (40) 9 (25.7) 5 (14.3) 1.8 5.6 9.1 3.6
0.85 0.7 41 (45.0) 26 (28.6) 11 (11.8) 0.7 1.2 9.7 4.3
0.27* 0.23** 0.75** 0.76** 0.26* 0.55*
Values represent means standard deviations or numbers (percentages). The P value reports the difference between 35 patients with intention tremor of the legs and 93 without intention tremor of the legs. *Student’s t test. **Chi-square test.
legs; 3 of these had intention tremor of the legs. Subject characteristics are summarized in Table 1. The 35 patients with intention tremor in the legs did not differ from the remaining 93 patients in age, gender, duration of symptoms, family history of tremor, severity of action tremor in the arms, severity of intention tremor in the arms, presence of head tremor on examination, presence of voice tremor on examination, complaint of leg tremor by history, reported frequency of falls in the last year, or 9-m walk (Table 1). Additional analysis that compared the 14 patients with bilateral intention tremor of the legs to the 93 patients with no intention tremor of the legs showed nonsignificant trends toward longer disease duration (39.4 16.4 vs. 31.5 18.6 years; P = 0.15) and more-severe intentional arm tremor (1.2 0.7 vs. 0.85 0.7; P = 0.09). There was no difference in the reported frequency of falls in the last year (3.6 8.5 vs. 0.7 1.2; P = 0.23). Computerized tremor analysis showed a 3-fold increase in average tremor amplitude from just after movement onset to just before touching the target. Foot frequency tremor had a peak of approximately 7.0 to 8.5 Hz, reflecting the oscillations in foot position. The frequency is typical of ET range. Tremor analysis findings are summarized in Figure 1.
Discussion Although we have previously studied postural and kinetic tremor in the legs in ET,15 to our knowledge, this is the first study to assess the prevalence of intention tremor of the legs and its clinical correlates in ET. Our data suggest that intention tremor of the legs is common in ET patients (27.3%), but less common than intentional tremor in the arms (approximately 50%). The 35 patients with intention tremor of the legs did not differ from the remaining 93 in terms of demographics and most clinical features. It is worth mentioning that in the patients with intention tremor of the legs, only a small
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minority (14.3%) were aware of their leg tremor, suggesting the absence of functional impairment caused by this tremor. The lack of difference in the 9-m walking time also supports this lack of a functional correlate. Tremor analysis showed a significant 3-fold increase in tremor amplitude from movement onset to just before touching the target, thus supporting the clinical observation of an intentional component to the tremor. A subgroup of 14 patients with bilateral intentional tremor showed nonsignificant trends toward longer disease duration and more-severe intentional arm tremor, when compared to the 93 ET patients without intention tremor of the legs. This finding would be consistent with the view that ET is a progressive disease with the development of other forms of tremor (rest tremor and intention tremors) over time.17 This needs to be further explored in a longitudinal study, which would allow us to follow individuals over time and assess the change in the prevalence of intention tremor of the legs with time. Furthermore, these preliminary trends need to be assessed in larger study samples. This article had limitations. First, the tremor analysis was performed on only 2 cases, and though the findings support the clinical results, it would be of value to study a larger number of subjects in order to make a more general set of statements about the physiological properties of this type of tremor in ET. Also, a study of intention tremor of the legs in other disorders, such as tremor predominant PD, would further extend the study of this clinical phenomenology to other settings. In summary, intention tremor of the legs may be unrecognized, but is common in ET patients, among whom intentional tremors can occur in a variety of other body regions (e.g., arms and head). This and other cerebellar signs may serve as markers of an underlying disorder of cerebellar function in this disease. Whether the intention tremors of ET worsen over time similar to other ET tremors is not known, but this is worthy of study.
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Kestenbaum et al.
(A)
(B)
Figure 1 (A) Upper panel: movement tracing from 1 patient showing foot position from rest to target. Accelerometric data are sampled at 700 Hz, digitized with a 16-bit A/D board, smoothed, and processed to give displacement. Displacement data are calculated from 0.5-second epochs (solid lines A and B) from just after movement onset (indicated by single arrow) and just before reaching the target sensor (indicated by double arrow). Lower panel: An FFT with a peak of approximately 7.0 to 8.5 Hz at the asterisk (*) reflecting the oscillations in the upper panel in the ET range. Large, low-frequency peak reflects foot movement. (B) Bar graph showing data from 0.5-second epochs from six complete trials showing a 3-fold increase in average tremor amplitude from just after movement onset (corresponding to A) to just before touching the target (corresponding to B).
Author Roles (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
M.K.: 1B, 1C, 2B, 3A M.M.: 1B, 1C, 2C, 3B Q.Y.: 1B, 1C, 2C, 3B S.L.P.: 1B, 1C, 2C, 3B E.D.L.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
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Disclosures Funding Sources and Conflicts of Interest: Dr. Louis was funded by R01 NS039422 from the National Institutes of Health (NIH). The authors report no conflicts of interest. Financial Disclosures for previous 12 months: Dr. Louis has received research support from the NIH: National Institute of Neurological Disorders and Stroke (NINDS) #R01 NS042859 (principal investigator [PI]); NINDS #R01 NS39422 (PI); NINDS #R01 NS086736 (PI); NINDS #R01 NS073872 (PI); NINDS #R01 NS085136 (PI); NINDS #T32 NS07153-24 (PI); NINDS #R21 NS077094 (coinvestigator); and NINDS #R01 NS36630 (coinvestigator); 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); and he also acknowledges the support of NIEHS P30 ES09089 and the Irving Institute for Clinical and Translational Research (UL1 TR000040). Dr. Pullman has received research support from NINDS (#R01 NS085136; coinvestigator).
References 1. Louis ED, Ottman RA, Houser WA. How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13:5–10. 2. Louis ED, Ford B, Frucht S, Barnes LF, X-Tang M, 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. 3. Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post mortem enquiry. Lancet Neurol 2010;9:613–622. 4. Benito-Leon J, Alvarez-Linera J, Hernandez-Tamames JA, Alonso-Navarro H, Jimenez-Jimenez FJ, Louis ED. Brain structural changes in essential tremor: voxel-based morphometry at 3-Tesla. J Neurol Sci 2009;287:138–142. 5. Avanzino L, Bove M, Tacchino A, et al. Cerebellar involvement in timing accuracy of rhythmic finger movements in essential tremor. Eur J Neurosci 2009;30:1971–1979. 6. Bares M, Lungu OV, Husarova I, Gescheidt T. Predictive motor timing performance dissociates between early diseases of the cerebellum and Parkinson’s disease. Cerebellum 2010;9:124–135. 7. Zakaria R, Lenz FA, Hua S, Avin BH, Liu CC, Mari Z. Thalamic physiology of intentional essential tremor is more like cerebellar tremor than postural essential tremor. Brain Res 2013;1529:188–199. 8. Elias WJ, Shah BB. Tremor. JAMA 2014;311:948–954. 9. Thengannat MA, Louis ED. Distinguishing essential tremor from Parkinson’s disease: bedside tests and laboratory evaluations. Expert Rev Neurother 2012;6:687–696.
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Intention Tremor in Legs in Essential Tremor 10. Louis ED, Frucht SJ, Rios E. Intention tremor in essential tremor: prevalence and association with disease duration. Mov Disord 2009;24:626– 627. 11. Deuschl G, Wenzelburger R, Loffler K, Raethjen J, Stolze H. Essential tremor and cerebellar dysfunction Clinical and kinematic analysis of intention tremor. Brain 2000;123:1568–1580. 12. Leegwater-Kim J, Louis ED, Pullman S, Floyd AG, Borden S, Moskowitz CB. Intention tremor of the head in patients with essential tremor. Mov Disord 2006;21:2001–2005. 13. Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in patients with essential tremor: prevalence, clinical correlates, and electrophysiologic characteristics. Arch Neurol 2003;60:405–410. 14. Louis ED, Gerbin M, Mullaney MM. What is the functional significance of non-dominant arm tremor in essential tremor? Mov Disord 2010;25:2674–2678. 15. Poston KL, Rios E, Louis ED. Action tremor of the legs in essential tremor: prevalence, clinical correlates, and comparison with age-matched controls. Parkinsonism Relat Disord 2009;15:602–605. 16. Peters DM, Fritz SL, Krotish DE. Assessing the reliability and validity of a shorter walk test compared with the 10-Meter Walk Test for measurements of gait speed in healthy, older adults. J Geriatr Phys Ther 2013;36:24–30. 17. Louis ED, Jurewicz EC, Watner D. Community-based data on associations of disease duration and age with severity of essential tremor: implications for disease pathophysiology. Mov Disord 2003; 18:90–93.
Supporting Information Videos accompanying this article are available in the supporting information here. Video 1. Patient 1: Intention tremor is present on the right. This is not simply kinetic tremor because tremor is not present during the entire outward-upward movement from the floor, but only during the terminal phase of movement while approaching the target (i.e., tongue blade). In addition, kinetic tremor is not evident while moving away from the tongue blade or during the terminal phase of that movement (while coming to rest on the floor). A mild postural leg tremor is evident, but is of lower amplitude than the intention tremor. Video 2. Patient 2: Intention tremor is present on the right. As with patient 1, this is not simply kinetic tremor because tremor is not present during the entire outward-upward movement from the floor, but only during the terminal phase of movement while the foot approaches the tongue blade. In addition, this is not kinetic tremor because tremor is not evident while moving backward away from the tongue blade. No postural leg tremor is evident.
MOVEMENT DISORDERS CLINICAL PRACTICE doi:10.1002/mdc3.12099
CLINICAL PRACTICE
Intention Tremor of the Legs in Essential Tremor: Prevalence and Clinical Correlates Meir Kestenbaum, MD,1 Monika Michalec, MPH,2 Qiping Yu, PhD,1 Seth L. Pullman, MD,1 Elan D. Louis, MD, MSc1,2,3,4,*
Abstract: The aim of this study was to estimate the prevalence and assess the clinical correlates of intention tremor in the legs in essential tremor (ET) patients. The cerebellar features of ET are of growing interest to clinical neurologists. Arm tremor has an intentional component in many ET patients. Intention tremor in the legs, however, has never been systematically evaluated. One hundred twenty-eight ET patients were enrolled in a clinical-epidemiological study at Columbia University (New York, NY). A videotaped neurological examination included 10 toe-to-target movements with each foot. Videotapes were independently reviewed by two movement disorder neurologists who noted the presence versus absence of intentional leg tremor. Two patients underwent quantitative computerized tremor analysis to study the physiological characteristics of the tremor. Thirty-five patients (27.3%) had intentional leg tremor; in 21, tremor was unilateral and in 14 it was bilateral. The 35 patients with intentional leg tremor did not differ from the remaining 93 in their clinical characteristics. Analyses comparing the 14 patients with bilateral intentional leg tremor to the 93 with no intentional leg tremor showed trends toward longer disease duration and moresevere intentional arm tremor in the former. Tremor analysis showed a 3-fold increase in average tremor amplitude from movement onset to the point just before touching the target. Our data suggest that intentional leg tremor, another cerebellar feature, is common in ET patients. The tremor may be associated with longer disease duration and more-severe intentional arm tremor, but these preliminary trends need to be assessed in larger study samples.
Essential tremor (ET), the most common tremor disorder,1,2 is characterized by kinetic and postural tremors, affecting mainly the arms and hands. Current clinical, neuroimaging, and postmortem data indicate cerebellar involvement in ET.3–6 The identification and characterization of additional cerebellar features on neurological examination provides further evidence to support this. With this in mind, the cerebellar features of ET are of growing interest to clinical neurologists. Interestingly, the kinetic arm tremor in ET often has an intentional component. Intention tremor is defined as tremor that increases in amplitude as the target is approached during visually guided movements.7–11 Intention tremor in the arms occurs in 44% to 58% of ET patients.10,11 Intention tremor is not limited to the arms, and it occurs in the head in approximately 10% of ET patients.12 Some forms of tremor in ET are limited to specific
body regions (i.e., in ET, rest tremor occurs in the arms, but is not observed in the legs),13 so we posed the clinical question of whether intention tremor of the legs was a feature of ET. To our knowledge, this has never been assessed formally, and we could find no published data that addressed this question. The aims of this study were to (1) estimate the prevalence of intention tremor in the legs in ET patients and (2) assess its clinical correlates.
Patients and Methods Study Participants and Diagnoses As described previously, ET patients were enrolled in an ongoing clinical-epidemiological study of ET at Columbia University
1
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA; 2GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA; 3Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA; 4Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
* Correspondence to: Dr. Elan D. Louis, Department of Neurology, College of Physicians and Surgeons, Columbia University, 710 West 168th Street, New York, NY 10032-3784, USA; E-mail: [email protected]
Keywords: essential tremor, clinical, intention tremor, cerebellum. Relevant disclosures and conflicts of interest are listed at the end of this article. Received 28 July 2014; revised 11 September 2014; accepted 14 September 2014. Published online 23 October 2014 in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/mdc3.12099
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© 2014 International Parkinson and Movement Disorder Society doi:10.1002/mdc3.12099
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Kestenbaum et al.
(New York, NY), which began in 2000.14 All provided written informed consent approved by the Columbia University Internal Review Board. After a thorough assessment of both questionnaire-derived data and a videotaped neurological examination, ET diagnoses were confirmed by a senior movement disorder neurologist (E.D.L.) based on reliable and validated diagnostic criteria (moderate or greater amplitude kinetic tremor during at least three activities or a head tremor in the absence of Parkinson’s disease [PD], dystonia, or another known cause, e.g., thyroid disease, medications, or Wilson’s disease).2 As described previously,15 assessment of leg tremor by videotaped neurological examination, began in August 2007. For the current analyses, we selected the 128 patients who had had a digitized videotaped neurological examination after that date. There were also 74 age- and gender-matched controls enrolled in the same study during the same time period who had a digitized videotaped neurological examination; data on intention tremor in the legs in these controls were used as a comparison point.
Study Evaluation Cases underwent a comprehensive tremor questionnaire. During the questionnaire, age of onset and duration of tremor symptoms were assessed, as well as complaints of leg tremor (“Do you often have an uncontrollable tremor in your leg?”) and family history of tremor (first- and second-degree relatives). Reported frequency of falls in the last year was assessed (“How many falls have you had in the past year?”). The videotaped neurological examination included detailed assessments of postural, kinetic, and intention tremor in the arms. The severity of postural and kinetic tremor in the arms (total tremor score: range = 0–36) was based on the 0 to 3 ratings of six tasks with each arm. As in previous studies,10 intention tremor (i.e., tremor that occurs with goal-directed movement [finger-nose-finger movement] and worsens when approaching the target) was rated as 0 (absent), 0.5 (probable), and 1 (definite); severity of intention tremor (two arms combined) was therefore graded from 0 to 2. Presence of head and voice tremor was assessed during the videotaped neurological examination. The study began in 2000; however, assessment of leg tremor during the videotaped neurological examination did not begin until August 2007. Starting at that point, the videotaped neurological examination included an assessment of postural tremor of the legs, as previously described,15 as well as 10 repetitive toeto-target movements with each foot. Patients were examined while seated and asked to remove their shoes and socks, although a few preferred to keep their socks on. They were asked to raise their foot from the ground to reach the target (a tongue blade) and touch it with their big toe. The tongue blade was placed at least 16 inches from the ground level (see Videos 1 and 2). The videotapes were reviewed independently by two movement disorder neurologists (M.K. and E.D.L.), who noted the presence versus absence of intention tremor in the legs (i.e., tremor that worsened terminally as the patient’s foot was in
close proximity to the target). The more junior of the two neurologists (M.K.) was trained by the more senior neurologist (E.D.L.) to conservatively mark the presence of intention tremor in the legs. In the case of disagreements between the neurologists, the videotapes were coreviewed until a consensus was reached. There were 37 instances in which the junior neurologist marked the presence of intention tremor of the legs, but on further assessment by the senior neurologist, the tremor was deemed to be no more than kinetic tremor. There were no other sources of disagreement between the two neurologists. A 9-m walk was assessed by asking the patient to walk that distance.16 This task was performed twice and the average time was calculated. Two subjects with intention tremor of the legs (1 male and 1 female, both with intention tremor of the arms as well) were selected to undergo computerized quantitative tremor analysis using an ultralight piezoresistive miniature accelerometer (25 g; weight, 1.2 g) with linear sensitivities of approximately 4.5 mV/g in the biological tremor range (0–25 Hz). The accelerometer was attached to the distal phalanx of the great toe. Movement signals were obtained while performing a targeting task with the foot, moving from the floor to a pressure sensitive target cue 80 cm in height. The tremor acquisition setup allowed for relatively unrestrained activity of the leg and foot throughout testing, approximating the clinical state. Six 10-second trials were obtained per patient. Data from the more affected foot were used in the calculations of averages. Total testing time was approximately 1 hour. Two channels recorded the accelerometric and target sensor signals. Recordings were digitized at 700 Hz with a 16-bit A/D board, smoothed, and processed. Displacement (tremor amplitude) was derived offline by double integration of accelerometric data after filtering out low-frequency voluntary movements (less than 2 Hz) and averaging. Displacement data were calculated from 0.5-second epochs taken from 100 ms after movement onset and 100 ms before reaching the target sensor. Tremor frequencies were calculated from accelerometry using a fast Fourier transform (FFT) to generate auto spectra.
Statistical Analyses Statistical analyses were performed using SPSS software (version 21.0; SPSS, Inc., Chicago, IL). Differences between groups were evaluated using Student’s t and chi-square tests. Ninetyfive percent confidence intervals (CIs) were calculated.
Results Thirty-five (27.3%) of 128 ET patients had intention tremor in the legs (95% CI = 20.3–35.7); by comparison, only 2 (2.7%) of 74 age- and gender-matched controls had such tremor (chisquare test = 19.0; P < 0.001). In 21 (16.4%) of 128 ET patients, tremor was unilateral (in 9 affecting the right leg and in 12 affecting the left leg) and in 14 (10.9%) of 128 it was bilateral. Four (3.1%) ET patients had postural tremor of the MOVEMENT DISORDERS CLINICAL PRACTICE
doi:10.1002/mdc3.12099
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Intention Tremor in Legs in Essential Tremor
TABLE 1 Demographic and clinical characteristics of 128 ET patients P Value
Demographics/Characteristics
Total Patients
Intention Tremor of the Legs
No Intention Tremor of the Legs
No. of ET patients Age, years Female gender Duration of symptoms, years Family history of tremor Severity of action tremor in the arms, total tremor score Severity of intention tremor in the arms Presence of head tremor on examination Presence of voice tremor on examination Complaint of leg tremor by history Reported frequency of falls in the last year 9-m walk, seconds
128 71.5 12.9 66 (51.6) 32.5 18.9 85 (66.4) 20.4 6.1
35 70.5 12.5 15 (42.9) 35.1 19.6 24 (68.6) 19.9 5.3
93 71.8 13.1 51 (54.8) 31.5 18.6 61 (65.6) 20.6 6.4
0.61* 0.23* 0.36* 0.75** 0.56*
0.9 0.7 55 (43.6) 35 (27.8) 16 (12.5) 1.0 3.2 9.6 4.1
1.0 0.65 14 (40) 9 (25.7) 5 (14.3) 1.8 5.6 9.1 3.6
0.85 0.7 41 (45.0) 26 (28.6) 11 (11.8) 0.7 1.2 9.7 4.3
0.27* 0.23** 0.75** 0.76** 0.26* 0.55*
Values represent means standard deviations or numbers (percentages). The P value reports the difference between 35 patients with intention tremor of the legs and 93 without intention tremor of the legs. *Student’s t test. **Chi-square test.
legs; 3 of these had intention tremor of the legs. Subject characteristics are summarized in Table 1. The 35 patients with intention tremor in the legs did not differ from the remaining 93 patients in age, gender, duration of symptoms, family history of tremor, severity of action tremor in the arms, severity of intention tremor in the arms, presence of head tremor on examination, presence of voice tremor on examination, complaint of leg tremor by history, reported frequency of falls in the last year, or 9-m walk (Table 1). Additional analysis that compared the 14 patients with bilateral intention tremor of the legs to the 93 patients with no intention tremor of the legs showed nonsignificant trends toward longer disease duration (39.4 16.4 vs. 31.5 18.6 years; P = 0.15) and more-severe intentional arm tremor (1.2 0.7 vs. 0.85 0.7; P = 0.09). There was no difference in the reported frequency of falls in the last year (3.6 8.5 vs. 0.7 1.2; P = 0.23). Computerized tremor analysis showed a 3-fold increase in average tremor amplitude from just after movement onset to just before touching the target. Foot frequency tremor had a peak of approximately 7.0 to 8.5 Hz, reflecting the oscillations in foot position. The frequency is typical of ET range. Tremor analysis findings are summarized in Figure 1.
Discussion Although we have previously studied postural and kinetic tremor in the legs in ET,15 to our knowledge, this is the first study to assess the prevalence of intention tremor of the legs and its clinical correlates in ET. Our data suggest that intention tremor of the legs is common in ET patients (27.3%), but less common than intentional tremor in the arms (approximately 50%). The 35 patients with intention tremor of the legs did not differ from the remaining 93 in terms of demographics and most clinical features. It is worth mentioning that in the patients with intention tremor of the legs, only a small
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minority (14.3%) were aware of their leg tremor, suggesting the absence of functional impairment caused by this tremor. The lack of difference in the 9-m walking time also supports this lack of a functional correlate. Tremor analysis showed a significant 3-fold increase in tremor amplitude from movement onset to just before touching the target, thus supporting the clinical observation of an intentional component to the tremor. A subgroup of 14 patients with bilateral intentional tremor showed nonsignificant trends toward longer disease duration and more-severe intentional arm tremor, when compared to the 93 ET patients without intention tremor of the legs. This finding would be consistent with the view that ET is a progressive disease with the development of other forms of tremor (rest tremor and intention tremors) over time.17 This needs to be further explored in a longitudinal study, which would allow us to follow individuals over time and assess the change in the prevalence of intention tremor of the legs with time. Furthermore, these preliminary trends need to be assessed in larger study samples. This article had limitations. First, the tremor analysis was performed on only 2 cases, and though the findings support the clinical results, it would be of value to study a larger number of subjects in order to make a more general set of statements about the physiological properties of this type of tremor in ET. Also, a study of intention tremor of the legs in other disorders, such as tremor predominant PD, would further extend the study of this clinical phenomenology to other settings. In summary, intention tremor of the legs may be unrecognized, but is common in ET patients, among whom intentional tremors can occur in a variety of other body regions (e.g., arms and head). This and other cerebellar signs may serve as markers of an underlying disorder of cerebellar function in this disease. Whether the intention tremors of ET worsen over time similar to other ET tremors is not known, but this is worthy of study.
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RESEARCH ARTICLE
Kestenbaum et al.
(A)
(B)
Figure 1 (A) Upper panel: movement tracing from 1 patient showing foot position from rest to target. Accelerometric data are sampled at 700 Hz, digitized with a 16-bit A/D board, smoothed, and processed to give displacement. Displacement data are calculated from 0.5-second epochs (solid lines A and B) from just after movement onset (indicated by single arrow) and just before reaching the target sensor (indicated by double arrow). Lower panel: An FFT with a peak of approximately 7.0 to 8.5 Hz at the asterisk (*) reflecting the oscillations in the upper panel in the ET range. Large, low-frequency peak reflects foot movement. (B) Bar graph showing data from 0.5-second epochs from six complete trials showing a 3-fold increase in average tremor amplitude from just after movement onset (corresponding to A) to just before touching the target (corresponding to B).
Author Roles (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
M.K.: 1B, 1C, 2B, 3A M.M.: 1B, 1C, 2C, 3B Q.Y.: 1B, 1C, 2C, 3B S.L.P.: 1B, 1C, 2C, 3B E.D.L.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
MOVEMENT DISORDERS CLINICAL PRACTICE doi:10.1002/mdc3.12099
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RESEARCH ARTICLE
Disclosures Funding Sources and Conflicts of Interest: Dr. Louis was funded by R01 NS039422 from the National Institutes of Health (NIH). The authors report no conflicts of interest. Financial Disclosures for previous 12 months: Dr. Louis has received research support from the NIH: National Institute of Neurological Disorders and Stroke (NINDS) #R01 NS042859 (principal investigator [PI]); NINDS #R01 NS39422 (PI); NINDS #R01 NS086736 (PI); NINDS #R01 NS073872 (PI); NINDS #R01 NS085136 (PI); NINDS #T32 NS07153-24 (PI); NINDS #R21 NS077094 (coinvestigator); and NINDS #R01 NS36630 (coinvestigator); 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); and he also acknowledges the support of NIEHS P30 ES09089 and the Irving Institute for Clinical and Translational Research (UL1 TR000040). Dr. Pullman has received research support from NINDS (#R01 NS085136; coinvestigator).
References 1. Louis ED, Ottman RA, Houser WA. How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13:5–10. 2. Louis ED, Ford B, Frucht S, Barnes LF, X-Tang M, 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. 3. Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post mortem enquiry. Lancet Neurol 2010;9:613–622. 4. Benito-Leon J, Alvarez-Linera J, Hernandez-Tamames JA, Alonso-Navarro H, Jimenez-Jimenez FJ, Louis ED. Brain structural changes in essential tremor: voxel-based morphometry at 3-Tesla. J Neurol Sci 2009;287:138–142. 5. Avanzino L, Bove M, Tacchino A, et al. Cerebellar involvement in timing accuracy of rhythmic finger movements in essential tremor. Eur J Neurosci 2009;30:1971–1979. 6. Bares M, Lungu OV, Husarova I, Gescheidt T. Predictive motor timing performance dissociates between early diseases of the cerebellum and Parkinson’s disease. Cerebellum 2010;9:124–135. 7. Zakaria R, Lenz FA, Hua S, Avin BH, Liu CC, Mari Z. Thalamic physiology of intentional essential tremor is more like cerebellar tremor than postural essential tremor. Brain Res 2013;1529:188–199. 8. Elias WJ, Shah BB. Tremor. JAMA 2014;311:948–954. 9. Thengannat MA, Louis ED. Distinguishing essential tremor from Parkinson’s disease: bedside tests and laboratory evaluations. Expert Rev Neurother 2012;6:687–696.
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Intention Tremor in Legs in Essential Tremor 10. Louis ED, Frucht SJ, Rios E. Intention tremor in essential tremor: prevalence and association with disease duration. Mov Disord 2009;24:626– 627. 11. Deuschl G, Wenzelburger R, Loffler K, Raethjen J, Stolze H. Essential tremor and cerebellar dysfunction Clinical and kinematic analysis of intention tremor. Brain 2000;123:1568–1580. 12. Leegwater-Kim J, Louis ED, Pullman S, Floyd AG, Borden S, Moskowitz CB. Intention tremor of the head in patients with essential tremor. Mov Disord 2006;21:2001–2005. 13. Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in patients with essential tremor: prevalence, clinical correlates, and electrophysiologic characteristics. Arch Neurol 2003;60:405–410. 14. Louis ED, Gerbin M, Mullaney MM. What is the functional significance of non-dominant arm tremor in essential tremor? Mov Disord 2010;25:2674–2678. 15. Poston KL, Rios E, Louis ED. Action tremor of the legs in essential tremor: prevalence, clinical correlates, and comparison with age-matched controls. Parkinsonism Relat Disord 2009;15:602–605. 16. Peters DM, Fritz SL, Krotish DE. Assessing the reliability and validity of a shorter walk test compared with the 10-Meter Walk Test for measurements of gait speed in healthy, older adults. J Geriatr Phys Ther 2013;36:24–30. 17. Louis ED, Jurewicz EC, Watner D. Community-based data on associations of disease duration and age with severity of essential tremor: implications for disease pathophysiology. Mov Disord 2003; 18:90–93.
Supporting Information Videos accompanying this article are available in the supporting information here. Video 1. Patient 1: Intention tremor is present on the right. This is not simply kinetic tremor because tremor is not present during the entire outward-upward movement from the floor, but only during the terminal phase of movement while approaching the target (i.e., tongue blade). In addition, kinetic tremor is not evident while moving away from the tongue blade or during the terminal phase of that movement (while coming to rest on the floor). A mild postural leg tremor is evident, but is of lower amplitude than the intention tremor. Video 2. Patient 2: Intention tremor is present on the right. As with patient 1, this is not simply kinetic tremor because tremor is not present during the entire outward-upward movement from the floor, but only during the terminal phase of movement while the foot approaches the tongue blade. In addition, this is not kinetic tremor because tremor is not evident while moving backward away from the tongue blade. No postural leg tremor is evident.
MOVEMENT DISORDERS CLINICAL PRACTICE doi:10.1002/mdc3.12099
