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Asymmetry of tremor intensity and frequency in Parkinson's disease and essential tremor
Parkinsonism and Related Disorders 12 (2006) 49–55 www.elsevier.com/locate/parkreldis
Asymmetry of tremor intensity and frequency in Parkinson’s disease and essential tremor Zsuzsanna Farkas, Anita Csillik, Imre Szirmai, Anita Kamondi* Department of Neurology, Semmelweis University, Balassa u. 6., 1083 Budapest, Hungary Received 14 January 2005; revised 28 June 2005; accepted 25 July 2005
Abstract We investigated the asymmetry of tremor intensity, frequency and frequency dispersion of Parkinsonian (PT) and essential (ET) tremor using accelerometry. Data of the more and less trembling hands were statistically elaborated. We found that tremor intensity was significantly asymmetric not only in PT but also in ET, while frequency and frequency dispersion were symmetric in ET but asymmetric in PT. We conclude that bilateral assessment of frequency related tremor parameters may be used for differentiation between ET and PT, and provides further details on the central organization of tremor generators. q 2005 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Essential tremor; Accelerometry; Intensity; Center frequency; Frequency dispersion
1. Introduction The most frequent tremor syndromes are the Parkinsonian (PT) and essential (ET) tremor [1] that are generated by central mechanisms [2–4]. It is a clinical evidence, which has only recently been corroborated by a study using clinical score systems [5], that tremor intensity in Parkinson’s disease is asymmetric [1,6]. ET has long been considered a symmetric disorder, but it has been found by Louis et al. [7] that amplitude asymmetry is a fundamental property of ET. Although frequency/ amplitude dependency is an important characteristic of oscillating systems [8], it has not been examined, whether intensity asymmetry in PT and ET is associated with asymmetry of frequency. In studies, where amplitude and frequency were measured on one side only, this question could not be addressed [9–12]. In publications with bilateral recordings, data of the two hands were either combined, or the averages of the right/left, or dominant/non-dominant hands were compared, regardless of which hand was affected more [13–18]. It was shown, that frequency on the two sides was similar in physiological tremor [19], but * Corresponding author. Tel.: C36 1 210 0337; fax: C36 1 2101368. E-mail address: [email protected] (A. Kamondi).
1353-8020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2005.07.008
right-left difference was noted in Parkinson’s disease [16,20] and ET [16]. Calzetti et al. [21] reported that in ET frequency on the more affected hand was about 1 Hz lower than on the least affected one, although in another investigation no amplitude dependent frequency asymmetry was found in either PT or ET [22]. We carried out bilateral accelerometry and measured the intensity, center frequency and frequency dispersion of PT and ET. We analyzed, the side-to-side asymmetry of these parameters and described the relation between tremor intensity and frequency of the more and less affected hand. We expected, that the results might help the differentiation of the two most prevalent tremor syndromes in questionable cases.
2. Patients and methods 2.1. Subjects We examined 37 healthy controls, 48 PT and 47 ET patients. Demographic data and disease characteristics are shown in Table 1. There was no significant difference between the age of the three groups. All subjects were right handed. The experimental procedure was approved by the Local Ethical Committee, and all individuals gave written informed consent.
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Z. Farkas et al. / Parkinsonism and Related Disorders 12 (2006) 49–55
Table 1 Clinical characteristics of the groups
Number of patients Mean ageGSD Female/male Duration of illness Right side dominant tremor
Control
Parkinson’s disease
Essential tremor
37
48
47
58.78G15.52 20/17 –
65.02G11.17 20/28 5.01G3.73
63.74G13.94 22/25 13.28G12.12
17
27
24
Tremor severity* 1. 2. 3. 4.
WHIGET
UPDRS
– – – –
20
21
11 14 14 9
10 14 12 0
7 18 16 6
Based on item 20 (rest tremor) and 21 (postural and action tremor) of the UPDRS in Parkinson’s disease and on WHIGET scale in essential tremor.
Healthy subjects were staff members of our Department, and had no prior history of any neurological disorder. Patients were selected from our Movement Disorders Outpatient Service between September 2003 and January 2004. Patients were referred to the Outpatient Service by general practitioners and neurology specialists due to differential diagnostic difficulties and/or for control examinations. The only selection criteria for our study were age and gender, other aspects (tremor intensity, duration and severity of disease, medication etc.) were not taken into consideration. Patients were first evaluated by an independent movement disorder specialist, who based upon clinical findings and physical examination, assigned the diagnosis of essential tremor or Parkinson’s disease, using the criteria of the Movement Disorders Society and the Tremor Investigation Group [1,23–25]. Fifteen of our Parkinson patients had type I and 33 had type II tremor. Clinical assessment was followed by electrophysiological investigations 2–3 days later. Measurements were carried out within 0.5–2.0 h after patients took the first daily dose of their medication. This in the PT group included levodopa, dopamin agonist, selegilin, while in
the ET group beta blockers and primidone. In both groups there were patients who did not take medicine. Subjects were asked to refrain from taking sleeping pills, and drinking coffee and/or alcohol 24 h prior to tremorometry. 2.2. Accelerometry We used a computer assisted tremor analysis system (CATSYS 2000, Danish Product Development Ltd), which has been proved to provide a high degree of reproducibility of the tests [26–28]. A large set of normative data for the system was compiled by Despres et al. [29]. Tremor was recorded for 32.8 s by a biaxial micro-accelerometer embedded in the tip of a pen-like tube (weight: 10.5 g, sensitivity: O0.3 m/s2). Measurements were carried out consecutively on the right and left hands. Subjects sat in a chair and hold the tremor-pen like an ordinary pen. The wrist was resting on a table in front of them. The position of the index finger was marked on the pen (2 cm from the tip). Although, this is a combination of resting and postural position, we used it because it did not require any special supporting equipment and it was easily reproducible by patients. In addition, in a study, where the effect of limb posture on tremor differentiation was investigated, it was found, that, the optimal classification of ET and PT was obtained, using frequency and amplitude parameters, when the hand and forearm were both fully supported [30]. It was also reported that tremor abnormalities in PT could be better discriminated in postural position [17]. In the present study, we did not analyze EMG data. Accelerometric signals were digitized (128 Hz) and Fourier transformed. The normalized power spectrum was composed of 116 frequency bands (each approximately 0.12 Hz wide in the range of 0.9–15 Hz) based on the root of sum of squares of power values for each frequency band. Tremor intensity was calculated as the root-mean-square of acceleration (m/s2). The acceleration of movement is the second derivative of displacement (m). Center frequency (CF, Hz) is the median of the area below the power spectrum (Fig. 1). Our equipment calculates this parameter, because as it has been discussed by Edwards and Beuter [31], a computer based system must
Fig. 1. Power spectrum of a control subject (A) and a patient with essential tremor (B). The thin line shows the normalized power, the thick line shows the running average of the normalized power. Thick vertical line marks the center frequency, the two thin vertical lines mark the frequency dispersion.
Z. Farkas et al. / Parkinsonism and Related Disorders 12 (2006) 49–55
use a clearly defined algorithm for calculation of tremor frequency in all subjects. However, when there is no discernible tremor peak, CF may lie at a frequency without much power, unrelated to any oscillatory component of the signal. To avoid this pitfall of CF measurements, we excluded from the analysis those subjects who did not have a discernible tremor peak in the spectrum. Frequency dispersion (FD, Hz) is the frequency width of an interval around the center frequency that contains 66% of the total power of the spectrum. This parameter can be reliably used for quantifying the harmonicity of oscillations. For a more regular oscillation with a single narrow frequency peak in the spectrum (like parkinsonian or essential tremor), the dispersion bandwidth is small. In irregular tremors (like physiological tremor), which have several peaks in the spectrum, FD is broader [17,31] (Fig. 1). Although CF and FD are not entirely unrelated, they measure different aspects of the tremor. CF addresses the question of the dominant frequency of the oscillation, while FD describes the power concentration in the spectrum [17]. 2.3. Statistical analysis Our principal experimental hypothesis was that intensity, CF and FD are asymmetric in PT, but not in ET. This hypothesis was tested with analysis of variance (ANOVA) using Statistica software package (Statsoft Inc., 6.0 version). Tremor parameters were calculated in each group by pooling the data three different ways: (a) averaging the values of the two hands, (b) separating the data of the right and left hand, and (c) grouping the data of the higher and lower intensity side, according to the results of the accelerometry. In case (a) one-way ANOVA was used to compare group means. In case (b) and (c) dependent variables were analyzed using one-way repeated measures ANOVA with a between subjects factor for group and a within subject factor for right and left hand in (b) and for more and less trembling hand in (c). We also investigated the tremor parameters of two subgroups of PT and ET patients. In ‘subgroup A’ tremor intensity of the more affected hand was not higher than the averageC1SD (!0.2 m/s2) of the control group (nPTZ22, nETZ7). In subgroup B tremor intensity was considerably asymmetric, the difference between the more and less affected hand was higher than 0.1 m/s2, which was the averageC1SD of the controls (nPTZ21, nETZ32). Statistics were conducted similarly to case (c). If ANOVA was relevant, Tukey’s Honestly Significant Difference for unequal N (HSD for unequal N) post-hoc test was used to determine the specific effects. We investigated the relationship between tremor intensity and center frequency using regression analysis of log tremor displacement versus log center frequency as it has been reported by Elble [32].
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We analyzed the data of type I and type II PT groups separately, but since the results were similar, we presented the combined data of the two groups. Significance level for all statistical methods was set at p!0.05.
3. Results 3.1. Tremor intensity When values of the two hands were combined, intensity of ET was significantly higher than PT and controls, but there was no significant difference between controls and PT (control: 0.10G0.07 m/s2, PT: 0.36G0.58 m/s2, ET: 1.65G 1.26 m/s2). ANOVA did not reveal significant effect for side or group!side interaction when average intensity of the right and left hands were analyzed, which means that there was no significant right/left difference in the three groups (Fig. 2, Table 2). In controls there was no significant difference between the more and less trembling side, but both in PT and ET tremor intensity of the more affected hand was significantly higher than on the less affected one. PT intensity on the less trembling side was similar to control data (Fig. 2, Table 2). In subgroup A (patients with normal intensity) the significant intensity asymmetry between the more and less trembling hand was still present in both PT and ET (Fig. 3, Table 2). In patients with large intensity asymmetry (subgroup B for PT and ET), due to the selection criteria, statistics showed significant difference between the two hands in both groups (Fig. 3, Table 2). 3.2. Center frequency When data of the two hands were combined, frequency of PT and ET was significantly smaller compared to controls, and in ET it was significantly smaller than in PT (control: 9.00G1.32 Hz, PT: 7.32G1.74 Hz, ET: 6.49G 1.29 Hz). Statistical analysis of CF of the right and left hand did not reveal any difference between the two sides in either group (Fig. 2, Table 2). In controls and in ET patients tremor frequency was symmetric on the more and less trembling side. However, CF of PT was significantly higher on the less compared to the more affected hand (Fig. 2, Table 2). CF in patients with normal intensity (subgroup A) was similar on the two sides in ET, but it was asymmetric in PT (Fig. 3, Table 2). In subgroup B of PT the central frequency of the more affected side was significantly smaller, than that of the less
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Z. Farkas et al. / Parkinsonism and Related Disorders 12 (2006) 49–55
Fig. 2. Mean tremor intensity, center frequency and frequency dispersion in the different groups (vertical bars indicate 95% confidence interval). Left/right data are shown in the left column, while more trembling/less trembling data can be seen in the right column.
trembling side, while it was similar on both hands in ET (Fig. 3, Table 2). 3.3. Frequency dispersion Combining the data of the two hands ANOVA showed that frequency dispersion was significantly
larger in the control group compared to PT and ET, and also it was significantly higher in PT than ET (control: 3.05G0.59 Hz, PT: 1.66G1.08 Hz, ET: 0.89C 0.82 Hz). There was no side-to-side difference of FD in the three groups, when right and left hand averages were compared (Fig. 2, Table 2).
Table 2 Results of ANOVA Aspect of data grouping
Combined data of the two hands Right/left hand
More/less trembling hand
Subgroup A More/less trembling hand Subgroup B More/less trembling hand
Tremor intensity
Center frequency
Frequency dispersion
F
p
F
p
F
p
F(2,129)Z18.2 Fg(2,129)Z10.57 Fs(1,129)Z0.006 Fi(2,129)Z0.03 Fg(2,129)Z10.57 Ft(1,129)Z33.25 Fi(2,129)Z7.19 Fg(1,27)Z3.72 Ft(1,27)Z30.99 Fi(1,27)Z0.07 Fg(1,51)Z1.63 Ft(1,51)Z44.08 Fi(1,51)Z0.05
p!0.001 p!0.001 pZ0.937 pZ0.969 p!0.001 p!0.001 pZ0.001 pZ0.064 p!0.001 pZ0.789 pZ0.207 p!0.001 pZ0.818
F(2,129)Z40.72 Fg(2,129)Z40.72 Fs(1,129)Z0.32 Fi(2,129)Z0.74 Fg(2,129)Z40.70 Ft(1,129)Z6.54 Fi(2,129)Z2.76 Fg(1,27)Z3.25 Ft(1,27)Z3.52 Fi(1,27)Z0.67 Fg(1,51)Z3.26 Ft(1,51)Z6.33 Fi(1,51)Z6.58
p!0.001 p!0.001 pZ0.601 pZ0.482 p!0.001 pZ0.012 pZ0.067 pZ0.080 pZ0.038 pZ0.420 pZ0.077 pZ0.015 pZ0.013
F(2,129)Z110.09 Fg(2,129)Z120.18 Fs(1,129)Z1.47 Fi(2,129)Z0.12 Fg(2,129)Z120.54 Ft(1,129)Z31.16 Fi(2,129)Z11.73 Fg(1,27)Z1.93 Ft(1,27)Z3.57 Fi(1,27)Z2.23 Fg(1,51)Z23.30 Ft(1,51)Z42.14 Fi(1,51)Z16.27
p!0.001 p!0.001 pZ0.227 pZ0.887 p!0.001 p!0.001 p!0.001 pZ0.175 pZ0.045 pZ0.147 p!0.001 p!0.001 p!0.001
Fg, F group; Fs, F side; Ft, F trembling; Fi, F interaction. Subgroup A: less than 0.2 m/s2 tremor intensity (nPDZ22, nETZ7). Subgroup B: higher than 0.1 m/s2 side-to-side intensity difference (nPDZ21, nETZ32).
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Fig. 3. Mean tremor intensity, center frequency and frequency dispersion in the two subgroups of patients (vertical bars indicate 95% confidence interval). Subgroup A: patients with normal tremor intensity (nPTZ22, nETZ7). Subgroup B: patients with high side-to-side tremor intensity difference (nPTZ21, nETZ 32). C, more trembling hand; -, less trembling hand.
FD of the more and less tremulous hand was symmetric in control subjects and in ET patients, but it was significantly smaller on the more compared to the less trembling side in PT (Fig. 2, Table 2). Parkinson patients with low tremor intensity (subgroup A) had significantly asymmetric FD (smaller on the higher intensity side), while it was symmetrically low on both sides in ET (Fig. 3, Table 2.). In subgroup B of PT patients the intensity difference related FD asymmetry was highly significant, however, in ET a complete lack of asymmetry could be revealed (Fig. 3, Table 2). 3.4. Correlation between tremor intensity and center frequency To investigate the relationship between tremor intensity and CF we carried out regression analysis (Fig. 4). A strong inverse linear correlation was revealed between log tremor displacement and log center frequency in control subjects and in PT both on the more and less affected side. In ET, the linear correlation was found only on the more trembling side, intensity and frequency were not related on the less affected hand.
4. Discussion We examined the asymmetry of tremor on the right/left and the more/less trembling side of controls, PT and ET patients. In PT and ET tremor intensity of the right and left hand was higher compared to controls, but without any side-toside difference. Although similar data have already been reported [18], these results were in contradiction with the clinical evidence, that tremor is asymmetric in Parkinson’s disease. Louis et al. [7] have also reported, that in 12 ET patients accelerometry showed intensity side-difference. To investigate, the asymmetry of tremor parameters we reclustered the data according to more and less trembling hand. Statistics showed that both PT and ET intensity of the more affected side was 2.5 times higher than that of the less affected one. The intensity of ET even on the less affected side was significantly higher compared to controls. These data proved, for the first time quantitatively, that tremor intensity is indeed asymmetric in Parkinson’s disease, and confirmed the findings of Louis et al. [7] regarding tremor intensity asymmetry in ET. Frequency of PT in our study was higher than that of usually reported. This is due to the fact, that in the penholding position we measured a combination of resting
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Z. Farkas et al. / Parkinsonism and Related Disorders 12 (2006) 49–55
Fig. 4. Correlation between log (base 10) displacement (m) and log center frequency (Hz) of the more trembling hand (upper row) and less trembling hand (lower row). Physiologic tremor: p!0.001 for the more and pZ0.021 for the less trembling hand, Parkinson patients: p!0.001 for both hands, patients with essential tremor: p!0.001 for the more, and pZ0.116 for the less trembling hand.
(lower frequency) and action (higher frequency) tremor, and that two-third of our PT patients’ had type II tremor. Furthermore, tremor frequencies of up to 9 Hz can be found in early Parkinson’s disease [1], and disease duration of our PT patients was only 5.33G4.07 years, and half of the patients had only mild clinical symptoms. CF and FD in both PT and ET were significantly smaller than in controls. In PT these parameters were significantly smaller on the more compared to the less affected hand. Astonishingly in ET, despite the robust intensity difference between the two hands, CF and FD were symmetrically smaller on the two sides. It is important to emphasize that in Parkinson’s disease CF on the less trembling hand was significantly lower than that of controls, although tremor intensity of this hand was in the normal range. Asymmetric increase in the regularity of parkinsonian tremor, without higher amplitude, was reported by Vaillancourt and Newell [33] using approximate entropy analysis of acceleration. These findings prompted us to examine the intensity/ frequency relation of low intensity tremor (subgroups A). Unexpectedly, the intensity difference between the more and less affected hand was still strongly significant in both tremor types. CF and FD in subgroup A of Parkinson patients decreased asymmetrically, while in ET they are symmetrically low. Our results suggest, that the pathological tremor generators are already active at the early stage of the disease, even when tremor is visually hardly detectable. Regression analysis proved that inverse linear correlation between log displacement versus log frequency existed both on the more and less trembling side in PT. Similar data have not been presented previously. An inverse linear
relationship in ET has been reported [9,32], but the correlation in our ET cohort could be found only on the more affected side. These results, however, are not contradictory, since in previous studies correlations were investigated only on one side in all patients. Although the interpretation of power spectra of biological signals needs special care [8,34], asymmetric PT frequency on the two hands may suggest that regardless of the fine structure of the oscillatory network, there are separate, relatively independent hemispheric tremor generators in Parkinson’s disease. Similar results have been obtained by Raethjen et al. [35], who showed that there is a high intralimb but almost no interlimb coherence of EMG activity in parkinsonian tremor, suggesting separate uncoupled oscillators for each limb. In ET, we found symmetrically low tremor frequency on both sides, even when intensity was considerably asymmetric (subgroup B), which might be explained by interconnected hemispheric generators. Our results are in agreement with those of Hellwig et al. [36], who reported that tremor-EMGs were coherent with EEG activity over both the contra- and ipsilateral sensorimotor cortex, suggesting interhemispheric coupling of central oscillators in ET. The diagnosis of various tremor syndromes might be challenging, especially in cases of low tremor intensity. Our data show that bilateral measurement of tremor parameters can be used to distinguish the two most common tremor types, since symmetric decrease of frequency parameters regardless of intensity asymmetry is characteristic of ET, while asymmetric intensity and frequency data are the main features of PT.
Z. Farkas et al. / Parkinsonism and Related Disorders 12 (2006) 49–55
Acknowledgements The authors would like to thank Dr Annama´ria Taka´ts, ´ gnes Hanyecz for their help. AK Marianna Ke´zsma´rki and A was supported by the Istva´n Sze´chenyi Fellowship of the Ministry of Education of Hungary.
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Asymmetry of tremor intensity and frequency in Parkinson’s disease and essential tremor Zsuzsanna Farkas, Anita Csillik, Imre Szirmai, Anita Kamondi* Department of Neurology, Semmelweis University, Balassa u. 6., 1083 Budapest, Hungary Received 14 January 2005; revised 28 June 2005; accepted 25 July 2005
Abstract We investigated the asymmetry of tremor intensity, frequency and frequency dispersion of Parkinsonian (PT) and essential (ET) tremor using accelerometry. Data of the more and less trembling hands were statistically elaborated. We found that tremor intensity was significantly asymmetric not only in PT but also in ET, while frequency and frequency dispersion were symmetric in ET but asymmetric in PT. We conclude that bilateral assessment of frequency related tremor parameters may be used for differentiation between ET and PT, and provides further details on the central organization of tremor generators. q 2005 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Essential tremor; Accelerometry; Intensity; Center frequency; Frequency dispersion
1. Introduction The most frequent tremor syndromes are the Parkinsonian (PT) and essential (ET) tremor [1] that are generated by central mechanisms [2–4]. It is a clinical evidence, which has only recently been corroborated by a study using clinical score systems [5], that tremor intensity in Parkinson’s disease is asymmetric [1,6]. ET has long been considered a symmetric disorder, but it has been found by Louis et al. [7] that amplitude asymmetry is a fundamental property of ET. Although frequency/ amplitude dependency is an important characteristic of oscillating systems [8], it has not been examined, whether intensity asymmetry in PT and ET is associated with asymmetry of frequency. In studies, where amplitude and frequency were measured on one side only, this question could not be addressed [9–12]. In publications with bilateral recordings, data of the two hands were either combined, or the averages of the right/left, or dominant/non-dominant hands were compared, regardless of which hand was affected more [13–18]. It was shown, that frequency on the two sides was similar in physiological tremor [19], but * Corresponding author. Tel.: C36 1 210 0337; fax: C36 1 2101368. E-mail address: [email protected] (A. Kamondi).
1353-8020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2005.07.008
right-left difference was noted in Parkinson’s disease [16,20] and ET [16]. Calzetti et al. [21] reported that in ET frequency on the more affected hand was about 1 Hz lower than on the least affected one, although in another investigation no amplitude dependent frequency asymmetry was found in either PT or ET [22]. We carried out bilateral accelerometry and measured the intensity, center frequency and frequency dispersion of PT and ET. We analyzed, the side-to-side asymmetry of these parameters and described the relation between tremor intensity and frequency of the more and less affected hand. We expected, that the results might help the differentiation of the two most prevalent tremor syndromes in questionable cases.
2. Patients and methods 2.1. Subjects We examined 37 healthy controls, 48 PT and 47 ET patients. Demographic data and disease characteristics are shown in Table 1. There was no significant difference between the age of the three groups. All subjects were right handed. The experimental procedure was approved by the Local Ethical Committee, and all individuals gave written informed consent.
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Z. Farkas et al. / Parkinsonism and Related Disorders 12 (2006) 49–55
Table 1 Clinical characteristics of the groups
Number of patients Mean ageGSD Female/male Duration of illness Right side dominant tremor
Control
Parkinson’s disease
Essential tremor
37
48
47
58.78G15.52 20/17 –
65.02G11.17 20/28 5.01G3.73
63.74G13.94 22/25 13.28G12.12
17
27
24
Tremor severity* 1. 2. 3. 4.
WHIGET
UPDRS
– – – –
20
21
11 14 14 9
10 14 12 0
7 18 16 6
Based on item 20 (rest tremor) and 21 (postural and action tremor) of the UPDRS in Parkinson’s disease and on WHIGET scale in essential tremor.
Healthy subjects were staff members of our Department, and had no prior history of any neurological disorder. Patients were selected from our Movement Disorders Outpatient Service between September 2003 and January 2004. Patients were referred to the Outpatient Service by general practitioners and neurology specialists due to differential diagnostic difficulties and/or for control examinations. The only selection criteria for our study were age and gender, other aspects (tremor intensity, duration and severity of disease, medication etc.) were not taken into consideration. Patients were first evaluated by an independent movement disorder specialist, who based upon clinical findings and physical examination, assigned the diagnosis of essential tremor or Parkinson’s disease, using the criteria of the Movement Disorders Society and the Tremor Investigation Group [1,23–25]. Fifteen of our Parkinson patients had type I and 33 had type II tremor. Clinical assessment was followed by electrophysiological investigations 2–3 days later. Measurements were carried out within 0.5–2.0 h after patients took the first daily dose of their medication. This in the PT group included levodopa, dopamin agonist, selegilin, while in
the ET group beta blockers and primidone. In both groups there were patients who did not take medicine. Subjects were asked to refrain from taking sleeping pills, and drinking coffee and/or alcohol 24 h prior to tremorometry. 2.2. Accelerometry We used a computer assisted tremor analysis system (CATSYS 2000, Danish Product Development Ltd), which has been proved to provide a high degree of reproducibility of the tests [26–28]. A large set of normative data for the system was compiled by Despres et al. [29]. Tremor was recorded for 32.8 s by a biaxial micro-accelerometer embedded in the tip of a pen-like tube (weight: 10.5 g, sensitivity: O0.3 m/s2). Measurements were carried out consecutively on the right and left hands. Subjects sat in a chair and hold the tremor-pen like an ordinary pen. The wrist was resting on a table in front of them. The position of the index finger was marked on the pen (2 cm from the tip). Although, this is a combination of resting and postural position, we used it because it did not require any special supporting equipment and it was easily reproducible by patients. In addition, in a study, where the effect of limb posture on tremor differentiation was investigated, it was found, that, the optimal classification of ET and PT was obtained, using frequency and amplitude parameters, when the hand and forearm were both fully supported [30]. It was also reported that tremor abnormalities in PT could be better discriminated in postural position [17]. In the present study, we did not analyze EMG data. Accelerometric signals were digitized (128 Hz) and Fourier transformed. The normalized power spectrum was composed of 116 frequency bands (each approximately 0.12 Hz wide in the range of 0.9–15 Hz) based on the root of sum of squares of power values for each frequency band. Tremor intensity was calculated as the root-mean-square of acceleration (m/s2). The acceleration of movement is the second derivative of displacement (m). Center frequency (CF, Hz) is the median of the area below the power spectrum (Fig. 1). Our equipment calculates this parameter, because as it has been discussed by Edwards and Beuter [31], a computer based system must
Fig. 1. Power spectrum of a control subject (A) and a patient with essential tremor (B). The thin line shows the normalized power, the thick line shows the running average of the normalized power. Thick vertical line marks the center frequency, the two thin vertical lines mark the frequency dispersion.
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use a clearly defined algorithm for calculation of tremor frequency in all subjects. However, when there is no discernible tremor peak, CF may lie at a frequency without much power, unrelated to any oscillatory component of the signal. To avoid this pitfall of CF measurements, we excluded from the analysis those subjects who did not have a discernible tremor peak in the spectrum. Frequency dispersion (FD, Hz) is the frequency width of an interval around the center frequency that contains 66% of the total power of the spectrum. This parameter can be reliably used for quantifying the harmonicity of oscillations. For a more regular oscillation with a single narrow frequency peak in the spectrum (like parkinsonian or essential tremor), the dispersion bandwidth is small. In irregular tremors (like physiological tremor), which have several peaks in the spectrum, FD is broader [17,31] (Fig. 1). Although CF and FD are not entirely unrelated, they measure different aspects of the tremor. CF addresses the question of the dominant frequency of the oscillation, while FD describes the power concentration in the spectrum [17]. 2.3. Statistical analysis Our principal experimental hypothesis was that intensity, CF and FD are asymmetric in PT, but not in ET. This hypothesis was tested with analysis of variance (ANOVA) using Statistica software package (Statsoft Inc., 6.0 version). Tremor parameters were calculated in each group by pooling the data three different ways: (a) averaging the values of the two hands, (b) separating the data of the right and left hand, and (c) grouping the data of the higher and lower intensity side, according to the results of the accelerometry. In case (a) one-way ANOVA was used to compare group means. In case (b) and (c) dependent variables were analyzed using one-way repeated measures ANOVA with a between subjects factor for group and a within subject factor for right and left hand in (b) and for more and less trembling hand in (c). We also investigated the tremor parameters of two subgroups of PT and ET patients. In ‘subgroup A’ tremor intensity of the more affected hand was not higher than the averageC1SD (!0.2 m/s2) of the control group (nPTZ22, nETZ7). In subgroup B tremor intensity was considerably asymmetric, the difference between the more and less affected hand was higher than 0.1 m/s2, which was the averageC1SD of the controls (nPTZ21, nETZ32). Statistics were conducted similarly to case (c). If ANOVA was relevant, Tukey’s Honestly Significant Difference for unequal N (HSD for unequal N) post-hoc test was used to determine the specific effects. We investigated the relationship between tremor intensity and center frequency using regression analysis of log tremor displacement versus log center frequency as it has been reported by Elble [32].
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We analyzed the data of type I and type II PT groups separately, but since the results were similar, we presented the combined data of the two groups. Significance level for all statistical methods was set at p!0.05.
3. Results 3.1. Tremor intensity When values of the two hands were combined, intensity of ET was significantly higher than PT and controls, but there was no significant difference between controls and PT (control: 0.10G0.07 m/s2, PT: 0.36G0.58 m/s2, ET: 1.65G 1.26 m/s2). ANOVA did not reveal significant effect for side or group!side interaction when average intensity of the right and left hands were analyzed, which means that there was no significant right/left difference in the three groups (Fig. 2, Table 2). In controls there was no significant difference between the more and less trembling side, but both in PT and ET tremor intensity of the more affected hand was significantly higher than on the less affected one. PT intensity on the less trembling side was similar to control data (Fig. 2, Table 2). In subgroup A (patients with normal intensity) the significant intensity asymmetry between the more and less trembling hand was still present in both PT and ET (Fig. 3, Table 2). In patients with large intensity asymmetry (subgroup B for PT and ET), due to the selection criteria, statistics showed significant difference between the two hands in both groups (Fig. 3, Table 2). 3.2. Center frequency When data of the two hands were combined, frequency of PT and ET was significantly smaller compared to controls, and in ET it was significantly smaller than in PT (control: 9.00G1.32 Hz, PT: 7.32G1.74 Hz, ET: 6.49G 1.29 Hz). Statistical analysis of CF of the right and left hand did not reveal any difference between the two sides in either group (Fig. 2, Table 2). In controls and in ET patients tremor frequency was symmetric on the more and less trembling side. However, CF of PT was significantly higher on the less compared to the more affected hand (Fig. 2, Table 2). CF in patients with normal intensity (subgroup A) was similar on the two sides in ET, but it was asymmetric in PT (Fig. 3, Table 2). In subgroup B of PT the central frequency of the more affected side was significantly smaller, than that of the less
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Fig. 2. Mean tremor intensity, center frequency and frequency dispersion in the different groups (vertical bars indicate 95% confidence interval). Left/right data are shown in the left column, while more trembling/less trembling data can be seen in the right column.
trembling side, while it was similar on both hands in ET (Fig. 3, Table 2). 3.3. Frequency dispersion Combining the data of the two hands ANOVA showed that frequency dispersion was significantly
larger in the control group compared to PT and ET, and also it was significantly higher in PT than ET (control: 3.05G0.59 Hz, PT: 1.66G1.08 Hz, ET: 0.89C 0.82 Hz). There was no side-to-side difference of FD in the three groups, when right and left hand averages were compared (Fig. 2, Table 2).
Table 2 Results of ANOVA Aspect of data grouping
Combined data of the two hands Right/left hand
More/less trembling hand
Subgroup A More/less trembling hand Subgroup B More/less trembling hand
Tremor intensity
Center frequency
Frequency dispersion
F
p
F
p
F
p
F(2,129)Z18.2 Fg(2,129)Z10.57 Fs(1,129)Z0.006 Fi(2,129)Z0.03 Fg(2,129)Z10.57 Ft(1,129)Z33.25 Fi(2,129)Z7.19 Fg(1,27)Z3.72 Ft(1,27)Z30.99 Fi(1,27)Z0.07 Fg(1,51)Z1.63 Ft(1,51)Z44.08 Fi(1,51)Z0.05
p!0.001 p!0.001 pZ0.937 pZ0.969 p!0.001 p!0.001 pZ0.001 pZ0.064 p!0.001 pZ0.789 pZ0.207 p!0.001 pZ0.818
F(2,129)Z40.72 Fg(2,129)Z40.72 Fs(1,129)Z0.32 Fi(2,129)Z0.74 Fg(2,129)Z40.70 Ft(1,129)Z6.54 Fi(2,129)Z2.76 Fg(1,27)Z3.25 Ft(1,27)Z3.52 Fi(1,27)Z0.67 Fg(1,51)Z3.26 Ft(1,51)Z6.33 Fi(1,51)Z6.58
p!0.001 p!0.001 pZ0.601 pZ0.482 p!0.001 pZ0.012 pZ0.067 pZ0.080 pZ0.038 pZ0.420 pZ0.077 pZ0.015 pZ0.013
F(2,129)Z110.09 Fg(2,129)Z120.18 Fs(1,129)Z1.47 Fi(2,129)Z0.12 Fg(2,129)Z120.54 Ft(1,129)Z31.16 Fi(2,129)Z11.73 Fg(1,27)Z1.93 Ft(1,27)Z3.57 Fi(1,27)Z2.23 Fg(1,51)Z23.30 Ft(1,51)Z42.14 Fi(1,51)Z16.27
p!0.001 p!0.001 pZ0.227 pZ0.887 p!0.001 p!0.001 p!0.001 pZ0.175 pZ0.045 pZ0.147 p!0.001 p!0.001 p!0.001
Fg, F group; Fs, F side; Ft, F trembling; Fi, F interaction. Subgroup A: less than 0.2 m/s2 tremor intensity (nPDZ22, nETZ7). Subgroup B: higher than 0.1 m/s2 side-to-side intensity difference (nPDZ21, nETZ32).
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Fig. 3. Mean tremor intensity, center frequency and frequency dispersion in the two subgroups of patients (vertical bars indicate 95% confidence interval). Subgroup A: patients with normal tremor intensity (nPTZ22, nETZ7). Subgroup B: patients with high side-to-side tremor intensity difference (nPTZ21, nETZ 32). C, more trembling hand; -, less trembling hand.
FD of the more and less tremulous hand was symmetric in control subjects and in ET patients, but it was significantly smaller on the more compared to the less trembling side in PT (Fig. 2, Table 2). Parkinson patients with low tremor intensity (subgroup A) had significantly asymmetric FD (smaller on the higher intensity side), while it was symmetrically low on both sides in ET (Fig. 3, Table 2.). In subgroup B of PT patients the intensity difference related FD asymmetry was highly significant, however, in ET a complete lack of asymmetry could be revealed (Fig. 3, Table 2). 3.4. Correlation between tremor intensity and center frequency To investigate the relationship between tremor intensity and CF we carried out regression analysis (Fig. 4). A strong inverse linear correlation was revealed between log tremor displacement and log center frequency in control subjects and in PT both on the more and less affected side. In ET, the linear correlation was found only on the more trembling side, intensity and frequency were not related on the less affected hand.
4. Discussion We examined the asymmetry of tremor on the right/left and the more/less trembling side of controls, PT and ET patients. In PT and ET tremor intensity of the right and left hand was higher compared to controls, but without any side-toside difference. Although similar data have already been reported [18], these results were in contradiction with the clinical evidence, that tremor is asymmetric in Parkinson’s disease. Louis et al. [7] have also reported, that in 12 ET patients accelerometry showed intensity side-difference. To investigate, the asymmetry of tremor parameters we reclustered the data according to more and less trembling hand. Statistics showed that both PT and ET intensity of the more affected side was 2.5 times higher than that of the less affected one. The intensity of ET even on the less affected side was significantly higher compared to controls. These data proved, for the first time quantitatively, that tremor intensity is indeed asymmetric in Parkinson’s disease, and confirmed the findings of Louis et al. [7] regarding tremor intensity asymmetry in ET. Frequency of PT in our study was higher than that of usually reported. This is due to the fact, that in the penholding position we measured a combination of resting
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Fig. 4. Correlation between log (base 10) displacement (m) and log center frequency (Hz) of the more trembling hand (upper row) and less trembling hand (lower row). Physiologic tremor: p!0.001 for the more and pZ0.021 for the less trembling hand, Parkinson patients: p!0.001 for both hands, patients with essential tremor: p!0.001 for the more, and pZ0.116 for the less trembling hand.
(lower frequency) and action (higher frequency) tremor, and that two-third of our PT patients’ had type II tremor. Furthermore, tremor frequencies of up to 9 Hz can be found in early Parkinson’s disease [1], and disease duration of our PT patients was only 5.33G4.07 years, and half of the patients had only mild clinical symptoms. CF and FD in both PT and ET were significantly smaller than in controls. In PT these parameters were significantly smaller on the more compared to the less affected hand. Astonishingly in ET, despite the robust intensity difference between the two hands, CF and FD were symmetrically smaller on the two sides. It is important to emphasize that in Parkinson’s disease CF on the less trembling hand was significantly lower than that of controls, although tremor intensity of this hand was in the normal range. Asymmetric increase in the regularity of parkinsonian tremor, without higher amplitude, was reported by Vaillancourt and Newell [33] using approximate entropy analysis of acceleration. These findings prompted us to examine the intensity/ frequency relation of low intensity tremor (subgroups A). Unexpectedly, the intensity difference between the more and less affected hand was still strongly significant in both tremor types. CF and FD in subgroup A of Parkinson patients decreased asymmetrically, while in ET they are symmetrically low. Our results suggest, that the pathological tremor generators are already active at the early stage of the disease, even when tremor is visually hardly detectable. Regression analysis proved that inverse linear correlation between log displacement versus log frequency existed both on the more and less trembling side in PT. Similar data have not been presented previously. An inverse linear
relationship in ET has been reported [9,32], but the correlation in our ET cohort could be found only on the more affected side. These results, however, are not contradictory, since in previous studies correlations were investigated only on one side in all patients. Although the interpretation of power spectra of biological signals needs special care [8,34], asymmetric PT frequency on the two hands may suggest that regardless of the fine structure of the oscillatory network, there are separate, relatively independent hemispheric tremor generators in Parkinson’s disease. Similar results have been obtained by Raethjen et al. [35], who showed that there is a high intralimb but almost no interlimb coherence of EMG activity in parkinsonian tremor, suggesting separate uncoupled oscillators for each limb. In ET, we found symmetrically low tremor frequency on both sides, even when intensity was considerably asymmetric (subgroup B), which might be explained by interconnected hemispheric generators. Our results are in agreement with those of Hellwig et al. [36], who reported that tremor-EMGs were coherent with EEG activity over both the contra- and ipsilateral sensorimotor cortex, suggesting interhemispheric coupling of central oscillators in ET. The diagnosis of various tremor syndromes might be challenging, especially in cases of low tremor intensity. Our data show that bilateral measurement of tremor parameters can be used to distinguish the two most common tremor types, since symmetric decrease of frequency parameters regardless of intensity asymmetry is characteristic of ET, while asymmetric intensity and frequency data are the main features of PT.
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Acknowledgements The authors would like to thank Dr Annama´ria Taka´ts, ´ gnes Hanyecz for their help. AK Marianna Ke´zsma´rki and A was supported by the Istva´n Sze´chenyi Fellowship of the Ministry of Education of Hungary.
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