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Lower limb joints kinematics in essential tremor and the effect of thalamic stimulation
Gait & Posture 36 (2012) 187–193
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Lower limb joints kinematics in essential tremor and the effect of thalamic stimulation Alfonso Fasano a,b, Jan Herzog c, Jan Raethjen c, Franziska E.M. Rose c, Jens Volkmann d, Daniela Falk e, Gu¨nther Deuschl c,* a
Istituto di Neurologia, Universita` Cattolica del Sacro Cuore, Roma, Italy Department of Neuroscience, AFaR-Fatebenefratelli Hospital, Rome, Italy Department of Neurology, Christian-Albrechts-University, Kiel, Germany d Department of Neurology, University of Wu¨rzburg, Germany e Department of Neurosurgery, Christian-Albrechts-University, Kiel, Germany b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 August 2011 Received in revised form 18 January 2012 Accepted 19 February 2012
Following the hypothesis that thalamic deep brain stimulation improves ataxia in patients with essential tremor by modulating the cerebello-thalamo-cortical pathway, we examined the joint kinematics of lower limbs during uninterrupted gait in eleven patients who have been treated with bilateral thalamic stimulation for 24.7 20.3 months. Patients were assessed under routine chronic stimulation, supratherapeutic amplitude, and off stimulation by means of an infrared movement analysis system while walking on a treadmill. Chronic thalamic DBS normalized the highly variable excursion throughout the gait cycle that characterized the subgroup of patients with longest disease duration. Supratherapeutic thalamic DBS amplitude did not reproduce such improvements while, more importantly, it induced ataxic changes of joint excursion. The normalization of kinematic abnormalities argues against the hypothesis of a cerebellar neurodegeneration in ET. Moreover, these results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window. ß 2012 Elsevier B.V. All rights reserved.
Keywords: Cerebellum Deep drain stimulation Essential tremor Gait Kinematics
1. Introduction Essential tremor (ET) is a slowly progressive movement disorder of yet unknown origin. Clinically, core symptoms of the disease are action and postural tremor of head and arms while voice, leg and trunk tremor are less prevalent [1]. In recent years, perception of ET as a pure tremor disease has been challenged due to the observation that severely affected patients exhibit a broader spectrum of motor dysfunction like ataxia in reach-to-grasp hand movements [2,3] and abnormalities in tandem gait [4,5]. A cerebellar gait disorder in advanced ET has also been confirmed with more subtle and objective tests [4,6–10]. The majority of studies focused on tandem gait, consistently report a greater number of mis-steps [4,5,8–10] and increased step width [4,8]. The kinematics of joints motion in ET patients has never been formally assessed although some reports suggest that both single- and multi-joint excursions are controlled by the cerebellum [11,12].
We recently examined the effect of thalamic deep brain stimulation (DBS) on ataxic features of ET patients during different locomotor tasks; preliminary data have shown that during uninterrupted gait, thalamic DBS increases ankle rotation while supra-therapeutic stimulation worsens the variability of joint excursion [9]. In order to further explore the extent to which cerebellar dysfunction plays a role in the pathogenesis of ET, we sought to explore the joint kinematics of lower limbs during uninterrupted gait in patients with advanced ET. We have hypothesized that in ET patients DBS modulates two major circuits: the cortico-thalamocortical loop for tremor reduction and the cerebello-thalamocortical pathway for ataxia reduction and induction [9]. We predicted that thalamic DBS would have a strong influence on the multi-joint lower limb movements during locomotion. 2. Subjects and methods 2.1. Subjects
* Corresponding author at: Department of Neurology, Universityhospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 10, 24105 Kiel, Germany. Tel.: +49 431 597 8509; fax: +49 431 597 8502. E-mail address: [email protected] (G. Deuschl). 0966-6362/$ – see front matter ß 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.gaitpost.2012.02.013
We studied eleven consecutive ET patients treated with bilateral thalamic DBS for medically intractable tremor enrolled in a previous study on other locomotor tasks [9]. Demographic and
A. Fasano et al. / Gait & Posture 36 (2012) 187–193
188 Table 1 Demographic and clinical data of ET patients. ET case
Gender
Age (years)
Disease duration (years)
Follow up after DBS (months)
Normal joints kinematics (n = 6) 1 F 69
34
6
2
M
76
10
48
3
F
76
20
3
4
F
64
20
48
5
M
67
12
8
6
M
67
20
24
Mean sd
3M 3F
69.3 5.3
17.0 4.7§
22.8 20.8
Stimulation parameters Vim Side
Chronically used
Supra-therapeutic
V
ms
Hz
Contacts
V
ms
R L R L R L R L R L R L
3.3 3.1 2.3 3.5 1.5 1.5 2.5 1.7 1.6 2.6 2.8 2.6
60 60 60 90 60 60 120 90 60 60 60 60
130 130 180 180 130 130 210 210 130 130 150 150
0-case+ 4-case+ 1-case+ 4-case+ 0-case+ 4-case+ 1-case+ 4–5-case+ 1-case+ 4-case+ 1-case+ 4-case+
3.5 3.8 5.2 4.7 2.5 3.5 3.5 3 3 4.4 4.6 4
90 90 60 90 60 60 120 90 60 60 60 60
R L
2.3 0.7^ 2.5 0.8
3.7 1.0 3.9 0.6
75.0 25.1 75.0 16.4
R L R L R L R L R L
2.5 3 4 5.2 3.6 4 3.2 3 3 3
3 3.5 4 3 5 5.5 4.7 3.9 4.3 4.9
90 120 120 120 60 60 90 90 60 90
70.0 24.5 70.0 15.5
155.0 33.3 155.0 33.3
Impaired joints kinematics (n = 5) 7 F 69
30
6
8
M
66
20
36
9
M
70
50
36
10
F
72
22
54
11
M
72
30
3
Mean sd
3M 2F
69.8 2.5
30.4 11.9§
27.0 21.8
R L
3.3 0.6^ 3.6 1.0
72.0 16.4 90.0 21.2
177.0 29.1 177.0 29.1
4.2 0.8 4.2 1.0
84.0 25.1 96.0 25.1
69.8 3.9
24.4 11.2
24.7 20.3
R L
2.8 0.8 3.0 1.0
70.9 20.2 79.1 20.2
165 32.0 165 32.0
3.9 0.9 4.0 0.8
79.1 24.3 84.5 22.5
Total sample (n = 11) Mean sd 6M 5F § ^ *
90 120 60 90 60 60 90 90 60 90
180 180 180 180 210 210 185 185 130 130
0-case+ 5-case+ 0-case+ 4–5+* 1-case+ 4–5-case+ 2-case+ 6-case+ 0–1-case+ 3–4-case+
Oral therapy at latest visit (daily dosage in mg)
Primidone (100), Propanolol (40) Primidone (250), Propanolol (120)
Gabapentin (1600), Metoprolol (95), Primidone (750)
Propanolol (80) Primidone (250), Propanolol (160)
Significantly different (P = 0.031). Significantly different (P = 0.041). Supra-therapeutic stimulation was performed with unipolar stimulation (4-case+)
disease-related details of the patients are summarized in Table 1. Entry criteria, surgical procedure and coordinates of active contacts are presented in Supplemental Material Online. Ten age- and gender-matched individuals (4 women) with a mean age of 67.3 5.0 years served as healthy controls (HC). Body size, weight, and leg length were not significantly different from the patient group. The institutional ethical committee approved the experimental protocol and subjects gave informed consent before participating in it. 2.2. Clinical assessments and gait analysis Tremor severity was clinically assessed using a modified version of the Fahn–Tolosa–Marin Tremor Rating Scale (TRS) [13] composed by items 1–9 of part A (assessing tremor in different body regions) and items 11–13 of part B (drawing large and small Archimedes spirals and three straight lines). We rated the severity of ataxia using the International Cooperative Ataxia Rating Scale (ICARS) [14]. In order to assess dynamic stability, tandem gait was evaluated by requesting the subjects to walk 5.5 m by placing one foot exactly in front of the other on a red line; subjects were instructed to walk safely rather than fast and with both arms close to the body to prevent compensating balance control strategies like walking with horizontally outstretched arms. Medications for the treatment of tremor were allowed since they have been previously demonstrated to not interfere with the gait performance of ET patients [4,9].
Gait analysis was performed on a motor-driven treadmill (Woodway, Weil am Rhein, Germany), with a length of 2.2 m and a width of 0.7 m. The treadmill speed was adjusted exactly to the subject’s individual gait velocity measured during overground walking over a distance of 11 m at a freely selected comfortable speed (mean of two runs). Two trials of 20 s duration were recorded at identical treadmill velocity by an infrared movement analysis system (Qualisys, Sandva¨len, Sweden) consisting of six infrared cameras and video processors (240 Hz sampling rate) connected to a computer. Seven infrared light-reflective spherical markers (1.8 cm diameter) were attached to specific points of each leg (anterior superior iliac spine, greater trochanter, lateral thigh, knee joint, lateral malleolus, calcaneus, fifth metatarsal bone). Fifteen to twenty consecutive walking cycles were analyzed offline using self-developed software [4,15,16]. In addition to the standard spatio-temporal gait variables, we evaluated single support/double support time ratio as an indirect index of stability during gait [17]. The ataxia ratio, an index of spatial regularity of recorded strides [4,16,18], was calculated based on the standard deviation (SD) of foot placement in all three room directions according to the formula: (SD of step length + SD of step width + SD of step height)/3. In addition, the coefficient of variation (CV) of selected gait parameters was calculated according to the formula: (SD/mean) 100 [19]. Foot-, hip-, knee- and ankle rotations were also assessed by computing the following indexes [4,15]: maximum and minimum values of joint excursion on the sagittal (for hip, knee and ankle) or axial (for foot angle) planes; range of motion (ROM), defined as the averaged
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differences in peak flexion and extension angles during gait cycles; the CV of ROM values [19]. 2.3. Stimulation conditions In keeping with our previous paradigm [9], ET patients were assessed during the following stimulation conditions: thalamic DBS on (STIM-ON) with chronically used parameters (Table 1), thalamic DBS off (STIM-OFF) and supra-therapeutic DBS (STIM-ST). The order of stimulation conditions was pseudo-randomized among patients. Between different stimulation conditions, there was an interval of 30 min. STIM-ST was obtained by slowly increasing amplitude and, if needed, pulse width (Table 1) until proximal decomposition of the contralateral upper limb movements appeared during the finger to nose test. 2.4. Statistical analysis For statistical analysis, we tested for normal distribution of variables using the Kolmogorov–Smirnov test. All but the kinematic variables were normally distributed. Values were expressed as mean SD or median (25th–75th percentile) according to data distribution. We first explored the effect of stimulation conditions by means of one-way analysis of variance (ANOVA) and Friedman ANOVA by ranks and in case of a significant influence of the stimulation factor on the dependent variables, post hoc comparisons were calculated using paired Student’s t-test or Wilcoxon matched pair test. We compared ET under these conditions with HC by means of the Kruskal–Wallis ANOVA and in case of a significant influence of the group factor on the dependent variables, post hoc comparisons were calculated using Student’s t-test or Mann–Whitney U test depending on the data distribution. Primary endpoints were ROM values and their CV. Statistica 7.0 (StatSoft, Tulsa, OK) software was used for all statistical analyses. All tests were two-sided with a level of significance set at P < 0.05. 3. Results Thalamic DBS significantly reduced the severity of tremor by 66.1 15.7% (P < 0.001); intention and postural tremor were similarly improved. 3.1. Characterization of ET patients with and without normal joints kinematics On clinical exam, no ET patient had obvious signs of cerebellar dysfunction during gait. The visual qualitative analysis of individual ET patients’ gait kinematics disclosed two different patterns. One subgroup of ET patients demonstrated normal ankle and knee ROM with little variability from cycle to cycle, hardly indistinguishable from HC. The second subgroup had high interstep cycle variability of joints ROM (typical examples in Fig. 1). Given the notion that the ankle joint is particularly sensitive to pathological changes in ataxic patients due to its distance from the center of body mass, the cut-off criterion of 2.5 for CV of the mean ankle ROM (corresponding to the 95% confidence interval for the HC group) was chosen a priori to define patients with normal (ETnk; n = 6) or impaired kinematics (ET-ik, n = 5). Analysis of demographic, clinical and gait characteristics revealed that ET-ik had longer disease duration and more severe intention tremor than ET-nk (P = 0.03 for both comparisons; Tables 1 and 2). The two subgroups did not differ in other tremor scores or clinical evaluations. Furthermore, step length and height, swing phase duration, ataxia ratio and CV of lower limb joints ROM were significantly increased in the subgroup with impaired kinematics (see Table 2 for P values).
Fig. 1. Analysis of the kinematic pattern of the right (R) and left (L) leg: example of a healthy control (HC4), an ET patient during STIM-OFF with a normal kinematic profile (ET-6) vs. an ET patient during STIM-OFF with high variability of joint excursions and ROM (ET-11). Impairment was most prominent at the knee and ankle. In the ET patient with a high variability of joint excursion, STIM-ON led to a reduction of joint excursion and increase of ROM. By contrast, STIM-ST was no longer able to produce these beneficial effects.
190
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Table 2 Clinical features and gait parameters of ET patients with normal (ET-nk) and impaired (ET-ik) gait kinematic. Data are referring to the STIM-OFF condition.
Clinical features (mean sd) TRS: total score TRS: upper limbs score TRS: lower limbs score TRS: axial score TRS: postural tremor score TRS: intention tremor score Body sway eyes closed Routine walking velocity (m/s) Tandem gait velocity (m/s) Number of missteps during tandem gait ICARS Gait parameters (mean sd) Stride length (cm) Swing phase duration (ms) Double support time (msec) Cadence (steps/min) Step width (mm) Step height (mm) Ataxia score (mm) CV of swing phase duration Single/double support time ratio Kinematics of routine walking [median (25th–75th percentiles)] Hip ROM (8) Knee ROM (8) Ankle ROM (8) Foot angle (8) CV-Hip ROM CV-Knee ROM CV-Ankle ROM CV-Foot angle
ET-nk (n = 6)
ET-ik (n = 5)
34.5 11.4 30.7 8.2 2.0 2.4 1.8 2.6 23.8 5.3 6.8 W 1.6 0.5 0.5 0.5 0.2 0.2 0.0 5.3 3.2 24.3 W 5.0
43.0 9.3 38.8 5.9 1.6 3.0 2.6 2.7 30.4 2.1 7.2 W 5.1 0.4 0.5 0.7 0.2 0.2 0.0 3.2 2.4 31.0 W 1.6
0.215 0.097 0.814 0.641 0.881 0.029 0.770 0.115 0.236 0.266 0.020
55.9 W 21.2 391.2 W 88.0 195.0 52.5 101.2 12.9 139.1 35.4 177.7 W 67.9 26.8 W 6.1 9.1 4.6 2.1 0.7
92.1 W 20.3 531.6 W 42.1 180.5 49.4 89.4 6.9 140.9 66.5 278.2 W 59.3 65.4 W 26.0 14.9 7.4 3.1 0.8
0.019 0.010 0.652 0.100 0.955 0.030 0.006 0.145 0.057
18.5 32.7 17.8 14.6 1.6 0.9 2.1 20.2
(13.6–19.6) (16.9–36.7) (16.4–27.3) (14.3–24.3) (1.2–2.8) (0.5–1.3) (1.6–2.3) (12.6–24.4)
17.6 40.5 22.1 21.1 6.1 2.1 5.2 15.5
(9.2–20.1) (38.9–45.1) (21.1–25.9) (13.6–25.8) (3.9–9.0) (1.9–2.4) (2.8–7.4) (13.4–25.4)
P-value
0.855 0.100 0.201 0.715 0.028 0.045 0.048 0.855
Values are referring to the STIM-OFF condition. Significant differences are bold typed. The Fahn–Tolosa–Marin Tremor Rating Scale (TRS) subscales for intention and postural tremor were calculated from items 5, 6, 8, 9, and 11 to 13; subscales for tremor in axial body parts from items 1 to 4 and 7, for tremor in upper and lower extremities from items 5, 6, 11 to 13 and from items 8 and 9, respectively. ‘‘Body sway eyes closed’’ was rated according to the International Cooperative Ataxia Rating Scale (ICARS). Velocity is the mean of two runs; missteps are defined as steps taken with the whole foot outside the bounds of the red line (see Section 2).
3.2. Effect of thalamic DBS on lower limb joint kinematics during gait We found that in ET-nk patients, thalamic DBS did not influence excursion of joint movements whereas STIM-ST significantly disrupted the variability of ankle and knee joint (Fig. 2). By contrast, in ET-ik DBS reduced CV of ROM and increased joint rotation (example in Fig. 1). Accordingly, STIM-ON significantly increased ankle ROM from 22.1 (21.1–25.9) to 26.9 (23.6–28.4) (P = 0.04, Fig. 2). Moreover, CV of mean ROM of knee and ankle decreased from 2.1 (1.9–2.4) and 5.2 (2.8–7.4) during STIM-OFF to 0.9 (0.6–2.4) and 3.6 (2.6–6.7) during STIM-ON (P = 0.04). The variability of all these ROMs, with the only exception of foot angle, was significantly higher than HC during STIM-OFF and STIM-ST; STIM-ON led to the normalization of these parameters (Fig. 2).
By contrast, ET-ik patients displayed a different gait pattern characterized by values falling within the normal range (though cadences were significantly lower than HC; Supplemental Material Online – Table A) with the only exception of those assessing the spatial and temporal gait variability (as measured by ataxia ratio and CV of swing phase, respectively). Ataxia ratio was significantly improved by STIM-ON (Fig. 3).
3.3. The effect of thalamic DBS on standard gait parameters The next question was whether gait abnormalities in ET and the DBS effect were different in the two subgroups of patients. ET-nk patients walked significantly slower than HC both during STIMOFF and STIM-ON. This was due to a lower cadence or a significantly shorter stride length (Supplemental Material Online – Table A). In keeping with the data of joint variability, the spatial and temporal gait variability (as measured by ataxia ratio and CV of cycle duration, respectively) was within normal range and worsened during STIM-ST. Step height was lower than HC irrespective of stimulation condition (Supplemental Material Online – Table A). Finally, the single support/double support time ratio, a parameter linked to balance and gait stability, was lower than HC and was significantly increased by STIM-ON as compared with STIM-OFF and STIM-ST (Fig. 3).
Fig. 2. The mean ROMs (right and left leg averaged) and the ROM CVs are displayed in the figure (on the left and on the right, respectively; from top to bottom: hip, knee, ankle joints). In ET-nk patients, thalamic DBS did not influence excursion of joint movements whereas STIM-ST significantly disrupted the regularity of the ankle and knee joints excursion (*P < 0.05). By contrast, in ET-ik patients, DBS reduced CV of ROM and increased joint rotation (*P < 0.05). The variability of all these ROMs was significantly higher than HC during STIM-OFF and STIM-ST (#P < 0.05). Values are medians +758 percentile.
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Fig. 3. Main gait parameters and the effect of different stimulation condition in ET patients with normal (ET-nk) and impaired kinematic profile (ET-ik). ET-nk patients walked significantly slower than HC both during STIM-OFF and STIM-ON whereas ataxia ratio was within normal range and worsened during STIM-ST; single support/double support time ratio, a parameter linked to balance and gait stability, was lower than HC and was significantly improved by STIM-ON as compared with STIM-OFF and STIM-ST. By contrast, ET-ik patients were characterized by high spatial variability (ataxia ratio) at baseline (STIM-OFF), significantly improved by STIM-ON and again deteriorated during STIM-ST. *P < 0.05; #significantly different from HC (P < 0.05); ##significantly different from HC (P < 0.01).
4. Discussion We described for the first time the finding that during standard walking a subgroup of ET patients with advanced disease has abnormal kinematics of lower limbs joints characterized by a highly variable excursion. Secondly, thalamic DBS improved these abnormalities, while supra-therapeutic stimulation increases variability of joint movement in patients with normal kinematics at baseline, thus inducing gait ataxia. Gait analysis studies comparing ET patients with healthy subjects reported only basic gait deviations such as increased step width [4], lower velocity [4,9,10], higher double support time [4,10], and temporal asymmetry [10]. No study specifically assessed the kinematics of joint excursion with the exception of the early study by Stolze and colleagues [4], who did not find any abnormality in ET patients with a mean disease duration of 16 years This finding is very similar to that of the patients reported here as having normal kinematics. We demonstrated an impairment of joint kinematics and gait ataxia in a subset of patients with longer disease and more severe intention tremor. The correlation with the severity of intention tremor is in keeping with studies on the ataxic features of upper limbs [2,3] and further supports the cerebellar pathophysiology of these changes. Few studies have assessed multi-joint kinematics during walking in patients with cerebellar ataxia. These have reported that lower limbs move at abnormal rates with extreme variability and with delays in the relative movement of the knee and ankle throughout the gait cycle [16,20]. Recently, an increased temporal variability of joint coordination patterns has been found to be highly specific of cerebellar gait [21,22]. Interestingly, the mean ROMs of the three lower limb joints were found to fall within normal range in CD patients [16,22]. However, segmental kinematic and kinetic plots revealed that these parameters were more variable and characterized by a flattened shape, thus indicating that joint excursions were not reduced but temporally dispersed throughout the gait cycle. These findings are in keeping with those of ET-ik patients reported here (Fig. 1). Therefore we suggest that the joint kinematics of ET-ik indicate abnormal cerebellar function. The cerebellum is separated into three functional compartments with the medial zone being responsible for posture and
equilibrium, the intermediate zone for discrete ipsilateral limb movements and the lateral zone for complex, visually guided limb movements. All three compartments appear to function abnormally in ET. Impaired vestibulocerebellar function is expressed by the subtle abnormalities of eye movement [23]. Gait abnormalities [4,7–9] and learning deficits [24] reflect abnormalities of the intermediate zone. Rhythm generation [25] and ataxic movement of the upper [2] or lower [9] limbs suggest lateral or hemispheric cerebellar dysfunction. The kinematic findings of the present study are in keeping with a dysfunction of the intermediate and lateral zones of the cerebellum in ET patients. In fact, decomposition of multi-joint tasks into elemental movements typically occurs after lesions involving the dentate nucleus and interposed nuclei of the intermediate zone [11,12]. Lesions of the dentate nuclei are also typically associated with an overshoot of the target (hypermetria) [11,12]: ET-ik patients have longer and higher steps than ET-nk but they do not differ with respect to the number of miss-steps (depending on the functioning of the intermediate zone). We have already shown that thalamic DBS significantly influences ankle range of motion, with an increase during STIMON compared to STIM-OFF and STIM-ST [9]. We have now shown that this effect is only present in the subgroup of patients with impaired kinematics. Therapeutic stimulation was found to improve stability, reducing the number of mis-steps during tandem gait [9], and ataxia, reducing the temporal and spatial variability of hand movement during a reaching task [3] and foot displacement during balance-assisted tandem gait [9]. Such increase of ankle ROM might follow the improvement of dynamic stability, since fixation of the ankle can be an advantageous compensatory strategy to reduce potential instability associated with large movements of the center of mass as it is the joint located farthest from it [27]. Accordingly, the ankle joint seems to be particularly sensitive to pathological changes in CD patients [22,26,27] and increased stiffness of the leg has also been described in CD patients during gait [16]. The findings of the present study further demonstrated that the ataxic features of ET are a separate component of ET that can be influenced by neurostimulation, independent of coexisting tremor. Invisible trunk tremor or a subtle leg tremor have been previously excluded by means of surface EMG in calf and paraspinal muscles [9].
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Finally, we found that supra-therapeutic stimulation is not effective in improving lower limb joint motion in patients with impaired kinematics and, more interestingly, it can lead to deterioration of the kinematic variability in patients with normal kinematics at baseline. We have previously found that STIM-ST reestablished the cerebellar-like movement profile but did not produce a return of tremor [9]. Many investigators have proposed that ET tremor originates in the olivo-cerebellar system [28]. Therapeutic stimulation of the cerebellothalamic fibers could mediate its beneficial effect on tremor and ataxia by interrupting rhythmic cerebellothalamic entrainment that is tremorogenic and that produces a functional impediment of normal neuronal traffic. Our results as well as the normalization of upper and lower limbs coordination and motor learning with thalamic DBS in ET patients [3,9,29] support a functional impairment of the cerebellum. By contrast, supra-therapeutic stimulation of the same fiber-bundle is hypothesized to disrupt rhythmic tremorogenic activity but also normal physiologic activity, which produces continued suppression of tremor with the return (in ET-ik) or induction (in ET-nk) of ataxia. Interestingly, ataxic movement may arise following lesions of cerebellar target areas of the thalamus. The exact mechanism leading to this form of ataxia and the difference to cerebellar ataxia is very poorly understood as these are clinically indistinguishable. Detailed kinematics, however, have shown meaningful differences: following lesions of the thalamus, single-joint movements are impaired but reaching movements requiring multiple-joint synergy are preserved [30,31]. This is in strong contrast with both the single and multiple-joints movement found in patients with lateral cerebellar lesions involving the dentate nucleus [11,30]. No study has specifically addressed these effects in the lower limbs. Supra-therapeutic stimulation in our study affected multiple-joint kinematics, thus supporting a cerebellar dysfunction rather than a local effect within the thalamus. This study has some limitations including a small sample size and the choice of an artificial criterion for the definition of patients’ subgroups. Another important limitation is the lack of standardization of gait velocity across subjects, which would have provided more reliable comparisons; however, we preferred self-chosen rather than externally imposed walking speed to assess for compensatory mechanisms [16]. Moreover, long-term used stimulating parameters were partly different between ET-nk and ET-ik patients, with voltage on right side being significantly higher in the latter group (Table 1): this is probably related to their greater disease severity and is unlikely to have biased our results since the most relevant changes were detected in STIM-OFF condition. Finally, ET was diagnosed according to clinical criteria, which is still the most accurate way in absence of a gold standard for the diagnosis. In conclusion, we found that a subset of ET patients with very long disease duration display disrupted lower limb joint coordination during gait. Given the present debate about the origin of ET [28], the finding that thalamic DBS normalizes these abnormalities does not support the hypothesis of cerebellar neurodegeneration [32]. Excessive strength of stimulation did not lead to such improvements and, more importantly, it induced ataxic changes of joint excursion in patients with otherwise normal kinematics. These results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window. This finding would explain the lack of ataxia improvement reported by some studies [7,10,33] as well as some disadvantageous consequences such as increased likelihood to fall [10,34]. Acknowledgements Authors thank arch. Silvia Allori for the editing of Fig. 1 and Prof. Alberto J. Espay, University of Cincinnati – OH, for his invaluable
critical revision of the manuscript. Supported by the BMBF (Kompetenznetz Parkinson) and the German Research Council (SFB 855). Conflict of interest statement None of the authors has conflicts of interest to disclose. References [1] Deuschl G, Bain P, Brin M. Consensus statement of the movement disorder society on tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13(Suppl. 3):2–23. [2] 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(Pt 8):1568–80. [3] Herzog J, Hamel W, Wenzelburger R, Potter M, Pinsker MO, Bartussek J, et al. Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor. Brain 2007;130(Pt 6):1608–25. [4] Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain 2001;124(Pt 11):2278–86. [5] Louis ED, Rios E, Rao AK. Tandem gait performance in essential tremor: clinical correlates and association with midline tremors. Mov Disord 2010;25(11): 1633–8. [6] Parisi SL, Heroux ME, Culham EG, Norman KE. Functional mobility and postural control in essential tremor. Arch Phys Med Rehabil 2006;87(10): 1357–64. [7] Earhart GM, Clark BR, Tabbal SD, Perlmutter JS. Gait and balance in essential tremor: variable effects of bilateral thalamic stimulation. Mov Disord 2008. [8] Kronenbuerger M, Konczak J, Wolfram Z, Buderath P, Frank B, Coenen VA, et al. Balance and motor speech impairment in essential tremor. Cerebellum 2009;8(8):389–98. [9] Fasano A, Herzog J, Raethjen J, Rose FE, Muthuraman M, Volkmann J, et al. Gait ataxia in essential tremor is differentially modulated by thalamic stimulation. Brain 2010;133(Pt. 12):3635–48. [10] Rao AK, Gillman A, Louis ED. Quantitative gait analysis in essential tremor reveals impairments that are maintained into advanced age. Gait Posture 2011;34(1):65–70. [11] Thach WT, Goodkin HP, Keating JG. The cerebellum and the adaptive coordination of movement. Annu Rev Neurosci 1992;15:403–42. [12] Bastian AJ, Martin TA, Keating JG, Thach WT. Cerebellar ataxia: abnormal control of interaction torques across multiple joints. J Neurophysiol 1996;76(1):492–509. [13] Fahn S, Tolosa E, Marin C. Clinical rating scale for tremor. Philadelphia: Williams & Wilkins; 1988. [14] Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 1997;145(2):205–11. [15] Stolze H, Kuhtz-Buschbeck JP, Mondwurf C, Boczek-Funcke A, Johnk K, Deuschl G, et al. Gait analysis during treadmill and overground locomotion in children and adults. Electroencephalogr Clin Neurophysiol 1997; 105(6):490–7. [16] Stolze H, Klebe S, Petersen G, Raethjen J, Wenzelburger R, Witt K, et al. Typical features of cerebellar ataxic gait. J Neurol Neurosurg Psychiatry 2002;73(3): 310–2. [17] Whittle M. Gait analysis: an introduction. Oxford: Butterworth-Heinemann; 1991. [18] Klebe S, Stolze H, Grensing K, Volkmann J, Wenzelburger R, Deuschl G. Influence of alcohol on gait in patients with essential tremor. Neurology 2005;65(1):96–101. [19] Hausdorff JM, Edelberg HK, Mitchell SL, Goldberger AL, Wei JY. Increased gait unsteadiness in community-dwelling elderly fallers. Arch Phys Med Rehabil 1997;78(3):278–83. [20] Bastian AJ, Mink JW, Kaufman BA, Thach WT. Posterior vermal split syndrome. Ann Neurol 1998;44(4):601–10. [21] Ilg W, Golla H, Thier P, Giese MA. Specific influences of cerebellar dysfunctions on gait. Brain 2007;130(Pt 3):786–98. [22] Serrao M, Pierelli F, Ranavolo A, Draicchio F, Conte C, Don R, et al. Gait pattern in inherited cerebellar ataxias. Cerebellum 2011. [23] Helmchen C, Hagenow A, Miesner J, Sprenger A, Rambold H, Wenzelburger R, et al. Eye movement abnormalities in essential tremor may indicate cerebellar dysfunction. Brain 2003;126(Pt 6):1319–32. [24] Kronenbuerger M, Gerwig M, Brol B, Block F, Timmann D. Eyeblink conditioning is impaired in subjects with essential tremor. Brain 2007;130(Pt 6):1538– 51. [25] Farkas Z, Szirmai I, Kamondi A. Impaired rhythm generation in essential tremor. Mov Disord 2006;21:1196–9. [26] Bastian AJ, Zackowski KM, Thach WT. Cerebellar ataxia: torque deficiency or torque mismatch between joints? J Neurophysiol 2000;83(5):3019–30. [27] Earhart GM, Bastian AJ. Selection and coordination of human locomotor forms following cerebellar damage. J Neurophysiol 2001;85(2):759–69. [28] Deuschl G, Elble R. Essential tremor – neurodegenerative or nondegenerative disease towards a working definition of ET. Mov Disord 2009;24(14): 2033–41.
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Gait & Posture journal homepage: www.elsevier.com/locate/gaitpost
Lower limb joints kinematics in essential tremor and the effect of thalamic stimulation Alfonso Fasano a,b, Jan Herzog c, Jan Raethjen c, Franziska E.M. Rose c, Jens Volkmann d, Daniela Falk e, Gu¨nther Deuschl c,* a
Istituto di Neurologia, Universita` Cattolica del Sacro Cuore, Roma, Italy Department of Neuroscience, AFaR-Fatebenefratelli Hospital, Rome, Italy Department of Neurology, Christian-Albrechts-University, Kiel, Germany d Department of Neurology, University of Wu¨rzburg, Germany e Department of Neurosurgery, Christian-Albrechts-University, Kiel, Germany b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 August 2011 Received in revised form 18 January 2012 Accepted 19 February 2012
Following the hypothesis that thalamic deep brain stimulation improves ataxia in patients with essential tremor by modulating the cerebello-thalamo-cortical pathway, we examined the joint kinematics of lower limbs during uninterrupted gait in eleven patients who have been treated with bilateral thalamic stimulation for 24.7 20.3 months. Patients were assessed under routine chronic stimulation, supratherapeutic amplitude, and off stimulation by means of an infrared movement analysis system while walking on a treadmill. Chronic thalamic DBS normalized the highly variable excursion throughout the gait cycle that characterized the subgroup of patients with longest disease duration. Supratherapeutic thalamic DBS amplitude did not reproduce such improvements while, more importantly, it induced ataxic changes of joint excursion. The normalization of kinematic abnormalities argues against the hypothesis of a cerebellar neurodegeneration in ET. Moreover, these results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window. ß 2012 Elsevier B.V. All rights reserved.
Keywords: Cerebellum Deep drain stimulation Essential tremor Gait Kinematics
1. Introduction Essential tremor (ET) is a slowly progressive movement disorder of yet unknown origin. Clinically, core symptoms of the disease are action and postural tremor of head and arms while voice, leg and trunk tremor are less prevalent [1]. In recent years, perception of ET as a pure tremor disease has been challenged due to the observation that severely affected patients exhibit a broader spectrum of motor dysfunction like ataxia in reach-to-grasp hand movements [2,3] and abnormalities in tandem gait [4,5]. A cerebellar gait disorder in advanced ET has also been confirmed with more subtle and objective tests [4,6–10]. The majority of studies focused on tandem gait, consistently report a greater number of mis-steps [4,5,8–10] and increased step width [4,8]. The kinematics of joints motion in ET patients has never been formally assessed although some reports suggest that both single- and multi-joint excursions are controlled by the cerebellum [11,12].
We recently examined the effect of thalamic deep brain stimulation (DBS) on ataxic features of ET patients during different locomotor tasks; preliminary data have shown that during uninterrupted gait, thalamic DBS increases ankle rotation while supra-therapeutic stimulation worsens the variability of joint excursion [9]. In order to further explore the extent to which cerebellar dysfunction plays a role in the pathogenesis of ET, we sought to explore the joint kinematics of lower limbs during uninterrupted gait in patients with advanced ET. We have hypothesized that in ET patients DBS modulates two major circuits: the cortico-thalamocortical loop for tremor reduction and the cerebello-thalamocortical pathway for ataxia reduction and induction [9]. We predicted that thalamic DBS would have a strong influence on the multi-joint lower limb movements during locomotion. 2. Subjects and methods 2.1. Subjects
* Corresponding author at: Department of Neurology, Universityhospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 10, 24105 Kiel, Germany. Tel.: +49 431 597 8509; fax: +49 431 597 8502. E-mail address: [email protected] (G. Deuschl). 0966-6362/$ – see front matter ß 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.gaitpost.2012.02.013
We studied eleven consecutive ET patients treated with bilateral thalamic DBS for medically intractable tremor enrolled in a previous study on other locomotor tasks [9]. Demographic and
A. Fasano et al. / Gait & Posture 36 (2012) 187–193
188 Table 1 Demographic and clinical data of ET patients. ET case
Gender
Age (years)
Disease duration (years)
Follow up after DBS (months)
Normal joints kinematics (n = 6) 1 F 69
34
6
2
M
76
10
48
3
F
76
20
3
4
F
64
20
48
5
M
67
12
8
6
M
67
20
24
Mean sd
3M 3F
69.3 5.3
17.0 4.7§
22.8 20.8
Stimulation parameters Vim Side
Chronically used
Supra-therapeutic
V
ms
Hz
Contacts
V
ms
R L R L R L R L R L R L
3.3 3.1 2.3 3.5 1.5 1.5 2.5 1.7 1.6 2.6 2.8 2.6
60 60 60 90 60 60 120 90 60 60 60 60
130 130 180 180 130 130 210 210 130 130 150 150
0-case+ 4-case+ 1-case+ 4-case+ 0-case+ 4-case+ 1-case+ 4–5-case+ 1-case+ 4-case+ 1-case+ 4-case+
3.5 3.8 5.2 4.7 2.5 3.5 3.5 3 3 4.4 4.6 4
90 90 60 90 60 60 120 90 60 60 60 60
R L
2.3 0.7^ 2.5 0.8
3.7 1.0 3.9 0.6
75.0 25.1 75.0 16.4
R L R L R L R L R L
2.5 3 4 5.2 3.6 4 3.2 3 3 3
3 3.5 4 3 5 5.5 4.7 3.9 4.3 4.9
90 120 120 120 60 60 90 90 60 90
70.0 24.5 70.0 15.5
155.0 33.3 155.0 33.3
Impaired joints kinematics (n = 5) 7 F 69
30
6
8
M
66
20
36
9
M
70
50
36
10
F
72
22
54
11
M
72
30
3
Mean sd
3M 2F
69.8 2.5
30.4 11.9§
27.0 21.8
R L
3.3 0.6^ 3.6 1.0
72.0 16.4 90.0 21.2
177.0 29.1 177.0 29.1
4.2 0.8 4.2 1.0
84.0 25.1 96.0 25.1
69.8 3.9
24.4 11.2
24.7 20.3
R L
2.8 0.8 3.0 1.0
70.9 20.2 79.1 20.2
165 32.0 165 32.0
3.9 0.9 4.0 0.8
79.1 24.3 84.5 22.5
Total sample (n = 11) Mean sd 6M 5F § ^ *
90 120 60 90 60 60 90 90 60 90
180 180 180 180 210 210 185 185 130 130
0-case+ 5-case+ 0-case+ 4–5+* 1-case+ 4–5-case+ 2-case+ 6-case+ 0–1-case+ 3–4-case+
Oral therapy at latest visit (daily dosage in mg)
Primidone (100), Propanolol (40) Primidone (250), Propanolol (120)
Gabapentin (1600), Metoprolol (95), Primidone (750)
Propanolol (80) Primidone (250), Propanolol (160)
Significantly different (P = 0.031). Significantly different (P = 0.041). Supra-therapeutic stimulation was performed with unipolar stimulation (4-case+)
disease-related details of the patients are summarized in Table 1. Entry criteria, surgical procedure and coordinates of active contacts are presented in Supplemental Material Online. Ten age- and gender-matched individuals (4 women) with a mean age of 67.3 5.0 years served as healthy controls (HC). Body size, weight, and leg length were not significantly different from the patient group. The institutional ethical committee approved the experimental protocol and subjects gave informed consent before participating in it. 2.2. Clinical assessments and gait analysis Tremor severity was clinically assessed using a modified version of the Fahn–Tolosa–Marin Tremor Rating Scale (TRS) [13] composed by items 1–9 of part A (assessing tremor in different body regions) and items 11–13 of part B (drawing large and small Archimedes spirals and three straight lines). We rated the severity of ataxia using the International Cooperative Ataxia Rating Scale (ICARS) [14]. In order to assess dynamic stability, tandem gait was evaluated by requesting the subjects to walk 5.5 m by placing one foot exactly in front of the other on a red line; subjects were instructed to walk safely rather than fast and with both arms close to the body to prevent compensating balance control strategies like walking with horizontally outstretched arms. Medications for the treatment of tremor were allowed since they have been previously demonstrated to not interfere with the gait performance of ET patients [4,9].
Gait analysis was performed on a motor-driven treadmill (Woodway, Weil am Rhein, Germany), with a length of 2.2 m and a width of 0.7 m. The treadmill speed was adjusted exactly to the subject’s individual gait velocity measured during overground walking over a distance of 11 m at a freely selected comfortable speed (mean of two runs). Two trials of 20 s duration were recorded at identical treadmill velocity by an infrared movement analysis system (Qualisys, Sandva¨len, Sweden) consisting of six infrared cameras and video processors (240 Hz sampling rate) connected to a computer. Seven infrared light-reflective spherical markers (1.8 cm diameter) were attached to specific points of each leg (anterior superior iliac spine, greater trochanter, lateral thigh, knee joint, lateral malleolus, calcaneus, fifth metatarsal bone). Fifteen to twenty consecutive walking cycles were analyzed offline using self-developed software [4,15,16]. In addition to the standard spatio-temporal gait variables, we evaluated single support/double support time ratio as an indirect index of stability during gait [17]. The ataxia ratio, an index of spatial regularity of recorded strides [4,16,18], was calculated based on the standard deviation (SD) of foot placement in all three room directions according to the formula: (SD of step length + SD of step width + SD of step height)/3. In addition, the coefficient of variation (CV) of selected gait parameters was calculated according to the formula: (SD/mean) 100 [19]. Foot-, hip-, knee- and ankle rotations were also assessed by computing the following indexes [4,15]: maximum and minimum values of joint excursion on the sagittal (for hip, knee and ankle) or axial (for foot angle) planes; range of motion (ROM), defined as the averaged
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189
differences in peak flexion and extension angles during gait cycles; the CV of ROM values [19]. 2.3. Stimulation conditions In keeping with our previous paradigm [9], ET patients were assessed during the following stimulation conditions: thalamic DBS on (STIM-ON) with chronically used parameters (Table 1), thalamic DBS off (STIM-OFF) and supra-therapeutic DBS (STIM-ST). The order of stimulation conditions was pseudo-randomized among patients. Between different stimulation conditions, there was an interval of 30 min. STIM-ST was obtained by slowly increasing amplitude and, if needed, pulse width (Table 1) until proximal decomposition of the contralateral upper limb movements appeared during the finger to nose test. 2.4. Statistical analysis For statistical analysis, we tested for normal distribution of variables using the Kolmogorov–Smirnov test. All but the kinematic variables were normally distributed. Values were expressed as mean SD or median (25th–75th percentile) according to data distribution. We first explored the effect of stimulation conditions by means of one-way analysis of variance (ANOVA) and Friedman ANOVA by ranks and in case of a significant influence of the stimulation factor on the dependent variables, post hoc comparisons were calculated using paired Student’s t-test or Wilcoxon matched pair test. We compared ET under these conditions with HC by means of the Kruskal–Wallis ANOVA and in case of a significant influence of the group factor on the dependent variables, post hoc comparisons were calculated using Student’s t-test or Mann–Whitney U test depending on the data distribution. Primary endpoints were ROM values and their CV. Statistica 7.0 (StatSoft, Tulsa, OK) software was used for all statistical analyses. All tests were two-sided with a level of significance set at P < 0.05. 3. Results Thalamic DBS significantly reduced the severity of tremor by 66.1 15.7% (P < 0.001); intention and postural tremor were similarly improved. 3.1. Characterization of ET patients with and without normal joints kinematics On clinical exam, no ET patient had obvious signs of cerebellar dysfunction during gait. The visual qualitative analysis of individual ET patients’ gait kinematics disclosed two different patterns. One subgroup of ET patients demonstrated normal ankle and knee ROM with little variability from cycle to cycle, hardly indistinguishable from HC. The second subgroup had high interstep cycle variability of joints ROM (typical examples in Fig. 1). Given the notion that the ankle joint is particularly sensitive to pathological changes in ataxic patients due to its distance from the center of body mass, the cut-off criterion of 2.5 for CV of the mean ankle ROM (corresponding to the 95% confidence interval for the HC group) was chosen a priori to define patients with normal (ETnk; n = 6) or impaired kinematics (ET-ik, n = 5). Analysis of demographic, clinical and gait characteristics revealed that ET-ik had longer disease duration and more severe intention tremor than ET-nk (P = 0.03 for both comparisons; Tables 1 and 2). The two subgroups did not differ in other tremor scores or clinical evaluations. Furthermore, step length and height, swing phase duration, ataxia ratio and CV of lower limb joints ROM were significantly increased in the subgroup with impaired kinematics (see Table 2 for P values).
Fig. 1. Analysis of the kinematic pattern of the right (R) and left (L) leg: example of a healthy control (HC4), an ET patient during STIM-OFF with a normal kinematic profile (ET-6) vs. an ET patient during STIM-OFF with high variability of joint excursions and ROM (ET-11). Impairment was most prominent at the knee and ankle. In the ET patient with a high variability of joint excursion, STIM-ON led to a reduction of joint excursion and increase of ROM. By contrast, STIM-ST was no longer able to produce these beneficial effects.
190
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Table 2 Clinical features and gait parameters of ET patients with normal (ET-nk) and impaired (ET-ik) gait kinematic. Data are referring to the STIM-OFF condition.
Clinical features (mean sd) TRS: total score TRS: upper limbs score TRS: lower limbs score TRS: axial score TRS: postural tremor score TRS: intention tremor score Body sway eyes closed Routine walking velocity (m/s) Tandem gait velocity (m/s) Number of missteps during tandem gait ICARS Gait parameters (mean sd) Stride length (cm) Swing phase duration (ms) Double support time (msec) Cadence (steps/min) Step width (mm) Step height (mm) Ataxia score (mm) CV of swing phase duration Single/double support time ratio Kinematics of routine walking [median (25th–75th percentiles)] Hip ROM (8) Knee ROM (8) Ankle ROM (8) Foot angle (8) CV-Hip ROM CV-Knee ROM CV-Ankle ROM CV-Foot angle
ET-nk (n = 6)
ET-ik (n = 5)
34.5 11.4 30.7 8.2 2.0 2.4 1.8 2.6 23.8 5.3 6.8 W 1.6 0.5 0.5 0.5 0.2 0.2 0.0 5.3 3.2 24.3 W 5.0
43.0 9.3 38.8 5.9 1.6 3.0 2.6 2.7 30.4 2.1 7.2 W 5.1 0.4 0.5 0.7 0.2 0.2 0.0 3.2 2.4 31.0 W 1.6
0.215 0.097 0.814 0.641 0.881 0.029 0.770 0.115 0.236 0.266 0.020
55.9 W 21.2 391.2 W 88.0 195.0 52.5 101.2 12.9 139.1 35.4 177.7 W 67.9 26.8 W 6.1 9.1 4.6 2.1 0.7
92.1 W 20.3 531.6 W 42.1 180.5 49.4 89.4 6.9 140.9 66.5 278.2 W 59.3 65.4 W 26.0 14.9 7.4 3.1 0.8
0.019 0.010 0.652 0.100 0.955 0.030 0.006 0.145 0.057
18.5 32.7 17.8 14.6 1.6 0.9 2.1 20.2
(13.6–19.6) (16.9–36.7) (16.4–27.3) (14.3–24.3) (1.2–2.8) (0.5–1.3) (1.6–2.3) (12.6–24.4)
17.6 40.5 22.1 21.1 6.1 2.1 5.2 15.5
(9.2–20.1) (38.9–45.1) (21.1–25.9) (13.6–25.8) (3.9–9.0) (1.9–2.4) (2.8–7.4) (13.4–25.4)
P-value
0.855 0.100 0.201 0.715 0.028 0.045 0.048 0.855
Values are referring to the STIM-OFF condition. Significant differences are bold typed. The Fahn–Tolosa–Marin Tremor Rating Scale (TRS) subscales for intention and postural tremor were calculated from items 5, 6, 8, 9, and 11 to 13; subscales for tremor in axial body parts from items 1 to 4 and 7, for tremor in upper and lower extremities from items 5, 6, 11 to 13 and from items 8 and 9, respectively. ‘‘Body sway eyes closed’’ was rated according to the International Cooperative Ataxia Rating Scale (ICARS). Velocity is the mean of two runs; missteps are defined as steps taken with the whole foot outside the bounds of the red line (see Section 2).
3.2. Effect of thalamic DBS on lower limb joint kinematics during gait We found that in ET-nk patients, thalamic DBS did not influence excursion of joint movements whereas STIM-ST significantly disrupted the variability of ankle and knee joint (Fig. 2). By contrast, in ET-ik DBS reduced CV of ROM and increased joint rotation (example in Fig. 1). Accordingly, STIM-ON significantly increased ankle ROM from 22.1 (21.1–25.9) to 26.9 (23.6–28.4) (P = 0.04, Fig. 2). Moreover, CV of mean ROM of knee and ankle decreased from 2.1 (1.9–2.4) and 5.2 (2.8–7.4) during STIM-OFF to 0.9 (0.6–2.4) and 3.6 (2.6–6.7) during STIM-ON (P = 0.04). The variability of all these ROMs, with the only exception of foot angle, was significantly higher than HC during STIM-OFF and STIM-ST; STIM-ON led to the normalization of these parameters (Fig. 2).
By contrast, ET-ik patients displayed a different gait pattern characterized by values falling within the normal range (though cadences were significantly lower than HC; Supplemental Material Online – Table A) with the only exception of those assessing the spatial and temporal gait variability (as measured by ataxia ratio and CV of swing phase, respectively). Ataxia ratio was significantly improved by STIM-ON (Fig. 3).
3.3. The effect of thalamic DBS on standard gait parameters The next question was whether gait abnormalities in ET and the DBS effect were different in the two subgroups of patients. ET-nk patients walked significantly slower than HC both during STIMOFF and STIM-ON. This was due to a lower cadence or a significantly shorter stride length (Supplemental Material Online – Table A). In keeping with the data of joint variability, the spatial and temporal gait variability (as measured by ataxia ratio and CV of cycle duration, respectively) was within normal range and worsened during STIM-ST. Step height was lower than HC irrespective of stimulation condition (Supplemental Material Online – Table A). Finally, the single support/double support time ratio, a parameter linked to balance and gait stability, was lower than HC and was significantly increased by STIM-ON as compared with STIM-OFF and STIM-ST (Fig. 3).
Fig. 2. The mean ROMs (right and left leg averaged) and the ROM CVs are displayed in the figure (on the left and on the right, respectively; from top to bottom: hip, knee, ankle joints). In ET-nk patients, thalamic DBS did not influence excursion of joint movements whereas STIM-ST significantly disrupted the regularity of the ankle and knee joints excursion (*P < 0.05). By contrast, in ET-ik patients, DBS reduced CV of ROM and increased joint rotation (*P < 0.05). The variability of all these ROMs was significantly higher than HC during STIM-OFF and STIM-ST (#P < 0.05). Values are medians +758 percentile.
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Fig. 3. Main gait parameters and the effect of different stimulation condition in ET patients with normal (ET-nk) and impaired kinematic profile (ET-ik). ET-nk patients walked significantly slower than HC both during STIM-OFF and STIM-ON whereas ataxia ratio was within normal range and worsened during STIM-ST; single support/double support time ratio, a parameter linked to balance and gait stability, was lower than HC and was significantly improved by STIM-ON as compared with STIM-OFF and STIM-ST. By contrast, ET-ik patients were characterized by high spatial variability (ataxia ratio) at baseline (STIM-OFF), significantly improved by STIM-ON and again deteriorated during STIM-ST. *P < 0.05; #significantly different from HC (P < 0.05); ##significantly different from HC (P < 0.01).
4. Discussion We described for the first time the finding that during standard walking a subgroup of ET patients with advanced disease has abnormal kinematics of lower limbs joints characterized by a highly variable excursion. Secondly, thalamic DBS improved these abnormalities, while supra-therapeutic stimulation increases variability of joint movement in patients with normal kinematics at baseline, thus inducing gait ataxia. Gait analysis studies comparing ET patients with healthy subjects reported only basic gait deviations such as increased step width [4], lower velocity [4,9,10], higher double support time [4,10], and temporal asymmetry [10]. No study specifically assessed the kinematics of joint excursion with the exception of the early study by Stolze and colleagues [4], who did not find any abnormality in ET patients with a mean disease duration of 16 years This finding is very similar to that of the patients reported here as having normal kinematics. We demonstrated an impairment of joint kinematics and gait ataxia in a subset of patients with longer disease and more severe intention tremor. The correlation with the severity of intention tremor is in keeping with studies on the ataxic features of upper limbs [2,3] and further supports the cerebellar pathophysiology of these changes. Few studies have assessed multi-joint kinematics during walking in patients with cerebellar ataxia. These have reported that lower limbs move at abnormal rates with extreme variability and with delays in the relative movement of the knee and ankle throughout the gait cycle [16,20]. Recently, an increased temporal variability of joint coordination patterns has been found to be highly specific of cerebellar gait [21,22]. Interestingly, the mean ROMs of the three lower limb joints were found to fall within normal range in CD patients [16,22]. However, segmental kinematic and kinetic plots revealed that these parameters were more variable and characterized by a flattened shape, thus indicating that joint excursions were not reduced but temporally dispersed throughout the gait cycle. These findings are in keeping with those of ET-ik patients reported here (Fig. 1). Therefore we suggest that the joint kinematics of ET-ik indicate abnormal cerebellar function. The cerebellum is separated into three functional compartments with the medial zone being responsible for posture and
equilibrium, the intermediate zone for discrete ipsilateral limb movements and the lateral zone for complex, visually guided limb movements. All three compartments appear to function abnormally in ET. Impaired vestibulocerebellar function is expressed by the subtle abnormalities of eye movement [23]. Gait abnormalities [4,7–9] and learning deficits [24] reflect abnormalities of the intermediate zone. Rhythm generation [25] and ataxic movement of the upper [2] or lower [9] limbs suggest lateral or hemispheric cerebellar dysfunction. The kinematic findings of the present study are in keeping with a dysfunction of the intermediate and lateral zones of the cerebellum in ET patients. In fact, decomposition of multi-joint tasks into elemental movements typically occurs after lesions involving the dentate nucleus and interposed nuclei of the intermediate zone [11,12]. Lesions of the dentate nuclei are also typically associated with an overshoot of the target (hypermetria) [11,12]: ET-ik patients have longer and higher steps than ET-nk but they do not differ with respect to the number of miss-steps (depending on the functioning of the intermediate zone). We have already shown that thalamic DBS significantly influences ankle range of motion, with an increase during STIMON compared to STIM-OFF and STIM-ST [9]. We have now shown that this effect is only present in the subgroup of patients with impaired kinematics. Therapeutic stimulation was found to improve stability, reducing the number of mis-steps during tandem gait [9], and ataxia, reducing the temporal and spatial variability of hand movement during a reaching task [3] and foot displacement during balance-assisted tandem gait [9]. Such increase of ankle ROM might follow the improvement of dynamic stability, since fixation of the ankle can be an advantageous compensatory strategy to reduce potential instability associated with large movements of the center of mass as it is the joint located farthest from it [27]. Accordingly, the ankle joint seems to be particularly sensitive to pathological changes in CD patients [22,26,27] and increased stiffness of the leg has also been described in CD patients during gait [16]. The findings of the present study further demonstrated that the ataxic features of ET are a separate component of ET that can be influenced by neurostimulation, independent of coexisting tremor. Invisible trunk tremor or a subtle leg tremor have been previously excluded by means of surface EMG in calf and paraspinal muscles [9].
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Finally, we found that supra-therapeutic stimulation is not effective in improving lower limb joint motion in patients with impaired kinematics and, more interestingly, it can lead to deterioration of the kinematic variability in patients with normal kinematics at baseline. We have previously found that STIM-ST reestablished the cerebellar-like movement profile but did not produce a return of tremor [9]. Many investigators have proposed that ET tremor originates in the olivo-cerebellar system [28]. Therapeutic stimulation of the cerebellothalamic fibers could mediate its beneficial effect on tremor and ataxia by interrupting rhythmic cerebellothalamic entrainment that is tremorogenic and that produces a functional impediment of normal neuronal traffic. Our results as well as the normalization of upper and lower limbs coordination and motor learning with thalamic DBS in ET patients [3,9,29] support a functional impairment of the cerebellum. By contrast, supra-therapeutic stimulation of the same fiber-bundle is hypothesized to disrupt rhythmic tremorogenic activity but also normal physiologic activity, which produces continued suppression of tremor with the return (in ET-ik) or induction (in ET-nk) of ataxia. Interestingly, ataxic movement may arise following lesions of cerebellar target areas of the thalamus. The exact mechanism leading to this form of ataxia and the difference to cerebellar ataxia is very poorly understood as these are clinically indistinguishable. Detailed kinematics, however, have shown meaningful differences: following lesions of the thalamus, single-joint movements are impaired but reaching movements requiring multiple-joint synergy are preserved [30,31]. This is in strong contrast with both the single and multiple-joints movement found in patients with lateral cerebellar lesions involving the dentate nucleus [11,30]. No study has specifically addressed these effects in the lower limbs. Supra-therapeutic stimulation in our study affected multiple-joint kinematics, thus supporting a cerebellar dysfunction rather than a local effect within the thalamus. This study has some limitations including a small sample size and the choice of an artificial criterion for the definition of patients’ subgroups. Another important limitation is the lack of standardization of gait velocity across subjects, which would have provided more reliable comparisons; however, we preferred self-chosen rather than externally imposed walking speed to assess for compensatory mechanisms [16]. Moreover, long-term used stimulating parameters were partly different between ET-nk and ET-ik patients, with voltage on right side being significantly higher in the latter group (Table 1): this is probably related to their greater disease severity and is unlikely to have biased our results since the most relevant changes were detected in STIM-OFF condition. Finally, ET was diagnosed according to clinical criteria, which is still the most accurate way in absence of a gold standard for the diagnosis. In conclusion, we found that a subset of ET patients with very long disease duration display disrupted lower limb joint coordination during gait. Given the present debate about the origin of ET [28], the finding that thalamic DBS normalizes these abnormalities does not support the hypothesis of cerebellar neurodegeneration [32]. Excessive strength of stimulation did not lead to such improvements and, more importantly, it induced ataxic changes of joint excursion in patients with otherwise normal kinematics. These results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window. This finding would explain the lack of ataxia improvement reported by some studies [7,10,33] as well as some disadvantageous consequences such as increased likelihood to fall [10,34]. Acknowledgements Authors thank arch. Silvia Allori for the editing of Fig. 1 and Prof. Alberto J. Espay, University of Cincinnati – OH, for his invaluable
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