Re-emergent tremor in Parkinson s disease: the effect of dopaminergic treatment

ORIGINAL ARTICLE Re-emergent tremor in Parkinson s disease: the effect of dopaminergic treatment D. Belvisi a, A. Conte a,b, C. Cutrona b, M. Costanzo b, G. Ferrazzano a, G. Fabbrini a,b and A. Berardelli a,b a Neuromed Institute, Pozzilli; and b Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy Keywords: action tremor, dopaminergic treatment, Parkinson s disease, re-emergent tremor, resting tremor Received 1 November 2017 Accepted 1 March 2018 European Journal of Neurology 2018, 0: 1 6 doi:10.1111/ene.13619 Introduction Patients with Parkinson s disease (PD) with resting tremor may also have a tremor that appears after a varying latency while they maintain the upper limbs outstretched. This type of tremor is called re-emergent tremor (RET) [1]. RET differs from the postural tremor that is present in PD while a posture is maintained [1]. As both the frequency [1 3] and muscle Correspondence: A. Berardelli, Department of Human Neuroscience, Sapienza, University of Rome, Viale dell Universita, 30, 00185 Rome, Italy (tel.: 0039 06 49914700; fax: 0039 06 49914700; e-mail: alfredo.berardelli@uniroma1.it). Background and purpose: Patients with Parkinson s disease (PD) with resting tremor may be affected by a tremor that appears after a varying latency while a posture is maintained, a phenomenon referred to as re-emergent tremor (RET). The aim of the study was to evaluate the occurrence and clinical features of RET in patients with PD tested off and on treatment, and to compare the effect of dopaminergic treatment on RET with the effect on resting and action tremor. Methods: We consecutively enrolled 100 patients with PD. Patients were clinically evaluated 24 h after withdrawal of therapy (off-treatment phase) and 60 min after therapy administration (on-treatment phase). We collected the demographic and clinical data of patients with PD. The severity of the disease was assessed by means of the Hoehn and Yahr scale and Movement Disorder Society-sponsored revision of the Unified Parkinson s Disease Rating Scale part III. We evaluated the latency, severity and body side affected both off and on treatment in patients with RET. Results: Re-emergent tremor was present in 24% of the patients with PD off treatment and in 19% of the patients on treatment. Dopaminergic treatment reduced the clinical severity of RET. Dopaminergic treatment increased the number of patients with unilateral RET and reduced the number of those who had bilateral RET. RET and resting tremor responded similarly to dopaminergic treatment, whereas action tremor was less responsive. Patients with RET had milder motor symptoms than patients without RET both off and on treatment. Conclusions: Dopaminergic treatment modified RET occurrence, severity and body distribution. Dopaminergic depletion plays a role in the pathophysiology of RET. contraction pattern [4] are similar in RET and resting tremor, it has been suggested that RET is a variant of resting tremor [1]. A recent observational study that investigated the occurrence and clinical features of RET in 210 patients with PD revealed that RET was present in 20% of the patients studied and that patients with RET had milder axial symptoms and bradykinesia than those without RET [5]. Patients with PD were evaluated while they were taking their usual treatment regimen. Dopaminergic treatment might, however, have led to the occurrence of RET being underestimated and might have affected the clinical differences between patients with and those without RET. EUROPEAN JOURNAL OF NEUROLOGY 1

2 D. BELVISI ET AL. We designed the present study to ascertain whether dopaminergic medication modifies the occurrence and clinical features of RET. For this purpose, we studied 100 patients with PD off and on treatment. We also evaluated whether the effect of dopaminergic treatment on RET differs from that on resting tremor and action tremor. A better knowledge of the effects of dopaminergic treatment on RET may shed further light on the pathophysiology of RET. Methods A total of 100 patients with PD were consecutively enrolled in the study. From January 2017 to June 2017, all of the patients scheduled to attend our outpatient clinic were asked to come 24 h after treatment withdrawal (off-treatment evaluation). On the same day, patients were also evaluated 60 min after taking their usual dopaminergic treatment (on-treatment evaluation). The diagnosis of PD was based on clinical criteria [6,7]. We collected the demographic and clinical data of patients with PD, including age, age at disease onset, disease duration, duration of treatment with dopaminergic drugs, dopaminergic therapy dosages and presence of dyskinesia and motor fluctuations. The severity of the disease was assessed by means of the Hoehn and Yahr scale (H&Y) [8] and Movement Disorder Society-sponsored revision of the Unified Parkinson s Disease Rating Scale (MDS-UPDRS) part III [9]. Non-motor symptoms were evaluated by means of the Non-Motor Symptoms assessment scale for PD [10]. The levodopa-equivalent daily dose was also calculated. In order to assess the presence of resting tremor, we asked patients to sit comfortably on a chair, with the upper limbs at rest for 60 s. To evaluate the presence of RET and postural tremor, we asked patients to extend both arms and to hold them outstretched for 90 s. For the assessment of kinetic tremor, we asked patients to perform the finger-to-nose and finger-to-finger tests (15 times for each side for each test). RET was defined as a tremor that reappeared after a varying time lapse in the outstretched upper limbs of a patient with resting tremor [5]. The latency of RET was defined as the time interval between the arm extension and onset of tremor detected by the visual inspection (expressed in seconds). RET latency was tested three times in each patient and the values were then averaged. The severity of RET (0 4 according to the MDS-UPDRS item for resting and action tremor) [9] and body side affected (unilateral or bilateral) were also evaluated both off and on treatment. The presence of RET and other types of tremor and the severity of motor symptoms (MDS-UPDRS scores) were evaluated off and on treatment. All of the patients enrolled participated in the study. All of the experimental procedures were conducted in accordance with the Declaration of Helsinki. Each patient signed an informed consent form and the study was approved by the local ethics committee. Statistical analysis We used SPSS software version 25 (SPSS Inc., Chicago, IL, USA) for the statistical analysis. In order to clinically characterize the enrolled population of patients with PD, the mean and SDs of the demographic and clinical parameters examined were calculated. The mean latency and mean severity of tremor were calculated in patients with RET. We used the t-test to assess the effect of therapy on the severity and latency of RET and the Kruskall Wallis test to compare the effect of therapy on different types of tremor. The post hoc analysis was performed by applying the Mann Whitney U-test. We used the Mann Whitney U-test to compare the clinical and demographic characteristics (age, age at disease onset, disease duration, dosage and duration of treatment, presence of dyskinesias, motor fluctuations, H&Y scores, MDS-UPDRS scores and Non- Motor Symptoms assessment scale for PD scores) of patients with and without RET off and on treatment. In accordance with previous studies [11], for the statistical analysis we used combined MDS-UPDRS subscores to summarize the single item scores. The bradykinesia subscore included four limbs and the global bradykinesia item scores, the rigidity subscore included four limbs and neck item scores, and the axial symptoms subscore included speech, facial expression, arising from chair, gait, posture and postural stability item scores. Resting and action tremor scores were analyzed separately [11]. In a subsequent analysis, we compared the demographic and clinical characteristics of patients with different types of tremor off and on treatment by using the Kruskall Wallis test. The Mann Whitney U-test was used for the post hoc analysis. This analysis was performed separately for the data obtained from evaluations performed on and off treatment. We used Spearman s correlation coefficient to detect any correlations between the clinical features of RET, including the improvement in RET after dopaminergic treatment (expressed as severity on treatment/severity off treatment 9 100 ratio) and the other demographic and clinical features. Holm correction was applied for multiple comparisons. P < 0.05 was considered statistically significant.

RE-EMERGENT TREMOR AND DOPAMINERGIC TREATMENT 3 Results Demographic and clinical features of patients with Parkinson s disease A total of 40 women and 60 men participated in the study. Their mean age was 69.1 9.6 years and mean age at onset of parkinsonian symptoms was 63.4 9.9 years. The mean H&Y score was 2.1 1.5. When patients were evaluated off treatment, the MDS- UPDRS part III score was 29.4 7.8, whereas it significantly decreased when patients were evaluated on treatment (19 5.5; P < 0.005). A total of 82 patients were either on levodopa alone (40) or on levodopa combined with other drugs (42), whereas 7 were on dopamine agonists alone, 5 were on monoamine oxidase inhibitor type B alone and 6 were on dopamine agonists combined with monoamine oxidase inhibitor type B. No patients were on beta-blocker or anticholinergic drugs. Dyskinesias were present in 24 patients. Motor fluctuations were present in 46 patients. Effect of dopaminergic treatment on the occurrence of re-emergent tremor and other types of tremor When patients were off treatment, RET was present in 24 patients, resting tremor in 12 patients, resting tremor associated with action tremor in 43 patients (6 with postural tremor, 4 with kinetic tremor and 33 with both tremors), whereas the remaining 21 patients displayed no tremor. No patient had action tremor alone. When patients were on treatment, RET was present in 19 patients, resting tremor in 10 patients, resting tremor associated with action tremor in 37 patients (5 with postural tremor, 3 with kinetic tremor and 29 with both tremors), action tremor alone in 3 patients, whereas 31 patients displayed no tremor. According to the definition of RET, which requires the presence of resting tremor, we observed that all of the patients with RET also had resting tremor. The demographic and clinical data of the clinical subtypes are reported in Table 1. Figure 1 Correlations between re-emergent tremor and resting tremor severity off (a) and on (b) treatment. Effect of dopaminergic treatment on the characteristics of re-emergent tremor The severity of RET was significantly reduced by dopaminergic treatment (right side: off treatment, 2.2 0.8; on treatment, 1.5 0.66; P < 0.03; left side: off treatment, 2.1 0.9; on treatment, 1.4 0.7; P = 0.04) (range 1 4), whereas the latency of RET was increased slightly by dopaminergic treatment [off treatment, 7.6 4.6 s (range 2 40 s); on treatment, 9.1 5.2 s (range 2 45 s); P = 0.06]. Figure 2 Correlations between resting tremor (a) and re-emergent tremor (b) severity improvement (expressed as severity on treatment/severity off treatment 9100 ratio) and the dopaminergic treatment dose [expressed as levodopa equivalent daily dose (LEDD)].

4 D. BELVISI ET AL. Table 1 Clinical and demographic characteristics of patients with re-emergent tremor (RET), resting tremor, resting tremor associated with action tremor and no tremor RET Resting tremor Resting tremor + action tremor No tremor P-value Age (years) 70.5 6.5 67.4 5.5 69.5 6.9 69.2 6.7 n.s. Disease duration (years) 6.5 3.6 4.8 2.6 6.3 4.7 4.9 3.6 n.s. MDS-UPDRS part III score off treatment 22.7 8.4 22.7 8.1 37.9 14.5 34.3 15.5 <0.00001 MDS-UPDRS part III score on treatment 14.1 5.5 16 6.5 25.5 9.4 21.5 8.2 <0.0001 Hoehn and Yahr scale score 1.8 0.5 2.1 0.7 2.3 1.1 2.5 0.8 <0.03 LEDD (mg) 465 207 405 195 485 227 495 269 n.s. Treatment duration (years) 4.2 2.5 3.8 2.2 4.4 2.99 3.9 2.3 n.s. NMSS score 36 30 34 32 41 40 44 41 n.s. P-values refer to the comparisons between patients with RET and patients in the other three groups. LEDD, levodopa-equivalent daily dose; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson s Disease Rating Scale; NMSS, Non-Motor Symptoms assessment scale for Parkinson s disease; n.s., not significant. Data are given as mean SD. In the off-treatment evaluation, RET was bilateral in 16 patients and unilateral in the remaining 8 patients. In the on-treatment evaluation, RET was bilateral in 12 patients, unilateral in 7 patients and absent in 5 patients. In 4 of these 5 patients, dopaminergic treatment led to the disappearance of both RET and resting tremor. Dopaminergic treatment and the clinical characteristics of patients with and without re-emergent tremor When we compared the demographic and clinical characteristics of patients with and without RET, we observed that the two groups did not differ in terms of gender, age, age at onset, disease duration, dosage and duration of pharmacological therapy, presence of dyskinesias, motor fluctuations or Non-Motor Symptoms assessment scale for PD scores (P > 0.05; Table 1). By contrast, patients with RET had lower scores on the H&Y scale (P < 0.03) and MDS- UPDRS than those without RET (off treatment, P < 0.00001; on treatment, P < 0.0001). The analysis of the MDS-UPDRS subscores showed that the scores in patients with RET for bradykinesia, axial symptoms and rigidity were lower than those in patients without RET (Table 2). In a subsequent analysis, we observed that the MDS-UPDRS subscores in all four groups of patients (RET, resting tremor, resting tremor associated with action tremor and no tremor) differed both off and on treatment (Table 2). The post hoc analysis revealed that scores in patients with RET were lower than those in patients with resting tremor associated with action tremor or in patients with no tremor (Table 2). No significant differences were detected between patients with RET and those with resting tremor alone either off or on treatment (Table 2). Effect of dopaminergic treatment on re-emergent tremor and other types of tremor When we compared the effect of the therapy on the different types of tremor, we found that the Table 2 Movement Disorder Society-sponsored revision of the Unified Parkinson s Disease Rating Scale (MDS-UPDRS) subscores of patients with re-emergent tremor (RET), resting tremor, resting tremor associated with action tremor and no tremor Off On MDS-UPDRS score RET Resting tremor Resting + action tremor No tremor RET Resting tremor Resting + action tremor No tremor Bradykinesia 10.5 5.1 10.4 5.2 16.2 6.2** 17.7 6.5*** 6.2 3.9 7 4.2 10.5 4.9** 10.6 5.4*** Axial symptoms 3.7 2.3 3.5 2.7 7.6 6.7** 8.9 5*** 2.4 2.2 2.7 2.5 5.3 3.8*** 6.4 4.5*** Rigidity 3.5 2.1 4.3 2.2 6.3 2.5*** 6.9 2.6*** 2.2 1.7 3 1.6 3.6 2** 3.9 2.1*** RET 2.1 0.7 0 0 0 1.4 0.7 0 0 0 Resting tremor 2.9 1.4 2.6 1.3 2.7 2.6 0 1.9 1.3 1.7 0.5 2.3 1.6 0 Resting tremor 1.8 0.9 1.5 0.7 1.8 0.8 0 1.2 0.6 1.3 0.5 1.2 0.5 0 constancy Action tremor 0 0 2.7 2 0 0 0 2.3 1.6 0 Significant differences in the MDS-UPDRS subscores between patients with RET and patients in the other three groups: **P < 0.001; ***P < 0.0001. Data are given as mean SD.

RE-EMERGENT TREMOR AND DOPAMINERGIC TREATMENT 5 treatment-induced reduction in severity differed in the three types of tremor (RET, resting tremor and action tremor) that we analyzed (P < 0.03). The post hoc analysis revealed that the severity of RET and resting tremor was reduced to a similar extent by therapy (28% and 30%, respectively; P = 0.03), whereas that of action tremor was reduced to a significantly lower extent (16%; P > 0.05). Correlations The severity of RET correlated with that of resting tremor both off (r = 0.65, P < 0.0001) (Figure 1a) and on (Figure 1b) (r = 0.44, P < 0.002) treatment. The improvement in RET severity after dopaminergic treatment (expressed as severity on treatment/severity off treatment 9 100 ratio) positively correlated with the improvement in resting tremor (r = 0.45; P < 0.0001). We also found a correlation between the improvement in both RET (r = 0.49; P < 0.01) (Figure 2b) and resting tremor (r = 0.54, P < 0.001) (Figure 2b) and the dopaminergic treatment dose (expressed as levodopa-equivalent daily dose). No further correlations emerged between the RET features and the other demographic, motor and non-motor clinical characteristics (P > 0.05). Discussion The novel finding of the present study is the effect of dopaminergic treatment on RET. Dopaminergic treatment slightly reduced the occurrence of RET (off treatment: 24%; on treatment: 19%) but significantly reduced the severity of RET. The reduction in the severity of RET correlated with the dopaminergic treatment dose. Dopaminergic treatment also modified the body distribution of RET, as demonstrated by the reduction in the number of patients with bilateral RET and the increase in the number of patients with unilateral RET. Jankovic et al. reported that dopaminergic therapy reduced the severity of RET, although without quantifying the extent of the reduction in RET severity and without investigating the effect of therapy on the occurrence and body distribution of RET [1]. Overall, our findings suggest that RET is at least partially responsive to dopaminergic treatment. Dopaminergic therapy induced a slight, albeit not statistically significant, increase in RET latency. RET latency is believed to be related to the transient interruption of the oscillatory activity of the central generators of resting tremor and RET induced by proprioceptive input resulting from the repositioning of the upper limbs. These central generators, such as the ventro-lateral thalamus and globus pallidus, are significantly affected by sensory input. Studies on PD animal models suggest that dopaminergic depletion induces a reduction in the selectivity level of information passing through the basal ganglia circuits [12,13]. Dopaminergic therapy reduces this deficit [14]. It may therefore be possible to ascribe the mild increase in latency following the intake of dopaminergic therapy to a better elaboration of the proprioceptive input. Our study sheds new light on the relationship between RET and resting tremor. Not only did we observe that dopaminergic treatment reduced the occurrence and severity of RET and resting tremor to a similar extent, but we also found a correlation between the reduction in RET and resting tremor severity and the dopaminergic treatment dose. Indeed, no clinical differences were observed between patients with RET and those with resting tremor either off or on treatment. Overall, these findings further suggest that RET and resting tremor share similar pathophysiological mechanisms. Previous studies have shown that resting tremor is related to altered activity in the basal ganglia and cerebello-thalamo-cortical circuit [15,16], with a recent study demonstrating that dopaminergic medication reduces tremor onset-related activity in the globus pallidus and tremor amplituderelated activity in the thalamic ventral intermediate nucleus [17]. The fact that we detected an improvement in both resting tremor and RET following the intake of dopaminergic therapy suggests that dopaminergic depletion plays a role in the pathophysiology of both types of tremor. By contrast, our results show that action tremor is less responsive than RET to dopaminergic treatment. This observation is in keeping with the results of previous studies and suggests that the response of action tremor to dopaminergic therapy is somewhat limited [18,19]. These findings suggest that the pathophysiological mechanisms that underlie RET and action tremor are not the same. The greater involvement of non-dopaminergic systems, including the serotoninergic [20] and cerebellar systems [21,22], might explain the more limited response to dopaminergic treatment in patients with action tremor. This study has some limitations. The evaluation that we performed of RET and of other types of tremor in patients off and on treatment was exclusively clinical. Our results on the occurrence of RET confirmed previous observations from clinical investigations performed in patients on treatment [5,19]. The lack of any neurophysiological measurements might, however, have led to the occurrence of RET being underestimated, as suggested by reports of a higher occurrence of RET in the tremor-dominant phenotype of PD in previous neurophysiological studies [1,23]. The absence

6 D. BELVISI ET AL. of neurophysiological tools might, consequently, also have limited the accuracy of the RET latency measurement. The latency of RET reported in this study is, however, similar to that reported in previous neurophysiological investigations [1,3,24]. In conclusion, our study demonstrates that dopaminergic medication partially reduces the occurrence of RET and significantly reduces the severity of RET. The similarity of the response of both RET and resting tremor to dopaminergic treatment suggests that the pathophysiological mechanisms underlying the two types of tremor overlap and that dopaminergic depletion is involved in both. Conversely, RET and action tremor have a different response to dopaminergic treatment. The presence of RET has relevant pathophysiological, prognostic and therapeutic implications and therefore RET should always be evaluated when assessing PD. Acknowledgements We thank Lewis Baker for the English language editing. 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