Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease

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(1)Article. Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease FERRAYE, Murielle Ursulla, et al.. Reference FERRAYE, Murielle Ursulla, et al. Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease. European Neurology, 2013, vol. 69, no. 5, p. 281-288. DOI : 10.1159/000346432 PMID : 23445615. Available at: http://archive-ouverte.unige.ch/unige:95933 Disclaimer: layout of this document may differ from the published version..

(2) Original Paper Eur Neurol 2013;69:281–288 DOI: 10.1159/000346432. Received: July 19, 2012 Accepted: November 5, 2012 Published online: February 27, 2013. Levodopa-Resistant Freezing of Gait and Executive Dysfunction in Parkinson’s Disease M.U. Ferraye a, b, d C. Ardouin c E. Lhommée c V. Fraix a–c P. Krack a–c S. Chabardès a–c E. Seigneuret b, c A-L. Benabid a–c P. Pollaka–c B. Debûa,b a. Université J. Fourier Grenoble 1, b INSERM, U836, Grenoble Institut des Neurosciences, c Centre Hospitalier Universitaire de Grenoble, Grenoble, France, and d Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands. Abstract We examined executive functioning in patients with Parkinson’s disease exhibiting, or not, levodopa-resistant freezing of gait (L-FOG). 38 advanced-stage patients with L-FOG were identified in a consecutive series of 400 patients. They were matched with 38 patients without L-FOG. All patients underwent prospective evaluations of cognitive and motor functioning before subthalamic nucleus surgery, and 1 year after. A composite frontal score, a measure of executive functioning, was compared between the two groups. We also examined correlations between the frontal score and the score on the FOG item of the Unified Parkinson Disease Rating Scale II. Results show that after surgery, patients with L-FOG, as a group, were more impaired in executive functioning than control patients. However, individual data analysis showed preserved executive functions in 11 patients with L-FOG. In addition, there was no correlation between L-FOG severity and the degree of executive impairment. Therefore, frontal dysfunction may be one mechanism underlying L-FOG in a number of patients with Parkinson’s disease. However, since. © 2013 S. Karger AG, Basel 0014–3022/13/0695–0281$38.00/0 E-Mail [email protected] www.karger.com/ene. some patients develop L-FOG despite the preservation of executive functions, lesions or dysfunction of other neuronal structures are likely to be involved. Copyright © 2013 S. Karger AG, Basel. Introduction. The aim of the present study was to identify factors associated with levodopa-resistant freezing of gait (L-FOG) in patients with Parkinson’s disease (PD). Recent data indicate an association between FOG and executive dysfunction [1–3], suggesting the involvement of the frontal lobes in the emergence of L-FOG. FOG refers to the inability to produce effective steps, be it at initiation or in the course of walking [4]. It is a disabling phenomenon resulting in an increased risk of falls and decreased autonomy and quality of life [5]. Advanced stages of PD are dominated by axial symptoms including L-FOG [6] and postural instability, as well as executive dysfunction. In addition, gait difficulties have sometimes been reported after subthalamic nucleus (STN) surgery in patients with PD [6]. In our center, the surgical and clinical evaluation procedures have been very consistent over the years. Therefore, we took advantage of our large cohort of PD patients Murielle Ferraye Université J. Fourier Grenoble 1, INSERM, U836 CHU de Grenoble, Pavillon de neurologie, BP 217 FR–38043 Grenoble Cedex 9 (France) E-Mail murielle.ferraye @ fcdonders.ru.nl. Downloaded by: Université de Genève 129.194.22.139 - 4/27/2017 2:59:33 PM. Key Words Executive dysfunction · Levodopa-resistant freezing of gait · Parkinson’s disease · Subthalamic nucleus surgery · Unified Parkinson Disease Rating Scale.

(3) L-FOG (n = 38). PD controls (n = 38). Female/male 9/29 8/30 Mean age at evaluation, years 59.0±6.7 58.4±7.0 Mean disease duration, years 14.2±4.9 13.6±4.3 UPDRS II (/52) Before surgery Off med 27.4±7.9** 24.2±7.0 Before surgery On med 7.6±4.8 5.5±4.4 After surgery Off med/On stim 16.2±6.4* 10.4±6.4 After surgery On med/On stim 12.9±5.2* 7.4±4.0 UPDRS III (/108) Before surgery Off med 48.2±18.1 46.5±16.0 Before surgery On med 18.4±10.8 14.3±7.1 After surgery Off med/Off stim 48.2±18.1 41.0±14.9 After surgery Off med/On stim 27.2±12.5 18.6±10.3 After surgery On med/Off stim 23.6±13.0 18.8±8.5 After surgery On med/On stim 18.4±9.7 12.2±6.7 MATTIS Before surgery 135.1±5.2 137.2±4.8 After surgery 132.7±8.6 136.0±6.0 Beck Depression Inventory Before surgery 12.1±6.6 12.4±7.7 After surgery 11.8±7.3 9.9±7.2 Levodopa equivalent daily dose, mg Before surgery 1,316.6±414.2 1,403.6±546.3 After surgery 557.9±408.9 401.6±336.1 med = Medication; stim = stimulation. Data are presented as mean ± SD; * p < 0.002, ** p = 0.08 for the comparison with the PD control group.. with STN stimulation to compare the clinical and cognitive characteristics of two groups of patients presenting, or not, with treatment-resistant FOG 1 year after surgery. Based on previous studies, we hypothesized that patients with L-FOG would be more likely to show executive dysfunction than patients without L-FOG.. Methods Patients We examined the motor and cognitive data prospectively collected from 400 consecutive PD patients operated on in the STN between July 1993 and October 2009 in the Movement Disorders Unit of Grenoble University Hospital. All patients had been assessed off and on levodopa before and 1 year after surgery using the complete Unified Parkinson Disease Rating Scale (UPDRS). After surgery, the motor part of the UPDRS (UPDRS III) was administered under the four usual treatment conditions (off levodopa/off stimulation; off levodopa/on stimulation; on levodopa/off stimulation; on levodopa/on stimulation). Unblinded assessments were performed when patients had taken no medication for 8–12 h (off levodopa). 282. Eur Neurol 2013;69:281–288 DOI: 10.1159/000346432. and during periods of maximal clinical benefit after the administration of a dose of liquid levodopa that was 50% greater than the usual morning dose of dopaminergic treatment (on levodopa) [7]. After surgery, assessment was performed with the same levodopa dose as before surgery. Off stimulation evaluation was conducted 30–60 min after stimulation arrest [8]. On stimulation assessments were conducted at least 30 min after switching on the stimulator. Patients were selected and assigned to the L-FOG group if their on levodopa score on the FOG item of the Activity of Daily Living Part of the UPDRS (UPDRS II) was at least 2/4 (occasional freezing when walking) 1 year after surgery. In order not to include patients with levodopa-induced FOG, patients were excluded if their score on levodopa was greater than their score off levodopa, either before or 1 year after STN surgery. Out of 400 patients, 38 (8.5%) met the inclusion criteria. 38 PD patients matched for age, sex, overall educational level, disease duration, and off medication/off stimulation UPDRS III score were allotted to the control group. Patients from the control group scored 0/4 on the FOG item of the UPDRS II when on levodopa both before and after surgery, but could have levodopa-responsive FOG. The demographic and clinical characteristics of the two groups of patients are shown in table 1. Postoperative MRI was performed for all patients which enabled us to verify electrode placement and the absence of surgeryinduced hematoma or contusion. We did not perform precise localization of the STN electrodes for this study because the surgical procedure for electrode implantation remained similar during the course of the study period for both groups of patients. None of the 76 patients suffered surgery-induced hemispheric lesions liable to induce cognitive changes. Neuropsychological Assessment Thorough neuropsychological assessments were performed by a neuropsychologist during the month preceding surgery and 1 year after surgery. Assessments were conducted under the patients’ usual treatment, and with stimulation turned on using the chronic electrical parameters after surgery. For the purpose of this study, we focused on executive functions. Executive functions were assessed using the Wisconsin Card Sorting Test (number of categories, number of perseverative errors, maintaining errors, total number of errors; score out of 20) [9], a categorical and literal verbal fluency test (number of words in 1 min; score out of 10) [10], and Luria’s graphic and motor series (scores out of 10) [11–13]. A global frontal score was calculated as the sum of the scores obtained for each of these four measures, with a maximum score of 50 [14]. Specifically, regarding the Wisconsin Card Sorting Test, a score of 20 is obtained by multiplying the number of categories by 3 (max. 18). Patients who complete the test with more than 6 errors stay at 18. Patients who complete the test with 6 or less errors get a bonus of 2 points (20/20). For the scoring of verbal fluency, the examiner counts the number of correct items (complying with the rule, excluding repetitions) enumerated by the subject. The graphic and motor sequences are composed of 21 drawings/movements which are repeated 4 times. The total score is the number of correct transitions (out of 80) divided by 4. Mood was assessed using the Beck Depression Inventory. Statistical Analysis Demographic and clinical features of the two groups of patients were compared using t tests for independent samples. We compared treatment efficacy (levodopa or stimulation alone, and the combination levodopa + stimulation) across the two groups rela-. Ferraye et al.. Downloaded by: Université de Genève 129.194.22.139 - 4/27/2017 2:59:33 PM. Table 1. Demographic and clinical characteristics of the patients.

(4) 4. FOG group Control group. 3 FOG score (/4). 2 1 0 Off med. On med. Before surgery. On med Off med After surgery. Fig. 1. FOG scores (FOG item of part II, activities of daily living,. of the UPDRS) for the patients of the two groups, when off and on levodopa before and 1 year after surgery.. 50. FOG group Control group. 45 Frontal score (/50). Results. 40. The two groups did not differ in age, disease duration, overall disease severity (off treatment UPDRS III total score) whether before or 1 year after surgery, postoperative antiparkinsonian drug reduction, pre- and postoperative antiparkinsonian treatment, or Beck Depression Inventory scores (table 1). One year after surgery the patients with L-FOG had more severe UPDRS II total scores, both off and on levodopa. When off levodopa, the FOG score improved after surgery in the control group but not in the FOG group. Furthermore, in this latter group the on levodopa FOG score was worse 1 year after surgery than before surgery (fig. 1). Nevertheless, regarding the UPDRS III total score, the improvement brought about by levodopa or STN stimulation alone, or the combination of both treatments, relative to the postoperative off medication/off stimulation condition, did not differ between the groups. The effect of Group on the frontal score was significant (F(1,74) = 6.97 p < 0.05), the patients of the L-FOG group being more impaired than those of the control group (fig. 2). Planned comparisons revealed that the difference between the two groups was significant 1 year after surgery (p < 0.05), while there was only a trend before surgery (p = 0.06). The main effect of Surgery was non-significant, as was the Group by Surgery interaction (p > 0.05). Although the two groups did not differ regarding UPDRS III total score, because the patients in the L-FOG. group were slightly more severely affected than patients of the control group (table 1), we performed an analysis of covariance with the UPDRS III total score as a covariate. The results of this additional analysis showed that there was no frontal score difference between the two groups before surgery (p = 0.105) while the difference remained significant 1 year after surgery (p < 0.05). Spearman correlation tests did not reveal any correlation between the severity of L-FOG and frontal dysfunction as measured using the frontal score (Spearman’s ρ = 0.09; p = 0.57). The first and third quartiles of the frontal scores of the patients before surgery were respectively 32 and 44. Figure 3 shows the individual frontal scores. L-FOG and Executive Dysfunction in Parkinson’s Disease. Eur Neurol 2013;69:281–288 DOI: 10.1159/000346432. p < 0.05. 35 30 25. Before surgery. After surgery. Fig. 2. Frontal scores for the patients of the L-FOG and control. groups, before and 1 year after STN surgery.. 283. Downloaded by: Université de Genève 129.194.22.139 - 4/27/2017 2:59:33 PM. tive to the off levodopa/off stimulation condition. The threshold for significant effects was set at p < 0.002 to account for multiple comparisons (Bonferroni correction). Regarding the frontal score, UPDRS II and UPDRS III total scores, the distributions were normal and the equality of variances criterion for parametric statistics was met. We therefore performed analyses of variance with a Group (controls vs. L-FOG) by Surgery (before vs. after) design with repeated measures for the last factor. Planned comparisons were performed to test the hypothesis that executive functioning in patients with L-FOG would be more impaired than in control patients 1 year after surgery. The threshold for significant effects was set at p < 0.05. In addition, to account for potential differences in disease severity between the two groups, an analysis of covariance was performed for the frontal score using the preoperative off treatment UPDRS III total score as a covariate. Finally, a Spearman correlation test between the frontal score and the score on FOG item of the UPDRS II on medication 1 year after surgery was performed in the L-FOG group to assess the link between executive dysfunction and severity of L-FOG. Frontal scores were also examined for each patient individually. The cutoff values for impaired and preserved executive functions were defined, respectively, as the first and third quartiles of the scores of the combined groups before surgery. The number of patients below or above the cut-off values was computed in each group..

(5) Before surgery 35. 35. 30. 30. 25. 25. 20. 20. 15. 15. 10. 10. 5. 5. 15. 20. 30. 35. 40. 45. 50. 10. 30. 25. 25. 20. 20. 15. 15. 10. 10. 5. 5. b. Eur Neurol 2013;69:281–288 DOI: 10.1159/000346432. 20. 25. 30. 35. After surgery. 30. 15. 20. Before surgery 35. 10. 15. L-FOG group. 35. Fig. 3. Individual frontal scores of the patients from the L-FOG (a) and control (b). 284. 25. L-FOG group. 25. 30. 35. 40. 45. 50. 10. 15. 20. Control group. 25. 30. 35. 40. 45. 50. 40. 45. 50. Control group. Ferraye et al.. Downloaded by: Université de Genève 129.194.22.139 - 4/27/2017 2:59:33 PM. 10. a. groups before (left) and after (right) surgery. Dotted lines represent the cut-off for poor (≤32.0) and preserved (≥44) executive functioning. Black and white bars highlight patients below and above cut-off values respectively.. After surgery.

(6) To better understand the pathophysiology of L-FOG in PD, we compared the executive functioning of two groups of PD patients with and without L-FOG. We hypothesized that it would be impaired in patients with LFOG. Our results support this hypothesis, showing that, 1 year after surgery, patients with L-FOG displayed impairments of executive functioning as compared to control patients. This could not be accounted for by differences in disease severity, as shown by the ANCOVA analysis. These results point to frontal lobe dysfunction as one mechanism underlying L-FOG. However, individual data examination also showed that not all patients with L-FOG showed executive deterioration. Thus, altogether, our results support the idea that at least two distinct mechanisms underlie L-FOG in PD, the first being related to frontal networks dysfunction, the second one involving other circuits. Although the precise pathophysiology of L-FOG is unclear, it is believed to result from the progression of the pathological process to non-dopaminergic circuits [15]. Specifically, it has been suggested that frontal lesions were responsible for L-FOG [16]. Such hypothesis of frontal lobe involvement is supported by the occurrence of LFOG in a number of neurological disorders involving frontal lobe deficits, such as infarcts or tumors [17], as well as the co-occurrence of FOG and frontal cognitive impairment [1, 18]. Our results show that patients with L-FOG had lower scores on the frontal assessment battery 1 year after surgery. Other authors also observed a relation between executive dysfunction and L-FOG in patients with PD. For example, Amboni et al. [1, 2] reported that L-FOG was associated with cognitive frontal dysfunction in PD patients and that the cognitive performances of patients with L-FOG deteriorated faster than that of patients without L-FOG. In the DATATOP cohort [19], FOG was already reported to be associated with a decline in cognition. Our results thus feed the growing body of evidence that gait is not a fully automated motor. activity regulated by lower level structures but is also regulated at a frontal level [20]. They support the idea that executive functions, and therefore the frontal lobes, play a major role in gait control. Although the tests used in this study (Wisconsin, verbal fluency ...) have been reported to be the most sensitive to detect frontal dysfunction in PD [11, 13, 21], they are not specific enough to precisely identify which processes are impaired. Indeed, a number of processes are grouped under the umbrella concept of ‘executive functions’ (i.e. planning, attention, inhibition, initiation, mental flexibility, fluency, multitasking ...). Recently published results suggested that mental flexibility (set shifting) could be particularly involved [3], while others suggested that impaired visuospatial abilities could interfere with movement planning [22, 23]. In addition to frontal lobe dysfunction, imaging data showed that the metabolism of the parietal, occipital and temporal sensory cortices is decreased in patients with FOG [26], which is consistent with the reported visuospatial processing deficits. However, other structures also appear to be involved in the development of L-FOG, as individual data analysis showed that about one third of the patients of this study displayed L-FOG without any evidence of executive dysfunction. In addition, the correlation between L-FOG severity and the degree of executive impairment was non-significant. L-FOG was therefore not related to frontal impairment in these patients. According to the schema of the circuitries involved in locomotion proposed by Nutt et al. [24] the mesencephalic locomotor area (which includes the pedunculopontine and cuneiform nuclei) could be a key structure directly connected to the basal ganglia and cerebral cortex, and projecting to the spinal pattern generator through the pontomedullary reticular formation. Involvement of the region of the pedunculopontine nucleus (PPN) is thus another putative pathophysiology underlying L-FOG. Animal studies [25] as well as human physiopathological data [26] and recent human PPN stimulation studies reporting benefits on gait and/or FOG [27–29] support the hypothesis of PPN area involvement in the control of locomotion. The idea is further consistent with recent imagery data showing activations within the mesencephalic area during imagination of gait [30–32] and PPN involvement in the fall status in PD patients [33]. It is therefore very likely that, in some patients with preserved executive functions, L-FOG results from the dysfunction or lesion of neurons from the PPN region. Thus, our results are consistent with the idea that two distinct pathophysiological mechanisms can lead to L-. L-FOG and Executive Dysfunction in Parkinson’s Disease. Eur Neurol 2013;69:281–288 DOI: 10.1159/000346432. Discussion. 285. Downloaded by: Université de Genève 129.194.22.139 - 4/27/2017 2:59:33 PM. for the two groups. Twelve patients of the L-FOG group before surgery and 15 after surgery displayed a total score ≤32. In the control group, this was the case for 7 patients before surgery and 6 after surgery. However, among the 38 patients with L-FOG, 9 before surgery and 8 after surgery displayed frontal scores >44, as compared to 11 before surgery and 15 after surgery in the control group..

(7) 286. Eur Neurol 2013;69:281–288 DOI: 10.1159/000346432. The present study has some limitations that are inherent to the methodology. Our criterion for patients’ inclusion was the presence of moderate to severe LFOG 1 year after STN surgery. This was defined as a minimum score of 2/4 on the FOG item from the UPDRS II on levodopa. One could argue that an objective assessment of FOG based on a gait protocol including FOG-provoking circumstances, such as fast turns, would have been preferable [27]. However, FOG has only become a major research focus in recent years and its triggering circumstances were not well known at the time of the first surgeries. In addition, FOG is a highly unpredictable phenomenon that may not occur during objective assessments, although it is frequent at home. Therefore, interrogation of the patients is critical to document such symptoms. The presence of L-FOG before surgery can be a contraindication for STN surgery so that few patients with L-FOG are operated on. In the present cohort, 4 patients had some FOG when on medication before surgery. These patients were included because their FOG partly responded to levodopa, decreasing from 4 off medication to 2 on medication. For the 34 remaining patients, freezing had become levodoparesistant during the year following STN surgery. Also, it has been shown that STN stimulation can lead to gait worsening in some patients. Such an effect has mostly been reported after several years of STN stimulation [6] if not directly resulting from electrode misplacement. We controlled for such unwanted effect by checking electrode placement on the postoperative MRI and by verifying that the on stimulation scores were lower than the off stimulation scores on the objective gait item of the UPDRS III. Thus, in the patients of this cohort, it is unlikely that STN stimulation directly worsened gait, although it may have indirectly revealed a L-FOG that would eventually have developed. Indeed, L-FOG is not an all-or-none phenomenon over the course of the disease. In most patients, FOG first appears during off medication periods, responding well to levodopa. Its responsiveness then progressively wanes over time, and FOG becomes treatmentresistant. Another possibility is that the worsening of FOG 1 year after surgery in these patients could, at least partly, be due to the reduction of the levodopa daily intake enabled by the stimulation. Indeed, although gait difficulties were aggravated in daily life when on medication (as assessed by the FOG item of UPDRS II) in the L-FOG group but not in the control group, an acute supra-threshold dose of levodopa lead to similarly reduced improvements of motor functioning in the two groups, as comFerraye et al.. Downloaded by: Université de Genève 129.194.22.139 - 4/27/2017 2:59:33 PM. FOG in PD. The first would involve the frontal lobes, while the second one could involve lower centers, such as the region of the PPN. Could confounding factors affect our results? For example, the patients included in the present study had undergone STN surgery. Could this bear on the results, that is, could STN stimulation explain the impairment in executive functioning seen in the patients with L-FOG? It is unlikely. First, the outcome of STN stimulation on cognition is usually considered safe [11, 34] although some studies reported a worsening in executive functions, especially in verbal fluency [35]. In addition, the two groups of patients of the present study were homogeneous regarding disease evolution and severity, age, medication, and depressive status, and they all had been operated on in the STN for 1 year. Therefore the postoperative differences regarding executive functioning cannot be attributed to these potentially confounding factors. Yet, patients may have differed in their response to STN stimulation. Indeed, although there was no difference in the UPDRS III score’s improvement brought about by the stimulation, in the control group, off medication FOG was largely improved 1 year after surgery, whereas it was not the case in the L-FOG group (fig. 1). Thus, the response of off medication FOG to STN stimulation, rather than the presence of L-FOG, could explain the difference in executive functioning between the two groups. To test this hypothesis, we performed additional analyses. We classified patients according to the response of off medication FOG to STN stimulation, calling ‘responders’ the patients whose off FOG score was improved 1 year after surgery, and ‘non-responders’ the patients whose off FOG was not. Examination of this feature revealed that 26 patients of the control group and 17 patients of the L-FOG group were ‘responders’ while 7 patients of the control group and 21 patients of the L-FOG group were ‘non-responders’. Thus, the two patterns were present in the two groups. In addition, comparison of the frontal scores of the responders versus non-responders in each group failed to reveal any difference. Therefore, the response of off medication FOG to STN stimulation cannot explain the differences in executive functioning between the two groups. In contrast, between-group comparison confirmed the main results of the study, revealing that the frontal scores of the responders with L-FOG were impaired compared to the frontal scores of the responders without L-FOG. In conclusion, the only difference that remains between the groups and can be linked to the difference in executive functioning is the presence of L-FOG..

(8) pared to the improvements seen before surgery. It has been shown that in those PD patients treated with STN DBS allowing for marked reduction of levodopa, the magnitude of the levodopa response decreases with a worsening of the on UPDRS motor scores. This has been explained by long-term plastic changes of the dopaminergic system, with partial desensitization [28]. In addition to such plastic changes, the loss of the long-term effect of levodopa might also contribute to a reduction in the short-term effect of levodopa [19]. Finally, out of 400 patients, only 34 (8%) developed L-FOG 1 year after surgery. Such a ratio is expected in patients at advanced stages of PD as was the case in our study (mean disease duration: 14.2 years). For instance, Hely et al. [36] have found that 81% of PD patients develop L-FOG after 20 years of disease evolution.. In summary, our results support the idea that at least two distinct pathophysiological pathways underlie LFOG in PD. 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Levodopa-resistant freezing of gait and executive dysfunction in Parkinson&#039;s disease

Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease