Surgery for Parkinson s disease improves disability but not impairment components of the UPDRS-II

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1 Parkinsonism and Related Disorders 13 (2007) Surgery for Parkinson s disease improves disability but not impairment components of the UPDRS-II A. Haffenden, U. Khan, Z.H.T. Kiss, O. Suchowersky Movement Disorders and Therapeutic Brain Stimulation Program, Hotchkiss Brain Institute, University of Calgary, Canada Received 7 September 2006; received in revised form 2 January 2007; accepted 15 January 2007 Abstract The Unified Parkinson s Disease Rating Scale (UPDRS) activities of daily living (ADL) items have been described as reflecting both disability (true ADL items) and impairment (rather than ADLs). As a result of combining these scores, UPDRS part II scores may not accurately reflect the impact of surgery on ADLs [Hariz G.M., Lindberg M., Hariz M.I., Bergenheim A.T. Does the ADL part of the unified Parkinson s disease rating scale measure ADL? An evaluation in patients after pallidotomy and thalamic deep brain stimulation. Mov Disord 2003;18: ]. The goal of the present study was to assess the metric properties of the ADL section of the UPDRS in terms of its ability to measure surgical change. We tested the effects of unilateral pallidotomy (N ¼ 14) and bilateral subthalamic nucleus (STN) DBS (N ¼ 11) on both disability and impairment components of the UPDRS-II at uniform follow-up assessment periods of 6 months and 1 year, with a subset of pallidotomy patients (N ¼ 9) re-assessed at 2 years. Across the follow-up periods in both patient groups, items identified as best reflecting disability showed significant improvement from pre-surgical levels, whereas items representing impairment showed no overall change. Consistent with this, change in total ADL scores was tempered by the inclusion of the impairment items. Because the measurement of a patient s functional status is important in determining the effectiveness of an intervention, analysis of appropriate items from the UPDRS ADL section is imperative. r 2007 Elsevier Ltd. All rights reserved. Keywords: Activities of daily living; UPDRS; Pallidotomy; Deep brain stimulation; Parkinson s disease 1. Introduction The rebirth of surgical treatment for Parkinson s disease (PD) resulted in a burgeoning literature on the effectiveness and outcome of the various surgical techniques available, with the majority of authors reporting objective data from the Unified Parkinson Disease Rating Scale (UPDRS) [1 3]. In particular, the activities of daily living (ADL, UPDRS part II) and motor (UPDRS part III) scores not only correlate well with each other [4], but are the standard outcome measures. The ADL section of the UPDRS is supposed to measure disability, which is commonly defined as the reduction of a person s ability to perform basic tasks. Disability manifests Corresponding author. Department of Clinical Neurosciences, Area 3, 3350 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Tel.: ; fax: address: osuchowe@ucalgary.ca (O. Suchowersky). itself as dependence; therefore, items assessing ADLs should reflect functional issues, such as a decreased ability to manage hygiene, that result in dependence. In contrast, the motor section of the UPDRS is intended to measure impairment, which is defined as an abnormality in structure or function [5]. Although the ADL section of the UPDRS contains items that appropriately identify disabilities, it also includes items that measure the patient s perceptions of impairments, such as their degree of difficulty with excessive salivation. Using principle components analysis to identify a cluster of disability items, van Hilten et al. [6] found that 8 of the 13 ADL items best measured disabilities, and therefore ADLs. These items assessed speech, swallowing, handwriting, cutting food, dressing, hygiene, turning in bed, and walking. Other authors have since noted that swallowing difficulties represent an impairment rather than a disability [7,8] and should be moved from the ADL section to the motor section [8]. Overall, studies examining the appropriateness /$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi: /j.parkreldis

2 400 ARTICLE IN PRESS A. Haffenden et al. / Parkinsonism and Related Disorders 13 (2007) of the 13 individual UPDRS ADL items have consistently concluded that the same 6 8 items from the scale assess disability, and the remaining 5 7 items assess impairment [3,6,7,9,10]. Hariz et al. [7] recently examined surgical outcome in a unilateral pallidotomy group and a unilateral thalamic deep brain stimulation (DBS) group using the 13 UPDRS ADL items divided into those that described a disability (7 items) and those that described impairment (6 items). Although the total scores of the UPDRS ADL scale were ameliorated in both the pallidotomy and the thalamic DBS groups, analysis of the subdivided ADL scores showed improvement in disability related items (those reflecting ADLs) only in patients who underwent pallidotomy and not in patients who underwent unilateral thalamic DBS. Clearly, it is important to determine whether or not surgical treatments improve motor function in such a way that the change impacts a patient s level of dependence. The primary purpose of the present study was to assess the metric properties of the ADL section of the UPDRS in terms of measuring post-surgical change. Our goal was to replicate the findings of Hariz et al. [7] in patients undergoing pallidotomy and to extend their findings to the contemporary DBS target for PD. Bilateral subthalamic nucleus (STN) DBS has supplanted unilateral thalamic DBS for treatment of PD because STN DBS alleviates rigidity, akinesia, and drug-induced dyskinesia, while allowing for a reduction in anti-parkinsonian medications [11,12]. The main effect of thalamic DBS is limited to ameliorating tremor [13]. We examined the impact of dividing the ADL scores on outcome in patients who underwent either unilateral pallidotomy or bilateral STN DBS. In addition, we extended the findings of Hariz et al. [7] with regard to the follow-up period. Hariz et al. presented data from a follow-up period with a range of 5 25 months with an average of 11 months. In our data set, we were able to examine change over time using uniform follow-up assessment periods. Our pallidotomy group was assessed at 6 months, 1 year, and a subset of patients was assessed again at 2 years, while the STN DBS group was assessed at 6 months and 1 year. Taken together, these two extensions of the Hariz et al. [7] study examining the utility of UPDRS ADL scores allowed us to determine how two commonly performed surgeries for the treatment of PD impact ADLs over time, and investigate how the properties of the UPDRS affect conclusions about the impact of surgery on daily functioning. 2. Patients and methods 2.1. Patients All patients had failed optimal medical therapy and were referred by movement disorder neurologists. Pre-surgical patient characteristics are described in Table 1. All data was collected as part of a review of information gathered for routine clinical assessments. Surgical methods for unilateral pallidotomy followed those described previously [14]. Surgery was always performed contralateral to the side of the worst symptoms. Of the 19 patients who underwent unilateral pallidotomy between 1997 and 2000, a complete data set was available from follow-up visits at both 6 and 12 months in 14 patients. Of the five patients not included in the series, one underwent repeated surgery within the follow-up time period, one was followed in their home community rather than the surgical clinic, and all of the UPDRS part II or III items were not scored for three patients during their follow-up visits. A subgroup of nine patients had complete follow-up data at 2 years and had not gone on to have subsequent surgery for treatment of their PD. Following pallidotomy, medications remained unchanged. Bilateral insertion of DBS into the STN was performed between 1998 and 2003 (with the majority of operations from 2002 onwards) following methods described previously [15]. A series of 13 patients was operated on, and of those 11 had follow-up assessments at both 6 and 12 months. One patient had follow-up at 12 but not at 6 months, and another did not turn his stimulator on. Insufficient numbers of this group of patients had reached the 2-year post-surgical mark at the time the data were compiled to permit analysis for longer-term follow-up. There was a 35% reduction on average in the levodopa equivalent dose at the 12-month follow-up assessment, as compared to pre-operative medication levels shown in Table 1. For both surgical groups, all patients had post-operative MRIs that confirmed that lead and/or lesion placement was in the correct position. Inclusion in the study was retrospective, based on the availability of a complete data set for the variables that were analyzed Assessment protocol Pre-surgical examination was performed an average of 2 months prior to pallidotomy (SD ¼ 2.1) and an average of 3 months (SD ¼ 1.7) prior to the insertion of STN DBS. All patients were evaluated using the UPDRS and Hoehn and Yahr staging during their perceived best and worst clinical condition, with results reported for the worst condition ( off ), consistent with the reporting of data in the Hariz et al. [7] study. Off periods were defined as having been off from medications for at least 12 h overnight. On periods were considered to be a minimum of 1 h after medications were taken, with a clinical evaluation used to determine when medications were most effective. Best on effects sometimes required an extra 50 mg dose of levodopa. Post-surgical assessments were conducted at 6 and 12 months, and data are also reported for a subset of pallidotomy patients who were assessed again at 24 months. Post-operative results are reported for both surgical groups off medication, with the stimulators on for the STN DBS group. To accurately capture ratings for the on off state, patients were provided with a point of reference: they were asked to think about how they function when they first wake up in the morning, or during the night, before their medications begin working Description of UPDRS items and subscores The focus of the present investigation was on part II of the UPDRS, the subscale assessing ADLs. The sum of the 13 ADL items contained in part II was analyzed across time periods within each surgical group and divided into the same 7 disability items and 6 impairment items as per the methods of Hariz et al. [7]. The disability subscore comprised items 5 (speech), 8 (handwriting), 9 (cutting food), 10 (dressing), 11 (hygiene), 12 (turning in bed), and 15 (walking). The impairment subscore comprised items 6 (salivation), 7 (swallowing), 13 (falling), 14 (freezing), 16 (tremor), and 17 (sensory symptoms). In addition, part III of the UPDRS reflecting motor symptoms was analyzed to determine the correspondence between overall improvements in total ADL scores, disability items from the ADL section, impairment items from the ADL section, and motor function. Friedman tests were used to assess differences between pre- and postoperative scores within each group across the multiple follow-up periods.

3 A. Haffenden et al. / Parkinsonism and Related Disorders 13 (2007) Table 1 Pre-operative clinical features of individual patients Unilateral pallidotomy patients Patient number Sex Age at surgery Disease duration L-dopa daily dose equiv. (mg) Other meds Hoehn & Yahr Follow-up period Side of surgery 1 M R 2 F R 3 M a 3 2 R 4 M R 5 M to 3 2 R 8 F a, to 3 2 R 10 M tr, to 3 2 L 13 M R 14 F R 15 F R 16 M to 3 2 L 17 M L 18 M L 19 F R Bilateral STN DBS patients Patient number Sex Age at surgery Disease duration L-dopa daily dose equiv. (mg) Other meds Hoehn & Yahr Follow-up period 1 M a, s, o M et F a M tr, et M M M en M M a, en F a, tr M a ¼ amantidine, en ¼ entacapone, et ¼ ethopropazine, o ¼ orphenadrine, s ¼ selegiline, to ¼ tolcapone, tr ¼ trihexyphenidyl. Hoehn & Yahr scores were taken when the patients were off. Age, disease duration, and follow-up period are indicated in years. Two-tailed Wilcoxon signed rank tests were used to make paired comparisons between pre- and post-operative scores within groups at each follow-up period. 3. Results Pre- and post-operative scores for parts II (ADL) and III (motor) of the UPDRS, and the subdivided ADL items, are summarized in Table 2. For patients who underwent unilateral pallidotomy with 1-year follow-up, significant differences across the pre- and post-surgical assessments were evident in total ADL scores and disability subscores, but not in impairment subscores. Paired comparisons demonstrated that the UPDRS ADL total scores were significant when pre-operative scores were compared with 6 month post-operative scores, but not when compared with 12 month post-operative scores. Analysis of the subdivided ADL scores revealed that significant changes were evident in the disability items at both 6 and 12 months relative to pre-operative scores. In contrast, significant changes were seen in impairment items when pre-operative scores were compared to 6 month scores, but not when compared to 12 month scores. For the motor section of the UPDRS, an overall significant difference was evident across the pre- and post-operative follow-up assessments. Paired comparisons demonstrated that significant changes were seen relative to pre-operative scores in UPDRS motor scores at both 6 and 12 months. The subset of pallidotomy patients with complete followup data to 24 months were younger than those patients with shorter follow-up periods of only 6 or 12 months (M ¼ 61 and 70 years, respectively), but did not differ significantly in any other respect. Once again, overall significant changes across pre- and post-operative followup assessments were seen for total ADL scores and

4 402 ARTICLE IN PRESS A. Haffenden et al. / Parkinsonism and Related Disorders 13 (2007) Table 2 Pre- and post-operative values of UPDRS parts II and III in patients treated with pallidotomy and subthalamic DBS Measure Assessment period Pallidotomy STN DBS 1 year follow-up 2 year follow-up 12 month follow-up n ¼ 14 n ¼ 9 n ¼ 11 (Mean7SD) (Mean7SD) (Mean7SD) UPDRS II: ADL total score preop months post ** ** * 12 months post * * 24 months post * Friedman test p o.05 o.01 o.05 UPDRS II: Disability items preop months post ** ** ** 12 months post * * * 24 months post * Friedman test p o.01 o.01 o.01 UPDRS II: Impairment items preop months post * * months post months post Friedman test p n.s. n.s. n.s. UPDRS III: Motor total score preop months post ** * ** 12 months post * * 24 months post Friedman test p o.05 n.s. o.01 In the subthalamic DBS cases, pre-operative off medication state was compared to the post-operative off medication state with stimulators turned on. For paired comparisons with pre-operative scores : * o.05, ** o.01. Friedman tests assess differences across all follow-up periods. The 2 year follow-up group is a subset of the 1 year follow-up group. disability subscores, but not for impairment subscores. Paired comparisons of the UPDRS ADL total scores were significant when pre-operative scores were compared with 6, 12, or 24 month post-operative scores. Analysis of the subdivided UPDRS ADL scores showed that improvement in true ADL items seen at 6 months remained significant at both 12 and 24 months. In contrast, significant changes were only seen in impairment items when pre-operative scores were compared to 6 month post-operative scores, but not when compared with either 12 or 24 month postoperative scores. In contrast to the 1-year follow-group, no overall significant difference was seen across assessments in UPDRS motor scores for the pallidotomy group with follow-up to two years. Paired comparisons showed that a pre- to post-operative difference was present only at the 6 month evaluation. By 12 months, the motor benefits were no longer statistically evident, and this remained true at the 24 month evaluation. Results from the patients who underwent bilateral insertion of STN DBS showed overall significant differences across pre- and post-operative assessments for both total ADL scores and disability subscores, but not for impairment subscores. For the STN DBS group, the preoperative off medication state was always compared to the post-operative off medication state with stimulators turned on. Paired comparisons of the ADL total scores were significant when pre-operative scores were compared with either the 6 or 12 month post-operative scores. Similarly, paired comparisons of the pre-operative disability subscore with either the 6 or 12 month postoperative results were significant. None of the pre- to post-operative paired comparisons were significant for the impairment subscores. For the STN DBS group, overall improvement was seen across follow-up periods in motor scores. Paired comparisons demonstrated significant improvement relative to preoperative scores at both the 6- and the 12-month follow-up assessments. 4. Discussion Patients who underwent either unilateral pallidotomy or bilateral STN DBS showed a similar pattern of improvement in ADLs. When change was examined across the multiple follow-up periods, the seven UPDRS ADL items identified as reflecting disability showed a significant improvement from pre- to post-operative follow-up periods, whereas the six items designated as reflecting impairment showed no overall change. Paired comparisons of

5 A. Haffenden et al. / Parkinsonism and Related Disorders 13 (2007) pre-operative function with each follow-up period demonstrated that the effect of dividing the UPDRS ADL items into disability and impairment items was most evident at follow-up periods beyond 6 months. These findings point both to the impact of parceling out the true ADL items from part II of the UPDRS and to the importance of analysis using uniform follow-up periods over time. Relative to pre-operative scores, pallidotomy resulted in significant improvements in both true ADL items and impairment items from the UPDRS ADL subscale at 6 months, though only improvement in disability items was retained at the 12- or 24-month follow-up assessments. For patients who underwent STN DBS, significant improvement was only evident in disability items and not in impairment items, even at the earliest follow-up period of 6 months. Combining impairment and disability items in the total UPDRS ADL score reduced the degree of postoperative improvement seen in ADLs in both surgical groups. This was most obvious for the group of pallidotomy patients who were evaluated at 6 and 12 months. By 12 months, total ADL scores were no longer significant when compared to pre-operative scores, whereas the subset of seven ADL items remained significantly different from pre-operative scores. In this case, if only the total ADL scores had been analyzed, it would be concluded that pallidotomy does not result in improvement in ADL beyond 6 months. Examination of the subdivided ADL scores reveals that this conclusion is flawed. Overall, in our sample both unilateral pallidotomy and STN stimulation resulted in amelioration in ADL scores. This result is consistent with a recent randomized, observer-blind, multicenter trial that compared unilateral pallidotomy and STN stimulation across pre-operative and 6-month post-operative assessments. Esselink et al. [16] demonstrated that ADLs, as measured by the total score of part II of the UPDRS, improved in both treatment groups. Although the magnitude of the difference was greater in the STN group, no significant difference between the groups in the degree of amelioration was found. It would certainly be informative to assess subdivided UPDRS ADL scores in a sample randomized to type of surgery to determine if a significant difference was present between groups when true ADL items were considered. Our goal was not only to replicate the findings of Hariz et al. [7] in terms of changes in ADL scores following unilateral pallidotomy, but also to assess these changes over uniform follow-up periods. Compared to the pallidotomy group presented by Hariz et al. [7] that had an average follow-up period of 11 months (range 5 25 months), our pallidotomy samples showed a similar degree of change relative to pre-operative scores at their 6, 12, and 24 month assessments. The Hariz et al. [7] sample did not show a significant reduction in impairment items, and this change was evident in our sample only at the 6-monthfollow-up assessment. Because the follow-up period of the Hariz et al. [7] sample ranged from 5 to 25 months, a preponderance of patients with follow-up measures taken beyond 6 months could have contributed to the lack of change in impairment items. Indeed, the average follow-up period of the Hariz sample was 11 months, well beyond the 6 months period at which the difference in impairment items was identified in our sample. The use of multiple follow-up periods at set intervals allowed us to characterize the post-operative change in the ADL section of the UPDRS over time, and points to the importance of differences between short-term follow-up periods of 6 months or less, and longer-term follow-up of 12 months or greater. The results for the group of patients examined by Hariz et al. [7] who underwent thalamic stimulation demonstrated that this surgery results in marked improvement in tremor, though this improvement did not impact ADLs. In examining the Hariz et al. [7] data, minor amelioration (an average decrease of.5 or less from pre- to post-operative measures) was seen on 2 of the 6 items designated as measuring impairment, with no change or a very slight increase in scores on 3 items. By far the largest change was on the tremor item included within the impairment items, which showed an average decrease of 2.2 points from preto post-operative measurement. The average change on the tremor item alone may well account for the overall significant change seen in that group on the impairment items. This result is consistent with findings demonstrating that items from the UPDRS assessing tremor exhibit remarkable independence from other symptoms of PD [4,17]. The suggestion has also been made that tremor items would be better represented as a separate section in the UPDRS [18]. When assessing the effects of thalamic DBS surgery where the primary goal is the amelioration of tremor, the most prudent solution would be to analyze tremor items separately, rather than grouping tremor with the impairment items from the ADL section of the UPDRS. Another important difference between the average scores for disability items as compared to impairment items is the pre-surgical starting point. For the six impairment items, the average pre-surgical score in our study was approximately 8. In other words most patients scored 1 on most items indicating that they did not have significant presurgical difficulty on the majority of these items. These results are consistent with previous studies in which scores for individual items of the UPDRS-II were reported as percent of patients scoring X1 on impairment items as compared to disability items [7,19]. This factor alone made it difficult to show significant improvement on the items post-surgically. One item was particularly notable. For Falling (item 13), the average pre-surgical score in the STN DBS group was.36. In a recent study examining the responsiveness of the ADL section to drug therapy in early PD, the authors emphasized that the greater the number of non-responsive items in a scale, the greater the measurement error and the lower the overall sensitivity of the measure to change [20]. Thus, the inclusion of Falling when examining the STN DBS population in the present

6 404 ARTICLE IN PRESS A. Haffenden et al. / Parkinsonism and Related Disorders 13 (2007) study is unlikely to contribute to the responsiveness of the ADL section to post-surgical change. In addition to a floor effect making significant change on the disability items unlikely, the internal consistency of the impairment items is also lower than that for the disability items. Indeed, the majority of the items described as true disability items are grouped together in factor analytic studies [4,6]. As noted above, the impairment items do not necessarily comprise a unitary factor as tremor has been suggested as a unitary concept [4,17,18]. Taken together, the lower pre-surgical scores and internal consistency make finding significant change on the impairment items much less likely than finding significant change on the disability items. Of note, a unifying feature of the impairment items aside from tremor is their characterization as PD features that do not respond to L-dopa. Falling, freezing, sensory complaints, excessive salivation, and some aspects of swallowing typically do not show improvement with dopaminergic medications [for review see 21,22]. Given the poor response of these items to traditional dopaminergic therapy, outside of the floor effect in the present study and relatively low internal consistency of these items, there is little evidence that surgical treatment alleviates these types of symptoms [21]. 5. Conclusion We replicated the findings of Hariz et al. [7] demonstrating that the subsection of the UPDRS ADL items best reflecting disability show clear improvement after unilateral pallidotomy, and we mapped this change across uniform follow-up periods. We also demonstrated that for bilateral STN DBS surgery, the disability subscores of UPDRS ADL items show clear and sustained improvement for at least one year after surgery, with the remaining items from the ADL section showing no such change. Though the retrospective nature of our data collection warrants caution in interpretation, it appears that for both types of surgery, the clearest picture of the ameliorating effects of surgery on functional status was presented by examining those items from the ADL section of the UPDRS that measure disability. Analyzing the total UPDRS ADL score can lead to erroneous conclusions because this score is tempered by non-adl items. To the patient, the degree to which a disease interferes with the ability to carry out ADLs is likely to be more important than a formal measure of disease severity [23]. It is critical that the measure used to assess ADLs is both valid and reliable, and not confounded by items reflecting impairments rather than ADLs. Acknowledgements All pallidotomies were performed by Dr. Jerry Krcek. Dr. Kiss is a CIHR Clinician-Scientist Phase II and an AHFMR Clinical Investigator. References [1] Laitinen LV, Bergenheim AT, Hariz MI. 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