Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease

Abstract

Background and objectives: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications.

Methods: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT.

Results: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS.

Discussion: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection.

Classification of evidence: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Figure 1. Selection of Participating Centers/Patients/ATs and End Points of CAT-PD

(A) Flowchart depicting the choice of the 22 participating PD centers shown in the map (C). (B) Flowchart depicting the patient sample of CAT-PD, chosen by inclusion/exclusion criteria, and the end points of CAT-PD. *The numbers were extrapolated from new installations per year. (C) Map of the participating centers throughout Germany. Centers are numbered from north to south and from east to west; size of the bubble depicts the number of contributed cases. (1) Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel. (2) Klinik und Poliklinik für Neurologie, Universitätsmedizin Greifswald. (3) Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf. (4) Klinik für Neurologie, Charité Universitätsmedizin Berlin. (5) Klinik für Neurologie, Klinikum Ernst von Bergmann Potsdam. (6) Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson, Beelitz-Heilstätten. (7) Klinik für Neurologie, Christophorus-Klinik Dülmen. (8) Klinik für Neurologie, Universitätsmedizin Göttingen. (9) Klinik für Neurologie, Elblandklinikum Meißen. (10) Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus an der TU Dresden. (11) Klinik und Poliklinik für Neurologie, Uniklinik Köln. (12) Klinik für Neurologie, Universitätsklinikum Jena. (13) Gertrudis-Klinik Biskirchen, Parkinson-Zentrum, Leun-Biskirchen. (14) Neurologische Klinik und Poliklinik, Universitätsklinikum Würzburg. (15) Klinik für Neurologie, Marienhaus Klinikum St. Wendel-Ottweiler. (16) Klinik für Neurologie und Gerontoneurologie, DIAKONEO Diak Klinikum, Diakonie-Klinikum Schwäbisch Hall. (17) Klinik und Poliklinik für Neurologie der Universität Regensburg am medbo Bezirksklinikum Regensburg. (18) Neurologische Universitätsklinik, Universitätsklinikum Tübingen. (19) Parkinson-Klinik Ortenau, Wolfach. (20) Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar der TU München. (21) Parkinson Fachklinik Haag i. OB. (22) Klinik für Neurologie und Neurophysiologie, Universitätsklinikum Freiburg. (D) Priority of different selection criteria for ATs in the participating centers. Guidelines of the DGN (German Society for Neurology), contraindications, and patients' preference were deemed most important. AT = advanced therapy; CAT-PD = Combinations of Advanced Therapies in PD; PD = Parkinson disease.

Figure 2. Documented AT Modifications, Their Reasons and Their Changes in Side Effect Profile

(A) Sankey plot of all AT modifications documented in CAT-PD. Colors of the streams sorted by overall number of modifications documented in the clinical course of the individual patients. Stream width correlates to number of patients with the respective AT modification. Colors of nodes indicating the AT (combination) used. The vast majority of patients had 1 AT modification and thereby used 2 out of the 3 ATs. The most common changes were the replacement of a CSAI by a DBS or LCIG or the addition of a pump therapy (CSAI or LCIG) to an existing DBS. (B) Aggregated reasons for modifying the ATs (further details in Table 2; multiple selection per modification permitted). The most important reasons for modifying the AT were insufficient therapeutic efficacy and adverse effects of the previous therapy. (C) Percentage of patients affected by different side effect categories. Cumulative data for all AT modifications are shown, detailed data in eTable 2 (links.lww.com/WNL/D156). The percentage of affected patients decreased after the AT modification and did not reach the baseline level at the last assessment (except for device-associated side effects). AT = advanced therapy; CAT-PD = Combinations of Advanced Therapies in PD; CGI = Clinical Global Impression—Improvement Scale; CSAI = continuous subcutaneous apomorphine infusion; DBS = deep brain stimulation; LCIG = levodopa-carbidopa intestinal gel; PD = Parkinson disease.

Figure 3. Clinical Outcome of AT Combinations

MDS-UPDRS Part III (A), IV (B), and Part IV—dyskinesia (item 4.1) (C)/off-time (item 4.3) (D) scores premodification and postmodification. With the exception of the dyskinesia item, all evaluated MDS-UPDRS scores decreased significantly in the cumulative analysis of all modifications and in the first modification, pointing to an objective clinical benefit by AT combinations. (E) Clinical Global Impression score by physicians (blue) and patients (red) for all modifications and stratified for first, second, third, and fourth modification. The used scale ranges from −3 (very much worse) over 0 (no change) to +3 (very much improved). Both physicians and patients mainly perceived the AT modifications as beneficial. n: number of pairwise available data. For modifications not mentioned in individual score figures, no data were available. AT = advanced therapy; LMM/TT/W = significant in linear mixed model/paired t test/Wilcoxon signed-rank test; MDS-UPDRS = Movement Disorder Society–Sponsored Revision of the Unified Parkinson's Disease Rating Scale; PD = Parkinson disease.

Figure 4. Clinical Outcome of AT Combinations, Stratified by the Added AT

MDS-UPDRS Part III (A), IV (B), and Part IV—dyskinesia (item 4.1) (C)/off-time (item 4.3) (D) scores before and after all available modifications, stratified by the added AT. For DBS, a significant improvement of the dyskinesia item was observed; for LCIG, a significant benefit for MDS-UPDRS Part III, IV, and the off-time item; for CSAI, only for the off-time item. (E) Dynamics (difference postmodification − premodification) of side effects, stratified by the added AT. (F) Clinical Global Impression score by physicians (blue) and patients (red) for all modifications, stratified by the added AT. The used scale ranges from −3 (very much worse) over 0 (no change) to +3 (very much improved). Both physicians and patients mainly perceived the AT modifications as beneficial for all added ATs. n: number of pairwise available data. For modifications not mentioned in individual score figures, no data were available. Note: Addition of the numbers in this figure results in a smaller total number than the n for all modifications of the respective score in Figure 2 because the analyses in Figure 2 also comprise modifications with omission of an AT (e.g., DBS + LCIG > DBS) which are not considered in this figure. AT = advanced therapy; DBS = deep brain stimulation; LCIG = levodopa-carbidopa intestinal gel; LMM/LM = significant in linear mixed model/linear model; MDS-UPDRS = Movement Disorder Society–Sponsored Revision of the Unified Parkinson's Disease Rating Scale; PD = Parkinson disease.

Figure 5. Time of Use of the 3 ATs Before Requiring AT Modification

DBS was the most long-lasting AT, CSAI the shortest. AT = advanced therapy; CSAI = continuous subcutaneous apomorphine infusion; DBS = deep brain stimulation; LCIG = levodopa-carbidopa intestinal gel; n = number of available data.