24 hour levodopa-carbidopa intestinal gel may reduce “unresponsive” freezing of gait and falls in Parkinson’s disease Florence CF Chang, David S Tsui, Neil Mahant, Nigel Wolfe, Samuel D Kim, Ainhi D Ha, Jane M Griffith, Victor SC Fung Movement Disorders Unit & Sydney Medical School, Westmead Hospital, Sydney, Australia Florence Chang, Movement Disorders unit in Westmead hospital in Sydney Australia Reporting ongoing prospectively collected data on 7 patients with “unresponsive FOG” and falls treated with 24 hour levodopa carbidopa intestinal infusion., which I will now refer to as LCIG. Unresponsive FOG is defined as FOG that does not improve despite upward titration of levodopa during 16 hour LCIG or levodopa challenge. The median age of patients was 65 years and had PD for 13 years before starting LCIG therapy. Patients had 16 hour LCIG therapy for a median of 27 months before changing to 24 hour LCIG infusion. Before commencement with 24 hour LCIG infusion, all 7 patients had gait assessments, FOG questionnaire and documentation of falls frequency These measures were repeated at 3,6,9,12 and 18 months by the same assessor. Daytime LCIG infusion rate was unchanged across 9 months. Friedman’s test was used to test for statistical significance for these measures up to 9 months, with statistical significance defined as p< 0.05. Wilcoxon signed rank test was used for post-hoc analysis. The median falls frequency decreased significantly from 2 to 6 times per week to no falls in 3 months or less than one fall per week. There was significant reduction in fall frequency between baseline and 3 and 9 months after starting 24 hour LCIG infusion. Median 360 degree turn time reduced from 15.6 seconds at baseline to 6.9 seconds at 9 months but did not reach statistical significance. 8 meter up and go time was similar between baseline and at 9 months. Median score on the FOG questionnaire reduced from 19 to 15 but did not reach statistical significance. Two subjects had transient dyskinesia or postural hypotension, one subject withdrew from study after persistent visual hallucinations. 6 out of 7 patients had clinically significant benefit from 24 hour LCIG infusion with reduction in unresponsive FOG and falls frequency and chose to continue the therapy. The limitation of our study is the small number of patients and a lack of placebo controlled arm. Larger prospective placebo controlled study is needed to confirm this finding. Introduction Patient characteristics Results Advanced Parkinson’s disease (PD) is characterized by motor fluctuations, reduced by therapies such as levodopa-carbidopa intestinal gel (LCIG) infusion, deep brain stimulation surgery (DBS) and apomorphine infusion therapy. However, the pathophysiology of freezing of gait (FOG) in PD is not clear and its treatment is challenging. “Off” period FOG is treated with increased dopaminergic therapy whereas "unresponsive" FOG (u-FOG) is not responsive to levodopa or deep brain stimulation. In the past, several studies have reported the use of 24 hour LCIG infusion without tolerance or development of clinical side effects(1). We report ongoing data on a prospective, open label study of 24 hour LCIG, as treatment for levodopa-unresponsive FOG and falls in PD. The falls frequency reduced after 24 hour LCIG (p=0.048) and post-hoc analysis showed significant reduction in falls frequency at 3 and 9 months compared to baseline. The LCIG daytime infusion rate was unchanged relative to baseline. Two subjects had transient dyskinesia or postural hypotension. One subject withdrew from the study following persistent visual hallucinations. Otherwise it was well tolerated without side effects. Age at PD onset Age Duration PD at LCIG initiation (years) Sex (F/M) Duration of LCIG therapy before 24 hour LCIG (months) 45 (40-62) 65 (61-75) 13 (11-23) 1/6 27 (1-31) Table 1. Median (interquartile range) value of baseline patient characteristics Results a b Discussion Six out of seven patients experienced clinically significant benefit, after switching to 24 hour LCIG infusion, most evident in the reduced falls frequency. FOG questionnaire is a useful screening tool, it may not be reliable in assessing the severity of FOG over time, as it does not correlate with the frequency or duration of freezing episodes during objective assessment. The main limitations of our study are the small number of patients and the lack of a placebo controlled arm to exclude the placebo effect. Method Patients already on 16 hour LCIG infusions (n=6) or oral levodopa (n=1) who had u-FOG and falls were recruited. U-FOG was confirmed by lack of improvement following upward titration of 16 hour LCIG infusion or a levodopa dose cycle. 7 patients underwent baseline gait assessments (timed up and go (TUG) 8 meter walk and 360 degree turning), FOG questionnaire and documentation of falls frequency. Patients were commenced on continuous 24 hour infusion through the LCIG pump with the night-time rate at 70% of daytime infusion rate. Gait assessment, FOG questionnaire and falls frequency were repeated at 3 and 6, 9, 12 and 18 months by the same assessor. The change in falls frequency were recorded and Friedman’s test was used to test for statistical significance for variables up to 9 months, defined as p< 0.05. Post-hoc analysis used Wilcoxon signed rank test. Falls frequency was scored according to Table 1. Graph 1. a. Box plot of gait assessments (median ± interquartile range). b. FOG questionnaire (median ± interquartile range). c d Conclusion Our study suggests that continuous 24 hour LCIG infusion may reduce unresponsive FOG and associated falls, in PD patients. However, a larger prospective, placebo controlled study is needed to confirm this. References Fall frequency Score No falls in 3 months Once a quarter to < 1 per week 1 One per week 2 2-6 times a week 3 Daily 4 Zibetti M, Rizzone M, Merola A, Angrisano S, Rizzi L, Montanaro E, et al. Sleep improvement with levodopa/carbidopa intestinal gel infusion in Parkinson disease. Acta Neurol Scand. 2013;127(5):e28-32. Morris TR, Cho C, Dilda V, Shine JM, Naismith SL, Lewis SJ, et al. A comparison of clinical and objective measures of freezing of gait in Parkinson's disease. Parkinsonism Relat Disord. 2012;18(5):572-7. Graph 1. c. Fall frequency scores. (median ± interquartile range) * denotes p< 0.05 on Wilcoxon signed rank test. d. Box plot of daytime infusion rate across 9 months. (median ± interquartile range) Table 1. Falls frequency scoring