Improvement of dyskinesias with continuous jejunal L-dopa infusion

Jonathan Timpka1*, Thomas Fox2, Karen Fox2, Holger Honig2, Pablo Martinez-Martin3, Angelo Antonini5, Per Odin1, 2, Kallol Ray Chaudhuri4

1: Department of Clinical Sciences, Neurology, Lund University, Lund, Sweden

2: Department of Neurology, Central Hospital, Bremerhaven, Germany

3: Research Unit, Alzheimer Center Reina Sofia Foundation and CIBERNED. Carlos III Institute of Health, Madrid, Spain

4: National Parkinson Foundation Centre of Excellence, King's College Hospital, King's College, London, UK

5: Parkinson's Disease and Movement Disorders Unit, IRCCS Hospital San Camillo, Venice, Italy

*: Corresponding author, e-mail: jonathan.timpka.248@student.lu.se

Word count: 2991

1

Running title:

Improvement of dyskinesias with LCIG

2

AbstractObjectives: To investigate whether continuous intrajejunal levodopa-carbidopa intestinal gel (LCIG) therapy has an anti-dyskinetic effect in patients with Parkinson’s disease (PD) and troublesome dyskinesias. We also wanted to examine the effect of LCIG therapy on motor function and health-related quality of life (HRQoL).

Materials & methods: This open label pilot study used a single group pre-post design with follow-up at 6 months. Nine patients with PD who reported to spend at least 3 hours per day in on with troublesome dyskinesia were included. The patients were examined at baseline using clinical and self-assessment measures and then switched from peroral/transdermal pharmacotherapy to LCIG therapy. Data collection was repeated 6 months after the pharmaceutical intervention. Non-parametric statistical methods were used for data analyses.

Results: The mean time spent in on with troublesome dyskinesia per day after 6 months of LCIG therapy reduced by 47% (p<0.05). This observation was paralleled by a 112% increase in mean time spent in on without troublesome dyskinesia (p<0.01). Patient self-assessment of dyskinesia intensity on the visual analog scale displayed a 90% reduction of mean dyskinesia intensity (p<0.01) and patients also exhibited less dyskinesia during standardized levodopa tests. Furthermore, we noted improvements in motor function and HRQoL.

Conclusions: In this pilot study, we found indications that LCIG therapy has a substantial anti-dyskinetic effect and could be an alternative also for PD patients with dyskinesias as a major symptom. However, further studies with blinded evaluation and larger number of patients are warranted to confirm the findings.

Word count: 250

3

Keywords Continuous dopaminergic stimulation

Dyskinesias

Levodopa-carbidopa intestinal gel

Motor complications

Parkinson’s disease

IntroductionLevodopa in combination with a decarboxylase inhibitor serve as the gold standard for treatment of Parkinson’s disease (PD) and is, in most cases, a very effective treatment in early stages of the disease. However, as the disease progresses, motor complications often arise. After 4-6 years of treatment, at least 40% of patients develop significant dyskinesias and motor fluctuations (1), which are difficult to manage properly using the conventional oral medication. In addition to disease duration, these complications are related to the dose and duration of levodopa treatment (2) and are considered to be effects of fluctuating plasma concentrations caused by the oral, pulsatile distribution of levodopa (3). In later stages of the disease, the oral levodopa therapy has been shown to lead to increasingly unphysiological variations in striatal dopamine concentrations (4).

Continuous intestinal delivery of levodopa has been a potential way of treating PD since its introduction in the late 1980’s and early 1990’s (5). The current formulation., levodopa-carbidopa intestinal gel (LCIG; AbbVie, North Chicago, IL, USA), is an aqueous carboxymethylcellulose gel containing levodopa (20 mg/l) and carbidopa (5 mg/l) and is often given as a monotherapy. Using a portable infusion pump (CADD-Legacy, Smiths Medical, Minneapolis, MN, USA), the LCIG is continuously administered into the proximal part of the jejunum via a percutane endoscopic gastrostomy with a jejunal tube (PEG-J). The goal of advanced therapies for PD, such as LCIG therapy and subcutaneous continuous apomorphine therapy, is to keep plasma levels of the dopamine precursor or dopamine agonist stable; thereby making the stimulation of dopamine receptors more continuous and less pulsative.

There are at least two major studies dedicated to demonstrating the anti-dyskinetic effect of continuous apomorphine therapy (6, 7) and the anti-dyskinetic effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) is well-established (8, 9). In the case of STN-DBS, this seems to primarily be an effect of a reduction in the needed daily peroral levodopa dose (10). Many of the effects of LCIG therapy have now been well established, such as reductions in off-time, increases in on-time, and improvements in health-related quality of life (HRQoL), but most studies are primarily designed to examine effects on off-time and degree of off symptomatology. They are therefore ill-suited to investigate the effects of LCIG therapy on dyskinesias. In a recent, large randomized controlled trial with a follow-up of 12 weeks, patients with complicating off-periods were found to decrease their mean off-time by 4 hours per day and increase the mean time in on without troublesome dyskinesia by 4 hours per day when switched to LCIG therapy (11). However, in the same study, only non-significant reductions in time in on with troublesome dyskinesia were found. Thus, there has been suggestions of a positive effect of LCIG therapy on dyskinesias, although the evidence base remains weak.

4

In this pilot study, our primary research question was whether LCIG therapy has an effect on the temporal occurrence and intensity of dyskinesias in patients with advanced PD. Secondarily, we also sought to examine whether LCIG therapy has an effect on motor function and if any changes in the patients' HRQoL can be detected.

Materials & methodsStudy designThis study used a prospective observational design with 6 months of follow-up and was performed at the neurological clinic of the Central Hospital in Bremerhaven, Germany. The primary endpoint was change in mean time in on with troublesome dyskinesia according to data from patient diaries. The secondary endpoints were changes in mean time in on without troublesome dyskinesia and mean scores of the Visual Analog Scale (VAS) regarding intensity of dyskinesia, Abnormal Involuntary Movement Scale (AIMS), Goetz scale, and Unified Parkinson’s Disease Rating Scale (UPDRS) items 32 and 33. Additional endpoints were UPDRS parts II and III, Parkinson’s Disease Questionnaire-39 (PDQ-39), UPDRS total, and changes in mean time in off. ParticipantsInclusion criteria for the study were: I) being diagnosed with PD, II) having developed motor complications in form of dyskinesia, III) having reported to spend at least 3 hours per day in on with troublesome dyskinesia, in spite of optimized peroral/transdermal PD therapy, and IV) being able to participate in the filling in of questionnaires and diaries. Pregnant patients and patients with pronounced dementia (i.e. a mini-mental state evaluation score below 24), hallucinations, or other psychotic symptoms were excluded from the study. 9 patients fulfilled the inclusion criteria and were included in the study.

LCIG therapy and medicationThe total daily dose of LCIG is constituted of a morning bolus dose, the continuous maintenance dose and, if required, extra bolus doses. To begin the LCIG treatment, the patient stopped the conventional pharmacotherapy and received a PEG-J under local anaesthesia and a short-acting sedative. The PEG-J was then connected to a portable infusion pump and the LCIG therapy was initiated with a maintenance dose based on previous peroral/transdermal dopaminergic therapy by using the Levodopa Equivalent Unit (LEU) estimation below. During a hospital stay of 14-33 days, the maintenance dose was titrated in steps of 2 to 4 mg levodopa per hour until an optimal clinical response, i.e. a maximal on-time without any disabling dyskinesias, was reached. The patients were also able to give themselves additional bolus doses of 20 to 50 mg levodopa in case of hypokinetic events. After discharge from the hospital, the patients had the opportunity to contact a Parkinson nurse or a neurologist and were followed-up after 6 months. In 7 of the 9 patients, LCIG was given as a monotherapy and was administered during all 24 hours of the day, albeit at a 30% lower rate by-night. In the remaining 2 patients, LCIG was given during the 16 waking hours of the day, after which an additional dose of long-acting levodopa or dopamine agonist was given before going to bed.

The LEU was calculated using a formula based on works by Parkin (12) and the German Neurological Society: levodopa dose + levodopa dose x 1/3 if on concurrent entacapone +

5

bromocriptine (mg) x 10 + cabergoline (mg) x 67 + pramipexol (mg) x 100 + ropinirole (mg) x 20 + pergolide (mg) x 100 + rotigotine (mg) x 25 + apomorphine (mg) x 8 at intermittent injections + daily levodopa dose (mg) x 1/3 if on concurrent rasagiline.

Instruments for measurement of dyskinesiaThe patients were instructed to keep a diary where they once in every waking hour noted whether they were off, on with troublesome dyskinesia, or on without troublesome dyskinesia.

The patients also used the VAS for self-assessment of intensity of dyskinesia. They were instructed concerning scoring methodology by Parkinson nurses and the self-assessments were not allowed in the study until correlations of 80% regarding off and on states and good correlations between the VAS ratings were established. The diaries and VAS lists were collected for three days at baseline and after six months of LCIG therapy.

The AIMS and the Goetz rating scale rate the degree of dyskinesia in the neck, trunk, or limbs (AIMS) or the overall impairment (Goetz) when performing seven set tasks, such as drinking a glass of water or walking 5 meters. Tasks 1, 2, 6, and 7 were rated using AIMS, while tasks 3 to 5 were rated on the Goetz scale. Ratings were made by certified examiners of patients in both off and on during standardized levodopa tests. For the levodopa tests, the patients were off medications for 12 hours overnight, after which the ratings in off were made. The patients were then given their medications (200 mg levodopa or 1.5 times the usual morning dose) and after 1 hour new assessments were made in on.

Furthermore, the self-assessment items 32 and 33 of the UPDRS were used to examine the duration and severity of dyskinesias.

Other instruments applied:PDQ-39 was used for assessing the HRQoL. The UPDRS was used for estimating non-motor symptoms (part I) activities of daily life (part II), motor function (part III) and motor fluctuations (part IV). Part III was performed in defined off and defined on during the levodopa test. Part II was estimated for off and on. The patients were also instructed to report adverse effects whenever such arose.

Statistical analysesThe statistical analyses were performed by the Institute of Biometry at the Hannover Medical School. Due to the small sample size, the nonparametric Wilcoxon test was used to compare mean values between the two measurement times, while the nonparametric Mann-Whitney U test was used to compare subgroups of patients.

Ethics approvalThe study was approved by the Ethics Committee of the Medical Association of Bremen (study number 162).

ResultsPatientsNine patients at a mean age of 62.7 years were included in the study (Table 1). The mean disease duration was 13.8 years and the mean Hoehn & Yahr stage was 3.9 in off state and 2.3 in on. Prior to LCIG therapy, the mean oral levodopa dose was 838 mg/day while the mean LEU was 1307 mg/day. Using the Mann-Whitney U test, none of the collected demographic or patient

6

variables showed any significant gender differences. All patients remained in the study until the 6-month follow-up.

DyskinesiaA 47% decrease of the mean time in on with troublesome dyskinesia was reported (p<0.05) (Figure 1) and the mean time in on without troublesome dyskinesia was increased by 112% (p<0.01) between baseline and after 6 months of treatment. However, one patient reported an increase in on with troublesome dyskinesia from 5.7 to 7.3 h/day. The reported mean VAS score regarding intensity of dyskinesia was decreased by 90% compared to baseline (p<0.01) (Figure 2) and 3 patients reported no dyskinesias at all at 6 months. When a standardized dose of levodopa was given after 6 months of LCIG therapy, significantly less dyskinesia was produced compared to before the treatment according to the AIMS (-70%, p<0.01) (Figure 3A) and the Goetz scale (-75%, p<0.01) (Figure 3B). The mean scores of the UPDRS self-assessment items 32 and 33 were significantly decreased at 6 months (-58%, p<0.05; -70%, p<0.05) (Figure 4) and all patients reported either an improvement or no change. Diaries, UPDRS, PDQ-39 and medicationThe mean time in off per day was decreased (-67%, p<0.01) (Figure 1) after 6 months of LCIG therapy. The mean scores on UPDRS II, UPDRS III in on, and the UPDRS total exhibited a significant decrease between baseline and after 6 months of therapy (Table 2). There was one exception: a patient who deteriorated on UPDRS III from 25 to 37 points in off and from 9 to 11 points in on. The change in mean score of UPDRS III in off was not significant. Furthermore, the mean PDQ-39 summary index (SI) score was decreased by 50% between the two time points (p<0.05), although one patient reported an increased score, i.e. a deterioration, from 44 to 63 points. Applying the formula for estimation of LEU, the mean LEU was increased by 73% (p<0.05), but the patient with the deteriorated PDQ-39 SI score also exhibited a decrease in LEU (-18%).

Adverse effectsDuring the 6 months of LCIG therapy, one patient reported on having hallucinations, another about having vivid dreams. Local infections at the site of the PEG in the abdominal wall were seen in 3 patients. However, these infections could be handled through improved local hygiene and no antibiotics were used. In one patient, the PEG dislocated twice, but after an endoscopic intervention no further irregularities were reported. In 4 of the patients, no complications or adverse effects of LCIG therapy occurred. 

DiscussionIn this pilot study of 9 patients with advanced PD and troublesome dyskinesia, we wanted to investigate the effects of LCIG therapy on dyskinesia. Our main findings were that the mean time in on with troublesome dyskinesia was decreased from 5.8 to 3.1 hours per day, meanwhile the mean time in on without troublesome dyskinesia was increased from 6.1 to 12.9 hours per day between baseline and after 6 months of treatment. In parallel, the mean VAS score regarding intensity of dyskinesia was decreased by 90%. The anti-dyskinetic effect of LCIG was also verified by the finding that after 6 months of LCIG therapy a single dose of levodopa produced significantly less dyskinesia when rated on the AIMS and the Goetz scale. At 6 months, the mean

7

scores had decreased significantly on all used scales for measurement of dyskinesias and significant improvements were also seen on the UPDRS and the PDQ-39. Furthermore, we observed that the mean time in off had been reduced in half.

There are several, however mostly pre-clinical, studies that have investigated the pathophysiological mechanisms that result in the origin of dyskinesia and motor complications in PD (13-15). There are also both pre-clinical and clinical data that seem to demonstrate that a therapy based on continuous dopaminergic stimulation (CDS) may decrease the tendency to exhibit dyskinesias. For example, it is shown that CDS normalizes the sensitivity of the receptors and is thereby having a positive effect on the long-term pathophysiological changes (16). Although direct comparisons between our study and the study of apomorphine pump therapy by Katzenschlager et al. (6) are difficult to make, our findings could in many ways be considered to be quite similar. If anything, it seems that LCIG could have an even better anti-dyskinetic effect, which is implied by the greater improvements on AIMS, Goetz, and VAS, but further, directly comparative study is needed. Using a different approach, STN- DBS has been shown to have a substantial anti-dyskinetic effect with a 54-74% decrease in dyskinesia-related scores after 6 months of treatment (8, 9).

As the dose of levodopa has been correlated to the occurrence of dyskinesias, it is noteworthy that in our study, the mean LEU was increased by 73% when patients switched from peroral/transdermal therapy to LCIG therapy, but dyskinesia was nonetheless significantly decreased. The underlying mechanisms are thus likely to correspond to the CDS and a gradual widening of the therapeutic window. This may also further imply that the conventional, pulsatile distribution of levodopa is the most important cause to dyskinetic complications.

We also found that the scores on the UPDRS were improved in on after 6 months of treatment. This is an indication of an improved quality of the on state when switched from peroral/transdermal therapy to LCIG therapy. Although the mechanism behind this improvement is not well established, a reduction of dyskinesias could lead to a better motor skill and, as a result, an improvement in UPDRS scores.

In our study, the mean PDQ-39 SI score was significantly decreased by 50% after 6 months of LCIG therapy. This finding is consistent with earlier studies showing improvements in HRQoL in PD patients on LCIG therapy (17-20). The minimal clinically important difference of the PDQ-39 SI score has been evaluated (21) and 7 of the 9 patients in our study exceeded this change. Thus, a real improvement in HRQoL is safe to assume in these patients. A recent study investigated if the occurrence of dyskinesias affected PDQ-39 scores and found no significant association to global scores, but detected detrimental effects on the subcategories activity of daily living, cognition, stigma, and bodily discomfort (22). Thus, the reduction of dyskinesias might contribute to the improvement of HRQoL in this study, but other factors like reduction of off-time could be even more relevant

We found it noteworthy that the patient who deteriorated in the PDQ-39 SI score was also the patient with the longest disease duration, i.e. 25 years, and the only patient in our study that exhibited a decrease in LEU after 6 months of treatment. Hence, it is important to consider which PD patients are suitable for LCIG therapy and to evaluate the effect of the treatment in each

8

individual patient after some months of therapy. In cases where the HRQoL has deteriorated after insertion on LCIG therapy, it may be reasonable to question the beneficial effect of the therapy for that individual patient.

The effect on dyskinesias is not universal and is consistent with clinical experience of this therapy. There seem to be some dyskinetic PD patients whose dyskinesias do not improve from therapies based on CDS. This is especially the case in patients who do not exhibit any periods of on without troublesome dyskinesia at all under peroral/transdermal treatment. This may be a category of patients where STN-DBS is a more suitable treatment.

In this study, we saw few serious adverse events over the six months of follow-up. Most complications were related to the PEG-J and it is shown that 18 % of complications from LCIG therapy are surgery-related (23). However, as 89% of patients in the largest randomized controlled trial in this area of late had some complication related to the device or tube (11), it is safe to state that this is an important issue for future improvement of LCIG therapy.

There are several limitations to this study that need to be considered when interpreting the results; particularly the absence of a control group, a placebo control, and blinding has to be taken into regard. Furthermore, this study relies on patient self-assessments and ratings done by examiners and the presence of a placebo effect is difficult to dismiss. Larger controlled studies further characterizing the effect of LCIG on dyskinesias are warranted. It would also be of interest to do a post-hoc analysis of the effects on dyskinesias in those patients who had most problems with dyskinesias in the recently published, large studies on LCIG therapy.

In this pilot study, we observed that LCIG appears to provide an attractive alternative to treatment of dyskinesias in patients with PD and motor complications. The results confirm and strengthen the findings from earlier studies indicating an anti-dyskinetic effect of this treatment (23-27). Our results are also in accord with previous studies concerning the effects on off-time and HRQoL in patients with PD. However, as the number of patients in this study was limited, further studies are needed to evaluate the effects of LCIG therapy on dyskinesias in PD.

AcknowledgmentsConflict of interest and source of funding statementJT, TF, and KF have reported no conflict of interest. HH has received funding as speaker from AbbVie, Novartis, Biogen, Teva, and Licher MT.

KRC

K Ray Chaudhuri Funding from - UCB, Britannia, Abbott (2).

- Boehringer-Ingelheim, Britannia, Abbott, Cephalon, UCB (5).

-Parkinson’s UK, PDNMG, UK Department of Heath (6)

9

This study was an observational audit of established clinical practice. No extra funding was allocated for the study.

References1. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Movement disorders : official journal of the Movement Disorder Society. 2001;16(3):448-58.2. Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson's disease. A community-based study. Brain : a journal of neurology. 2000;123 ( Pt 11):2297-305.3. Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications. Lancet neurology. 2006;5(8):677-87.4. de la Fuente-Fernandez R, Sossi V, Huang Z, Furtado S, Lu JQ, Calne DB, et al. Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias. Brain : a journal of neurology. 2004;127(Pt 12):2747-54.5. Kurlan R, Rubin AJ, Miller C, Rivera-Calimlim L, Clarke A, Shoulson I. Duodenal delivery of levodopa for on-off fluctuations in parkinsonism: preliminary observations. Annals of neurology. 1986;20(2):262-5.6. Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffman M, Swinn L, et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges. Movement disorders : official journal of the Movement Disorder Society. 2005;20(2):151-7.7. Kanovsky P, Kubova D, Bares M, Hortova H, Streitova H, Rektor I, et al. Levodopa-induced dyskinesias and continuous subcutaneous infusions of apomorphine: results of a two-year, prospective follow-up. Movement disorders : official journal of the Movement Disorder Society. 2002;17(1):188-91.8. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. The New England journal of medicine. 2006;355(9):896-908.9. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Jr., et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA : the journal of the American Medical Association. 2009;301(1):63-73.10. Follett KA. Comparison of pallidal and subthalamic deep brain stimulation for the treatment of levodopa-induced dyskinesias. Neurosurgical focus. 2004;17(1):E3.11. Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet neurology. 2014;13(2):141-9.12. Parkin SG, Gregory RP, Scott R, Bain P, Silburn P, Hall B, et al. Unilateral and bilateral pallidotomy for idiopathic Parkinson's disease: a case series of 115 patients. Movement disorders : official journal of the Movement Disorder Society. 2002;17(4):682-92.13. Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infusion in Parkinson's disease--long-term experience. Acta neurologica Scandinavica. 2001;104(6):343-8.14. Tedroff J, Pedersen M, Aquilonius SM, Hartvig P, Jacobsson G, Langstrom B. Levodopa-induced changes in synaptic dopamine in patients with Parkinson's disease as measured by [11C]raclopride displacement and PET. Neurology. 1996;46(5):1430-6.

10

15. Chase TN, Oh JD, Blanchet PJ. Neostriatal mechanisms in Parkinson's disease. Neurology. 1998;51(2 Suppl 2):S30-5.16. Chase TN. The significance of continuous dopaminergic stimulation in the treatment of Parkinson's disease. Drugs. 1998;55 Suppl 1:1-9.17. Nyholm D, Nilsson Remahl AI, Dizdar N, Constantinescu R, Holmberg B, Jansson R, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology. 2005;64(2):216-23.18. Isacson D, Bingefors K, Kristiansen IS, Nyholm D. Fluctuating functions related to quality of life in advanced Parkinson disease: effects of duodenal levodopa infusion. Acta neurologica Scandinavica. 2008;118(6):379-86.19. Antonini A, Mancini F, Canesi M, Zangaglia R, Isaias IU, Manfredi L, et al. Duodenal levodopa infusion improves quality of life in advanced Parkinson's disease. Neuro-degenerative diseases. 2008;5(3-4):244-6.20. Puente V, De Fabregues O, Oliveras C, Ribera G, Pont-Sunyer C, Vivanco R, et al. Eighteen month study of continuous intraduodenal levodopa infusion in patients with advanced Parkinson's disease: impact on control of fluctuations and quality of life. Parkinsonism & related disorders. 2010;16(3):218-21.21. Peto V, Jenkinson C, Fitzpatrick R. Determining minimally important differences for the PDQ-39 Parkinson's disease questionnaire. Age and ageing. 2001;30(4):299-302.22. Hechtner MC, Vogt T, Zollner Y, Schroder S, Sauer JB, Binder H, et al. Quality of life in Parkinson's disease patients with motor fluctuations and dyskinesias in five European countries. Parkinsonism & related disorders. 2014.23. Devos D, French DSG. Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society. 2009;24(7):993-1000.24. Antonini A, Isaias IU, Canesi M, Zibetti M, Mancini F, Manfredi L, et al. Duodenal levodopa infusion for advanced Parkinson's disease: 12-month treatment outcome. Movement disorders : official journal of the Movement Disorder Society. 2007;22(8):1145-9.25. Eggert K, Schrader C, Hahn M, Stamelou M, Russmann A, Dengler R, et al. Continuous jejunal levodopa infusion in patients with advanced parkinson disease: practical aspects and outcome of motor and non-motor complications. Clinical neuropharmacology. 2008;31(3):151-66.26. Honig H, Antonini A, Martinez-Martin P, Forgacs I, Faye GC, Fox T, et al. Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life. Movement disorders : official journal of the Movement Disorder Society. 2009;24(10):1468-74.27. Caceres-Redondo MT, Carrillo F, Lama MJ, Huertas-Fernandez I, Vargas-Gonzalez L, Carballo M, et al. Long-term levodopa/carbidopa intestinal gel in advanced Parkinson's disease. Journal of neurology. 2014;261(3):561-9.

11

Table 1: Patient demographic and medication data

Men Women TotalNumber of patients 4 5 9Patient age, years 64.3 (58-67) 61.4 (38-70) 62.7 (38-70)Disease duration, years 15.8 (7-25) 12.2 (9-16) 13.8 (7-25)Hoehn & Yahr, off 3.8 (3-4) 4 (3-5) 3.9 (3-5)Hoehn & Yahr, on 2.5 (2-3) 2.1 (1-3.5) 2.3 (1-3.5)Oral levodopa, mg/day 1,056.3 (500-2000) 663.8 (350-1000) 838.2 (350-2000)LEU, mg/day 1,492 (933-2160) 1,159 (900-1465) 1,307 (900-2160)

Data are expressed as mean (range). LEU, Levodopa Equivalent Unit.

12

Table 2: UPDRS, PDQ-39, and LEU at baseline and after 6 months of LCIG therapy

Baseline 6 months Change p-valuesUPDRS II, off 28.1 21.4 -24% <0.01UPDRS II, on 10.4 4.9 -53% <0.01UPDRS III, off 50.1 42.1 -16% 0.058UPDRS III, on 21.7 11.6 -47% <0.05UPDRS total, on 49.6 23.8 -53% <0.01PDQ-39 70.6 35.4 -50% <0.05LEU, mg/day 1,307 2,256 +73% <0.05

Data are expressed as mean. The change is in percent of the mean. UPDRS, Unified Parkinson’s Disease Rating Scale; PDQ-39, Parkinson’s Disease Questionnaire-39; LEU, Levodopa Equivalent Unit.

13

Figure 1: Diary measures

Mean time spent in different Parkinson’s disease motor states at baseline and after 6 months of treatment. Off, -67%, p<0.01; on with troublesome dyskinesia, -47%, p<0.05; on without troublesome dyskinesia, +112%, p<0.01. LCIG, Levodopa-carbidopa intestinal gel.

Figure 2: The VAS regarding intensity of dyskinesia

Mean scores on the VAS at baseline and after 6 months of treatment. -90%, p<0.01. VAS, visual analog scale; LCIG, Levodopa-carbidopa intestinal gel.

Figures 3A and 3B: The AIMS and the Goetz scale

(A) Mean score on the AIMS during standardized levodopa tests at baseline and after 6 months of treatment. -70%, p<0.01. (B) Mean score on the Goetz scale during standardized levodopa tests at baseline and after 6 months of treatment. -75%, p<0.01. AIMS, Abnormal Involuntary Movement Scale; LCIG, Levodopa-carbidopa intestinal gel.

Figure 4: UPDRS items 32 and 33

Mean scores of UPDRS items 32 (duration of dyskinesia) and 33 (severity of dyskinesia) at baseline and after 6 months of treatment. UPDRS item 32, -58%, p<0.05; UPDRS item 33, -70%, p<0.05. UPDRS, Unified Parkinson’s Disease Rating Scale; LCIG, Levodopa-carbidopa intestinal gel.

14

Figure 1. Diary measures

Off On with troublesome dyskinesia

On without troublesome dyskinesia

02468

101214

6.1 5.8 6.1

23.1

12.9

Before LCIG After 6 months of LCIG

Mea

n tim

e, h

ours

Figure 2. The VAS regarding intensity of dyskinesia

VAS05

10152025 23.1

2.4

Before LCIGAfter 6 months of LCIG

Mea

n sc

ore

Figures 3A and 3B. The AIMS and the Goetz scale

15

Goetz0

0.5

1

1.5

2 1.6

0.4

Before LCIGAfter 6 months of LCIG

Mea

n sc

ore

Figure 4. UPDRS items 32 and 33

Item 32 Item 33 0

0.51

1.52

2.51.9

2.3

0.8 0.7

Before LCIGAfter 6 months of LCIG

Mea

n sc

ore

16

AIMS02468

10 9.3

2.8

Before LCIGAfter 6 months of LCIG

Mea

n sc

ore