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Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson’s disease
Journal of Clinical Neuroscience 25 (2016) 41–45
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson’s disease Florence C.F. Chang a, Vu Kwan b, David van der Poorten b, Neil Mahant a, Nigel Wolfe a, Ainhi D. Ha a, Jane M. Griffith a, David Tsui a, Samuel D. Kim a, Victor S.C. Fung a,c,⇑ a b c
Movement Disorders Unit, Neurology Department, Westmead Hospital, Corner Darcy and Hawkesbury Road, Westmead, NSW 2145, Australia Gastroenterology Department, Westmead Hospital, Westmead, NSW, Australia Sydney Medical School, University of Sydney, Sydney, Australia
a r t i c l e
i n f o
Article history: Received 14 December 2014 Accepted 17 May 2015
Keywords: Impulse control disorder Levodopa-carbidopa intestinal gel Parkinson’s disease Peripheral neuropathy
a b s t r a c t We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson’s disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson’s disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (±standard deviation) improvement in Unified Parkinson’s Disease Rating Scale part III was 37 ± 11%, mean daily ‘‘off” period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily ‘‘on” time increased from 10.2 ± 3 to 13.7 ± 2 hours, ‘‘on” period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson’s Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily ‘‘on” period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153. Ó 2016 Published by Elsevier Ltd.
1. Introduction Most Parkinson’s disease (PD) patients eventually develop motor fluctuations that become difficult to control, even with frequent dosing of levodopa [1]. A significant component of motor fluctuations is related to fluctuating levels of serum levodopa secondary to delayed gastric emptying and competition with amino acids for intestinal absorption [2,3]. Intraduodenal delivery of levodopa achieves relatively steady serum levodopa levels and provides a therapeutic option in patients with severe motor fluctuations [2]. Levodopa-carbidopa intestinal gel (LCIG) (Duodopa; AbbVie, Botany NSW, Australia) infusion is approved for clinical use in over 30 countries and has been used in over ⇑ Corresponding author. Tel.: +61 2 9845 6793; fax: +61 2 9635 6684. E-mail address: [email protected] (V.S.C. Fung). http://dx.doi.org/10.1016/j.jocn.2015.05.059 0967-5868/Ó 2016 Published by Elsevier Ltd.
2,800 patients worldwide [4]. We report, to our knowledge, the largest single centre experience in an Australian movement disorder unit using LCIG infusion. 2. Method Data were collected prospectively from the first 15 consecutive patients treated with LCIG in the Movement Disorders Unit at Westmead Hospital. The first patient commenced treatment in March 2008. Four of the patients were treated compassionately via the Special Access Scheme and the remaining eleven treated through participation in an open-label, phase III, 12 month study of the safety and efficacy of LCIG in advanced PD, the full results of which have recently been published [5]. The following information was recorded at baseline: age, age at PD onset, sex, duration of PD (years), Minnesota Impulse Disorders Interview
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self-reported diary over 3 days. The PDQ-39 and UPDRS while the patient is ‘‘on” from the usual anti-parkinsonian medication was recorded at 6 and 12 month follow-up. From March 2008 to July 2011, we recorded complications for all study participants. The complications assessed were death, stoma site infection, bleeding, percutaneous endoscopic gastrojejunal tube problems, number of additional radiographs, fluoroscopy and endoscopy required, and development of peripheral neuropathy. The study was approved by the Human Research Ethic Committee at Western Sydney Area Health Service and written consent was obtained from all subjects. The authors had full access to all of the data in the study (Fig. 1). Results are reported as mean ± standard deviation unless otherwise stated. 3. Results 3.1. Patient demographics and baseline characteristics Five women and ten men participated in this study. The mean age was 62 ± 4.74 years. The mean age at Parkinson’s disease onset was 48 ± 11.15 years. The mean duration from onset of disease to requiring LCIG was 14 years. The patients’ mean UPDRS part III (on usual PD medications) was 52 ± 23.9 prior to LCIG infusion. The mean daily oral levodopa dose prior to LCIG infusion was 2141 ± 940 mg. Thirteen out of 15 patient were taking dopamine agonists, either apomorphine, pramipexole and/or pergolide at baseline. 3.2. Treatment duration and levodopa dose Following 6 months of LCIG infusion, 66% of patients had a reduction in total daily dose of levodopa by 28 ± 19.7% (from 2,540.0 ± 677.6 mg at baseline to 1,864.3 ± 701.3 mg per day). Thirty-three percent of patients had an increase in total daily dose of levodopa after 6 months of LCIG infusion. The mean 6 month increase in total daily levodopa dose in these patients was 19 ± 53.4%. 3.3. Discontinuations Fig. 1. Flowchart illustrating how intraduodenal levodopa-carbidopa intestinal gel infusion is set up and maintained in the hospital setting. DBS = deep brain stimulation, LCIG = levodopa-carbidopa intestinal gel, MMA = methylmalonic acid, NCS = nerve conduction study, NJ = nasojejunal, PD = Parkinson’s disease, PEJ = percutaneous endoscopic jejunostomy.
(MIDI), medication list, the total levodopa daily equivalent dose, Unified Parkinson’s Disease Rating Scale part III (UPDRS) 1 to 4 hours after the first usual parkinsonian medication, 39-item Parkinson’s Disease Questionnaire (PDQ-39), daily hours ‘‘off”, daily hours ‘‘on” without dyskinesia, daily total hours ‘‘on” and pre-existing psychiatric diagnosis or impulse control disorder (ICD). Following commencement of LCIG therapy, all dopamine agonists were ceased. LCIG was administered for up to 16 hours during the day, commencing on waking, and was turned off at night. The only treatment allowed for nocturnal ‘‘off” symptoms was immediate release oral levodopa/carbidopa. The doses of all antiparkinsonian medications at baseline were converted to equivalent levodopa daily dose using a standardised conversion table from the paper by Tomlinson et al. [6]. The total daily LCIG dose was calculated from the daily morning dose, total daily bolus dose plus the continuous dose per hour multiplied by total hours of infusion per day. The percentage change from baseline daily levodopa dose was compared to daily levodopa equivalent dose at 6 months. At 3, 6 and 12 months, the mean hours ‘‘off” per day, mean hours ‘‘on” per day without dyskinesia and mean total hours ‘‘on” (with or without dyskinesia) were obtained from the patient’s
LCIG was well tolerated and no patients discontinued LCIG due to its side effects. Five patients did not keep a daily diary at 3 months and this increased to seven patients at 6 months. No patient died during the study period. 3.4. Changes in UPDRS, hours ‘‘on” and ‘‘off” and PDQ-39 The mean improvement in part III of UPDRS was 31 ± 36% at 6 months and 37 ± 11% at 12 months. Patient mean daily ‘‘off” period reduced from 6.3 ± 2 hours to 1.9 ± 2 hours and this was maintained at 12 months. The total daily ‘‘on” period increased from
Fig. 2. Mean percentage change of Unified Parkinson’s Disease Rating Scale daily ‘‘on”, ‘‘off” hours and 39-item Parkinson’s Disease Questionnaire Summary Index from baseline at 6 and 12 months. PDQ-39 SI = 39-item Parkinson’s Disease Questionnaire Summary Index, UPDRS = Unified Parkinson’s Disease Rating Scale.
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not develop ICD, the mean daily levodopa dose at 6 months was 1,777 ± 760 mg. The mean number of self-administered boluses in those who developed ICD was 2.4 ± 1.26 per day compared to 1.7 ± 1.26 per day for those who did not develop ICD. The mean change of daily levodopa dose at 6 months of infusion compared to baseline was an increase of 72 ± 146.91% for those who developed ICD and a reduction by 23.80 ± 29.81% for those who did not develop ICD (Fig. 4).
Fig. 3. 39-item Parkinson’s Disease Questionnaire subsection score mean percentage change at 6 and 12 months compared to baseline. ADL = activities of daily living, PDQ-39 = 39-item Parkinson’s Disease Questionnaire.
10.2 ± 3 hours to 13.7 ± 2 hours at 6 months and was maintained at 12 months. The ‘‘on” period without dyskinesia increased from 4.5 ± 3 hours to 7.4 ± 4 hours at 6 months and remained steady at 7.5 ± 5 hours at 12 months (Fig. 2). The PDQ-39 Summary Index improved by 38.9 ± 36% at 6 months and 32.5 ± 35% at 12 months compared to baseline (Fig. 3). PDQ stigma, activities of daily living, communication, mobility, and emotion all improved by at least 28% at 12 month follow-up. Cognitive impairment improved the least, by 2.4 ± 102% at 6 months and 7.3 ± 97% at 12 months. All patients noticed functional improvement. Notably, one patient was wheelchair dependent prior to LCIG and following LCIG commencement she was able to walk independently and participate in international PD patient support group meetings (Table 1). 3.5. Complications – ICD Four out of 15 patients (27%) had ICD or dopamine dysregulation syndrome (DDS) at a mean of 8.5 ± 4 months after commencement of LCIG infusion. One patient developed punding, one developed DDS and two (13%) had recurrence of pathological gambling. Two out of these four patients had prior known ICD or DDS before starting LCIG infusion. Three patients who had prior ICD on dopamine agonists did not develop ICD or DDS on LCIG infusion. All four patients who developed ICD had prior psychiatric diagnosis of depression and/or anxiety, prior to starting LCIG therapy. At the screening MIDI questionnaire prior to starting LCIG therapy, all four patients scored negative overall for ICD.
3.7. Other complications Two out of 15 patients (13%) had stoma infection. No patients had bleeding complication or peritonitis post-percutaneous gastrojejunal tube insertion. Six out of 15 patients (40%) had local tube problems, four had accidental dislodgement of the jejunal tube, one had a kinked tube and one had splitting of the tube due to trauma. All these six patients required abdominal radiographs to check tube position. In total, 12 radiograph procedures were used. Seven were fluoroscopy during repeat endoscopic tube replacement. One patient underwent three endoscopic procedures due to recurrent tube malfunction secondary to punding with the tube. Seven out of 15 patients (40%) had sensorimotor peripheral neuropathy secondary to vitamin B12 or B6 deficiency following extensive workup for immunologic, paraneoplastic and infective causes. Three patients had vitamin B6 deficiency, four patients had vitamin B12 deficiency and two patients had both vitamin B12 and B6 deficiency. One patient required hospitalisation for subacute peripheral neuropathy resulting in gait instability, which recovered following intravenous immunoglobulin. The mean onset of peripheral neuropathy from LCIG infusion commencement was 13 ± 0.4 months.
3.6. ICD development and levodopa dose In patients who had ICD on LCIG, the mean daily levodopa dose at 6 months of infusion was 1,927 ± 295 mg. In patients who did
Fig. 4. Mean daily levodopa dose at 6 months compared to baseline between groups that did and did not develop an impulse control disorder. ICD = impulse control disorder.
Table 1 Results at baseline, 6 months and 12 months with percentage change compared to baseline for UPDRS, daily total ‘‘off” and ‘‘on” time and PDQ-39
UPDRS ‘‘Off” time (hours) Total ‘‘on” (hours) ‘‘On” without dyskinesia (hours) PDQ-39 SI PDQ mobility PDQ ADL PDQ emotion PDQ stigma PDQ social support PDQ cognitive impairment PDQ communication PDQ bodily discomfort
Baseline
6 months
% change
12 months
% change
53 ± 24 6.3 ± 2 10.2 ± 3 4.5 ± 3 38.3 ± 14 54.8 ± 24 48.6 ± 21 30.8 ± 19 37.5 ± 30 17.3 ± 19 33.3 ± 18 38.9 ± 22 45.1 ± 23
37 ± 11 1.9 ± 2 13.7 ± 2 7.4 ± 4 22.8 ± 17 26.6 ± 24 25.7 ± 23 20.3 ± 14 16.5 ± 22 15.1 ± 18 23.8 ± 16 27.9 ± 21 26.1 ± 16
31 ± 36 67 ± 33 42 ± 48 131.9 ± 150 38.9 ± 36 44.7 ± 45 42.9 ± 41 33.1 ± 39 52.6 ± 51 23.8 ± 145 2.4 ± 102 37.1 ± 44 22.6 ± 78
37 ± 11 1.8 ± 2 13.6 ± 2 7.5 ± 5 24.5 ± 16 35.4 ± 25 29.1 ± 23 23.5 ± 18 17.2 ± 22 13.9 ± 17 25.0 ± 16 23.2 ± 17 29.1 ± 15
42 ± 36 73 ± 35 62.5 ± 68 86.5 ± 184 32.5 ± 35 28.4 ± 52 40.7 ± 38 28.2 ± 54 44.3 ± 44 18.0 ± 155 7.3 ± 97 36.4 ± 36 15.5 ± 51
ADL = activities of daily living, PDQ-39 = 39-item Parkinson’s Disease Questionnaire, SI = Summary Index, UPDRS = Unified Parkinson’s Disease Rating Scale. Data are presented as mean ± standard deviation.
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4. Discussion Our patients’ demographics and the mean UPDRS at baseline, at 6 and 12 months is similar to those reported by Nyholm et al. [7]. The improvement in UPDRS and the mean daily ‘‘off” and ‘‘on” time with and without dyskinesia with enteral levodopa is similar to randomised controlled trials and observational studies published so far [7–12]. The improvement in UPDRS part III reflects the effect of the LCIG intervention as investigators performed serial ‘‘on” state morning assessments. The quality of life questionnaire PDQ-39 Summary Index showed improvement in all subsections at 6 and 12 months, except for social support at 6 months. This is consistent with a previous report by Santos-Garcia et al. [13]. LCIG was well tolerated in our group of patients, with no participants discontinuing due to side effects related to LCIG. The advanced therapies for PD include apomorphine infusion, deep brain stimulation (DBS), and LCIG. Reported benefit in reduction of motor fluctuation is comparable between the three therapies [15]. There have been several well-designed, blinded, prospective studies to support the use of DBS for PD with motor fluctuations. Whereas LCIG has been reported to be superior to best oral therapy in two blinded, prospective studies [7,14] and several case series. Apomorphine reduced motor fluctuations in three case controlled studies and several case series [15]. However these therapies have not been compared in a randomised controlled trial to our knowledge. Compared with other advanced therapies for PD, LCIG is suitable for all participants with long duration of PD [15] and has been shown to improve non-motor symptoms of PD and neuropsychiatric symptoms such as punding and ICD [16]. In contrast, DBS has more favourable outcomes in younger (<70 years) versus older patients, due to increase risk of cognitive decline or worsening gait and postural control in patients above age 70 [17]. DBS also benefits tremor predominant PD. DBS is contraindicated if the patient has severe depression, dementia, significant postural instability, brain atrophy or lesions that interfere with trajectory planning. DBS has not been studied for non-motor symptoms of PD to our knowledge, whereas LCIG improves non-motor symptoms such as cardiovascular, sleep, urinary, memory/attention, gastrointestinal and pain problems [18]. Apomorphine infusion is effective for older patients, however it is contraindicated if patients have ICD or poor wound healing (for example diabetes) and may aggravate confusion, visual hallucinations, paranoid delusions and hypersexuality [15]. LCIG infusion can be useful in all patients with motor fluctuations secondary to PD, particularly patients with advanced age, non-motor and/or axial motor symptoms and ICD. Objective and subjective measures of motor performance and quality of life improve with long term LCIG infusion.
4.1. ICD complication Although independent association between levodopa treatment and ICD has not been reported in previous cross-sectional studies to our knowledge, higher dosage of levodopa use has been associated with the development of ICD [19]. Twenty-seven percent of our patients developed ICD while on LCIG therapy, without dopamine agonist use. This is higher than those reported in the literature from LCIG, probably because the daily levodopa dose equivalent is higher in our participants than reported case series [7,16]. A previous study found dopaminergic medication creates enhanced learning from negative outcomes, whereas in the ‘‘off” state, subjects show impaired learning from positive feedback [20]. Our study found the subjects who did not develop ICD had reduction in daily levodopa dose at 6 months compared to baseline, whereas those who
developed ICD had an increase in daily levodopa. We propose maintenance of LCIG infusion close to baseline levodopa daily dose may prevent the development of ICD. 4.2. Other complications Our results demonstrated fewer intestinal tube problems at 40% compared to previous reported studies of 69% during the first year of infusion [21]. The rate of gastrostomy tube site infection was similar to published reports. Our site had no complications of bleeding or peritonitis, less than the 3% rate published in the literature, albeit with a larger number of participants. There has been recent literature describing a decrease in serum vitamin B12 and folate levels following LCIG infusion with a subset of patients developing generalised subacute axonal sensorimotor peripheral neuropathy secondary to vitamin B12 deficiency [8,22,23]. Vitamin B6 and folate deficiency in the setting of LCIG infusion has been associated with weight loss and subacute axonal sensorimotor peripheral neuropathy [24,25]. Supplementation of vitamin B6, B12, folate and LCIG dose adjustment improve symptoms of peripheral neuropathy [24,25]. 5. Conclusion Although our study had a small number of subjects, it showed the efficacy of intraduodenal LCIG infusion with improvement in UPDRS, quality of life, number of hours ‘‘on” without dyskinesia and in daily ‘‘off” time from baseline to 12 months. The rate of intestinal tube problem or infection was similar to previous studies. Prior to commencement of duodenal levodopa infusion, clinicians should check for peripheral neuropathy and vitamin B6, B12 and folate deficiency, as supplementation can prevent or improve any existing peripheral neuropathy. Our study suggests that an increased daily levodopa dose compared to baseline is associated with a later development of ICD, but larger sample studies are needed to confirm this finding. Conflicts of Interest/Disclosures This study was in part comprised of data obtained during a clinical trial sponsored by Abbvie (formerly Solvay Pharmaceuticals). Acknowledgements We would like to acknowledgement Professor Pablo FernándezPeñas for his clinical care for our subjects. References [1] Hely MA, Reid WG, Adena MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008;23:837–44. [2] Kurlan R, Rothfield KP, Woodward WR, et al. Erratic gastric emptying of levodopa may cause ‘‘random” fluctuations of parkinsonian mobility. Neurology 1988;38:419–21. [3] Nutt JG, Woodward WR, Hammerstad JP, et al. The ‘‘on-off” phenomenon in Parkinson’s disease. Relation to levodopa absorption and transport. N Engl J Med 1984;310:483–8. [4] Fernandez HH, Vanagunas A, Odin P, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease open-label study: interim results. Parkinsonism Relat Disord 2013;19:339–45. [5] Fernandez HH, Standaert DG, Hauser RA, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease: final 12-month, open-label results. Mov Disord 2015;30:500–9. [6] Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 2010;25:2649–85. [7] Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005;64:216–23. [8] Antonini A, Isaias IU, Canesi M, et al. Duodenal levodopa infusion for advanced Parkinson’s disease: 12-month treatment outcome. Mov Disord 2007;22: 1145–9.
F.C.F. Chang et al. / Journal of Clinical Neuroscience 25 (2016) 41–45 [9] Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infusion in Parkinson’s disease-long-term experience. Acta Neurol Scand 2001;104:343–8. [10] Nilsson D, Hansson LE, Johansson K, et al. Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson’s disease. Acta Neurol Scand 1998;97:175–83. [11] Antonini A, Mancini F, Canesi M, et al. Duodenal levodopa infusion improves quality of life in advanced Parkinson’s disease. Neurodegener Dis 2008;5:244–6. [12] Puente V, De Fabregues O, Oliveras C, 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 Relat Disord 2010;16:218–21. [13] Santos-Garcia D, Sanjurjo LF, Macias M, et al. Long-term exposure to duodenal levodopa/carbidopa infusion therapy improves quality of life in relation especially to mobility, activities of daily living, and emotional well-being. Acta Neurol Scand 2012;125:187–91. [14] Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomized, controlled, double-blind, double-dummy study. Lancet Neurol 2014;13:141–9. [15] Volkmann J, Albanese A, Antonini A, et al. Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review. J Neurol 2013;260:2701–14. [16] Catalan MJ, de Pablo-Fernandez E, Villanueva C, et al. Levodopa infusion improves impulsivity and dopamine dysregulation syndrome in Parkinson’s disease. Mov Disord 2013;28:2007–10.
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[17] Silberstein P, Bittar RG, Boyle R, et al. Deep brain stimulation for Parkinson’s disease: Australian referral guidelines. J Clin Neurosci 2009;16:1001–8. [18] Honig H, Antonini A, Martinez-Martin P, et al. Intrajejunal levodopa infusion in Parkinson’s disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life. Mov Disord 2009;24:1468–74. [19] Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010;67:589–95. [20] Frank MJ, Seeberger LC, O’Reilly RC. By carrot or by stick: cognitive reinforcement learning in parkinsonism. Science 2004;306:1940–3. [21] Nyholm D, Lewander T, Johansson A, et al. Enteral levodopa/carbidopa infusion in advanced Parkinson disease: long-term exposure. Clin Neuropharmacol 2008;31:63–73. [22] Santos-Garcia D, Macias M, Llaneza M, et al. Serum vitamin B(12) and folate levels in Parkinson’s disease patients treated with duodenal levodopa infusion. Mov Disord 2011;26:558–9. [23] Manca D, Cossu G, Murgia D, et al. Reversible encephalopathy and axonal neuropathy in Parkinson’s disease during duodopa therapy. Mov Disord 2009;24:2293–4. [24] Klostermann F, Jugel C, Muller T, et al. Malnutritional neuropathy under intestinal levodopa infusion. J Neural Transm 2012;119:369–72. [25] Urban PP, Wellach I, Faiss S, et al. Subacute axonal neuropathy in Parkinson’s disease with cobalamin and vitamin B6 deficiency under duodopa therapy. Mov Disord 2010;25:1748–52.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson’s disease Florence C.F. Chang a, Vu Kwan b, David van der Poorten b, Neil Mahant a, Nigel Wolfe a, Ainhi D. Ha a, Jane M. Griffith a, David Tsui a, Samuel D. Kim a, Victor S.C. Fung a,c,⇑ a b c
Movement Disorders Unit, Neurology Department, Westmead Hospital, Corner Darcy and Hawkesbury Road, Westmead, NSW 2145, Australia Gastroenterology Department, Westmead Hospital, Westmead, NSW, Australia Sydney Medical School, University of Sydney, Sydney, Australia
a r t i c l e
i n f o
Article history: Received 14 December 2014 Accepted 17 May 2015
Keywords: Impulse control disorder Levodopa-carbidopa intestinal gel Parkinson’s disease Peripheral neuropathy
a b s t r a c t We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson’s disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson’s disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (±standard deviation) improvement in Unified Parkinson’s Disease Rating Scale part III was 37 ± 11%, mean daily ‘‘off” period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily ‘‘on” time increased from 10.2 ± 3 to 13.7 ± 2 hours, ‘‘on” period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson’s Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily ‘‘on” period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153. Ó 2016 Published by Elsevier Ltd.
1. Introduction Most Parkinson’s disease (PD) patients eventually develop motor fluctuations that become difficult to control, even with frequent dosing of levodopa [1]. A significant component of motor fluctuations is related to fluctuating levels of serum levodopa secondary to delayed gastric emptying and competition with amino acids for intestinal absorption [2,3]. Intraduodenal delivery of levodopa achieves relatively steady serum levodopa levels and provides a therapeutic option in patients with severe motor fluctuations [2]. Levodopa-carbidopa intestinal gel (LCIG) (Duodopa; AbbVie, Botany NSW, Australia) infusion is approved for clinical use in over 30 countries and has been used in over ⇑ Corresponding author. Tel.: +61 2 9845 6793; fax: +61 2 9635 6684. E-mail address: [email protected] (V.S.C. Fung). http://dx.doi.org/10.1016/j.jocn.2015.05.059 0967-5868/Ó 2016 Published by Elsevier Ltd.
2,800 patients worldwide [4]. We report, to our knowledge, the largest single centre experience in an Australian movement disorder unit using LCIG infusion. 2. Method Data were collected prospectively from the first 15 consecutive patients treated with LCIG in the Movement Disorders Unit at Westmead Hospital. The first patient commenced treatment in March 2008. Four of the patients were treated compassionately via the Special Access Scheme and the remaining eleven treated through participation in an open-label, phase III, 12 month study of the safety and efficacy of LCIG in advanced PD, the full results of which have recently been published [5]. The following information was recorded at baseline: age, age at PD onset, sex, duration of PD (years), Minnesota Impulse Disorders Interview
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self-reported diary over 3 days. The PDQ-39 and UPDRS while the patient is ‘‘on” from the usual anti-parkinsonian medication was recorded at 6 and 12 month follow-up. From March 2008 to July 2011, we recorded complications for all study participants. The complications assessed were death, stoma site infection, bleeding, percutaneous endoscopic gastrojejunal tube problems, number of additional radiographs, fluoroscopy and endoscopy required, and development of peripheral neuropathy. The study was approved by the Human Research Ethic Committee at Western Sydney Area Health Service and written consent was obtained from all subjects. The authors had full access to all of the data in the study (Fig. 1). Results are reported as mean ± standard deviation unless otherwise stated. 3. Results 3.1. Patient demographics and baseline characteristics Five women and ten men participated in this study. The mean age was 62 ± 4.74 years. The mean age at Parkinson’s disease onset was 48 ± 11.15 years. The mean duration from onset of disease to requiring LCIG was 14 years. The patients’ mean UPDRS part III (on usual PD medications) was 52 ± 23.9 prior to LCIG infusion. The mean daily oral levodopa dose prior to LCIG infusion was 2141 ± 940 mg. Thirteen out of 15 patient were taking dopamine agonists, either apomorphine, pramipexole and/or pergolide at baseline. 3.2. Treatment duration and levodopa dose Following 6 months of LCIG infusion, 66% of patients had a reduction in total daily dose of levodopa by 28 ± 19.7% (from 2,540.0 ± 677.6 mg at baseline to 1,864.3 ± 701.3 mg per day). Thirty-three percent of patients had an increase in total daily dose of levodopa after 6 months of LCIG infusion. The mean 6 month increase in total daily levodopa dose in these patients was 19 ± 53.4%. 3.3. Discontinuations Fig. 1. Flowchart illustrating how intraduodenal levodopa-carbidopa intestinal gel infusion is set up and maintained in the hospital setting. DBS = deep brain stimulation, LCIG = levodopa-carbidopa intestinal gel, MMA = methylmalonic acid, NCS = nerve conduction study, NJ = nasojejunal, PD = Parkinson’s disease, PEJ = percutaneous endoscopic jejunostomy.
(MIDI), medication list, the total levodopa daily equivalent dose, Unified Parkinson’s Disease Rating Scale part III (UPDRS) 1 to 4 hours after the first usual parkinsonian medication, 39-item Parkinson’s Disease Questionnaire (PDQ-39), daily hours ‘‘off”, daily hours ‘‘on” without dyskinesia, daily total hours ‘‘on” and pre-existing psychiatric diagnosis or impulse control disorder (ICD). Following commencement of LCIG therapy, all dopamine agonists were ceased. LCIG was administered for up to 16 hours during the day, commencing on waking, and was turned off at night. The only treatment allowed for nocturnal ‘‘off” symptoms was immediate release oral levodopa/carbidopa. The doses of all antiparkinsonian medications at baseline were converted to equivalent levodopa daily dose using a standardised conversion table from the paper by Tomlinson et al. [6]. The total daily LCIG dose was calculated from the daily morning dose, total daily bolus dose plus the continuous dose per hour multiplied by total hours of infusion per day. The percentage change from baseline daily levodopa dose was compared to daily levodopa equivalent dose at 6 months. At 3, 6 and 12 months, the mean hours ‘‘off” per day, mean hours ‘‘on” per day without dyskinesia and mean total hours ‘‘on” (with or without dyskinesia) were obtained from the patient’s
LCIG was well tolerated and no patients discontinued LCIG due to its side effects. Five patients did not keep a daily diary at 3 months and this increased to seven patients at 6 months. No patient died during the study period. 3.4. Changes in UPDRS, hours ‘‘on” and ‘‘off” and PDQ-39 The mean improvement in part III of UPDRS was 31 ± 36% at 6 months and 37 ± 11% at 12 months. Patient mean daily ‘‘off” period reduced from 6.3 ± 2 hours to 1.9 ± 2 hours and this was maintained at 12 months. The total daily ‘‘on” period increased from
Fig. 2. Mean percentage change of Unified Parkinson’s Disease Rating Scale daily ‘‘on”, ‘‘off” hours and 39-item Parkinson’s Disease Questionnaire Summary Index from baseline at 6 and 12 months. PDQ-39 SI = 39-item Parkinson’s Disease Questionnaire Summary Index, UPDRS = Unified Parkinson’s Disease Rating Scale.
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not develop ICD, the mean daily levodopa dose at 6 months was 1,777 ± 760 mg. The mean number of self-administered boluses in those who developed ICD was 2.4 ± 1.26 per day compared to 1.7 ± 1.26 per day for those who did not develop ICD. The mean change of daily levodopa dose at 6 months of infusion compared to baseline was an increase of 72 ± 146.91% for those who developed ICD and a reduction by 23.80 ± 29.81% for those who did not develop ICD (Fig. 4).
Fig. 3. 39-item Parkinson’s Disease Questionnaire subsection score mean percentage change at 6 and 12 months compared to baseline. ADL = activities of daily living, PDQ-39 = 39-item Parkinson’s Disease Questionnaire.
10.2 ± 3 hours to 13.7 ± 2 hours at 6 months and was maintained at 12 months. The ‘‘on” period without dyskinesia increased from 4.5 ± 3 hours to 7.4 ± 4 hours at 6 months and remained steady at 7.5 ± 5 hours at 12 months (Fig. 2). The PDQ-39 Summary Index improved by 38.9 ± 36% at 6 months and 32.5 ± 35% at 12 months compared to baseline (Fig. 3). PDQ stigma, activities of daily living, communication, mobility, and emotion all improved by at least 28% at 12 month follow-up. Cognitive impairment improved the least, by 2.4 ± 102% at 6 months and 7.3 ± 97% at 12 months. All patients noticed functional improvement. Notably, one patient was wheelchair dependent prior to LCIG and following LCIG commencement she was able to walk independently and participate in international PD patient support group meetings (Table 1). 3.5. Complications – ICD Four out of 15 patients (27%) had ICD or dopamine dysregulation syndrome (DDS) at a mean of 8.5 ± 4 months after commencement of LCIG infusion. One patient developed punding, one developed DDS and two (13%) had recurrence of pathological gambling. Two out of these four patients had prior known ICD or DDS before starting LCIG infusion. Three patients who had prior ICD on dopamine agonists did not develop ICD or DDS on LCIG infusion. All four patients who developed ICD had prior psychiatric diagnosis of depression and/or anxiety, prior to starting LCIG therapy. At the screening MIDI questionnaire prior to starting LCIG therapy, all four patients scored negative overall for ICD.
3.7. Other complications Two out of 15 patients (13%) had stoma infection. No patients had bleeding complication or peritonitis post-percutaneous gastrojejunal tube insertion. Six out of 15 patients (40%) had local tube problems, four had accidental dislodgement of the jejunal tube, one had a kinked tube and one had splitting of the tube due to trauma. All these six patients required abdominal radiographs to check tube position. In total, 12 radiograph procedures were used. Seven were fluoroscopy during repeat endoscopic tube replacement. One patient underwent three endoscopic procedures due to recurrent tube malfunction secondary to punding with the tube. Seven out of 15 patients (40%) had sensorimotor peripheral neuropathy secondary to vitamin B12 or B6 deficiency following extensive workup for immunologic, paraneoplastic and infective causes. Three patients had vitamin B6 deficiency, four patients had vitamin B12 deficiency and two patients had both vitamin B12 and B6 deficiency. One patient required hospitalisation for subacute peripheral neuropathy resulting in gait instability, which recovered following intravenous immunoglobulin. The mean onset of peripheral neuropathy from LCIG infusion commencement was 13 ± 0.4 months.
3.6. ICD development and levodopa dose In patients who had ICD on LCIG, the mean daily levodopa dose at 6 months of infusion was 1,927 ± 295 mg. In patients who did
Fig. 4. Mean daily levodopa dose at 6 months compared to baseline between groups that did and did not develop an impulse control disorder. ICD = impulse control disorder.
Table 1 Results at baseline, 6 months and 12 months with percentage change compared to baseline for UPDRS, daily total ‘‘off” and ‘‘on” time and PDQ-39
UPDRS ‘‘Off” time (hours) Total ‘‘on” (hours) ‘‘On” without dyskinesia (hours) PDQ-39 SI PDQ mobility PDQ ADL PDQ emotion PDQ stigma PDQ social support PDQ cognitive impairment PDQ communication PDQ bodily discomfort
Baseline
6 months
% change
12 months
% change
53 ± 24 6.3 ± 2 10.2 ± 3 4.5 ± 3 38.3 ± 14 54.8 ± 24 48.6 ± 21 30.8 ± 19 37.5 ± 30 17.3 ± 19 33.3 ± 18 38.9 ± 22 45.1 ± 23
37 ± 11 1.9 ± 2 13.7 ± 2 7.4 ± 4 22.8 ± 17 26.6 ± 24 25.7 ± 23 20.3 ± 14 16.5 ± 22 15.1 ± 18 23.8 ± 16 27.9 ± 21 26.1 ± 16
31 ± 36 67 ± 33 42 ± 48 131.9 ± 150 38.9 ± 36 44.7 ± 45 42.9 ± 41 33.1 ± 39 52.6 ± 51 23.8 ± 145 2.4 ± 102 37.1 ± 44 22.6 ± 78
37 ± 11 1.8 ± 2 13.6 ± 2 7.5 ± 5 24.5 ± 16 35.4 ± 25 29.1 ± 23 23.5 ± 18 17.2 ± 22 13.9 ± 17 25.0 ± 16 23.2 ± 17 29.1 ± 15
42 ± 36 73 ± 35 62.5 ± 68 86.5 ± 184 32.5 ± 35 28.4 ± 52 40.7 ± 38 28.2 ± 54 44.3 ± 44 18.0 ± 155 7.3 ± 97 36.4 ± 36 15.5 ± 51
ADL = activities of daily living, PDQ-39 = 39-item Parkinson’s Disease Questionnaire, SI = Summary Index, UPDRS = Unified Parkinson’s Disease Rating Scale. Data are presented as mean ± standard deviation.
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4. Discussion Our patients’ demographics and the mean UPDRS at baseline, at 6 and 12 months is similar to those reported by Nyholm et al. [7]. The improvement in UPDRS and the mean daily ‘‘off” and ‘‘on” time with and without dyskinesia with enteral levodopa is similar to randomised controlled trials and observational studies published so far [7–12]. The improvement in UPDRS part III reflects the effect of the LCIG intervention as investigators performed serial ‘‘on” state morning assessments. The quality of life questionnaire PDQ-39 Summary Index showed improvement in all subsections at 6 and 12 months, except for social support at 6 months. This is consistent with a previous report by Santos-Garcia et al. [13]. LCIG was well tolerated in our group of patients, with no participants discontinuing due to side effects related to LCIG. The advanced therapies for PD include apomorphine infusion, deep brain stimulation (DBS), and LCIG. Reported benefit in reduction of motor fluctuation is comparable between the three therapies [15]. There have been several well-designed, blinded, prospective studies to support the use of DBS for PD with motor fluctuations. Whereas LCIG has been reported to be superior to best oral therapy in two blinded, prospective studies [7,14] and several case series. Apomorphine reduced motor fluctuations in three case controlled studies and several case series [15]. However these therapies have not been compared in a randomised controlled trial to our knowledge. Compared with other advanced therapies for PD, LCIG is suitable for all participants with long duration of PD [15] and has been shown to improve non-motor symptoms of PD and neuropsychiatric symptoms such as punding and ICD [16]. In contrast, DBS has more favourable outcomes in younger (<70 years) versus older patients, due to increase risk of cognitive decline or worsening gait and postural control in patients above age 70 [17]. DBS also benefits tremor predominant PD. DBS is contraindicated if the patient has severe depression, dementia, significant postural instability, brain atrophy or lesions that interfere with trajectory planning. DBS has not been studied for non-motor symptoms of PD to our knowledge, whereas LCIG improves non-motor symptoms such as cardiovascular, sleep, urinary, memory/attention, gastrointestinal and pain problems [18]. Apomorphine infusion is effective for older patients, however it is contraindicated if patients have ICD or poor wound healing (for example diabetes) and may aggravate confusion, visual hallucinations, paranoid delusions and hypersexuality [15]. LCIG infusion can be useful in all patients with motor fluctuations secondary to PD, particularly patients with advanced age, non-motor and/or axial motor symptoms and ICD. Objective and subjective measures of motor performance and quality of life improve with long term LCIG infusion.
4.1. ICD complication Although independent association between levodopa treatment and ICD has not been reported in previous cross-sectional studies to our knowledge, higher dosage of levodopa use has been associated with the development of ICD [19]. Twenty-seven percent of our patients developed ICD while on LCIG therapy, without dopamine agonist use. This is higher than those reported in the literature from LCIG, probably because the daily levodopa dose equivalent is higher in our participants than reported case series [7,16]. A previous study found dopaminergic medication creates enhanced learning from negative outcomes, whereas in the ‘‘off” state, subjects show impaired learning from positive feedback [20]. Our study found the subjects who did not develop ICD had reduction in daily levodopa dose at 6 months compared to baseline, whereas those who
developed ICD had an increase in daily levodopa. We propose maintenance of LCIG infusion close to baseline levodopa daily dose may prevent the development of ICD. 4.2. Other complications Our results demonstrated fewer intestinal tube problems at 40% compared to previous reported studies of 69% during the first year of infusion [21]. The rate of gastrostomy tube site infection was similar to published reports. Our site had no complications of bleeding or peritonitis, less than the 3% rate published in the literature, albeit with a larger number of participants. There has been recent literature describing a decrease in serum vitamin B12 and folate levels following LCIG infusion with a subset of patients developing generalised subacute axonal sensorimotor peripheral neuropathy secondary to vitamin B12 deficiency [8,22,23]. Vitamin B6 and folate deficiency in the setting of LCIG infusion has been associated with weight loss and subacute axonal sensorimotor peripheral neuropathy [24,25]. Supplementation of vitamin B6, B12, folate and LCIG dose adjustment improve symptoms of peripheral neuropathy [24,25]. 5. Conclusion Although our study had a small number of subjects, it showed the efficacy of intraduodenal LCIG infusion with improvement in UPDRS, quality of life, number of hours ‘‘on” without dyskinesia and in daily ‘‘off” time from baseline to 12 months. The rate of intestinal tube problem or infection was similar to previous studies. Prior to commencement of duodenal levodopa infusion, clinicians should check for peripheral neuropathy and vitamin B6, B12 and folate deficiency, as supplementation can prevent or improve any existing peripheral neuropathy. Our study suggests that an increased daily levodopa dose compared to baseline is associated with a later development of ICD, but larger sample studies are needed to confirm this finding. Conflicts of Interest/Disclosures This study was in part comprised of data obtained during a clinical trial sponsored by Abbvie (formerly Solvay Pharmaceuticals). Acknowledgements We would like to acknowledgement Professor Pablo FernándezPeñas for his clinical care for our subjects. References [1] Hely MA, Reid WG, Adena MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008;23:837–44. [2] Kurlan R, Rothfield KP, Woodward WR, et al. Erratic gastric emptying of levodopa may cause ‘‘random” fluctuations of parkinsonian mobility. Neurology 1988;38:419–21. [3] Nutt JG, Woodward WR, Hammerstad JP, et al. The ‘‘on-off” phenomenon in Parkinson’s disease. Relation to levodopa absorption and transport. N Engl J Med 1984;310:483–8. [4] Fernandez HH, Vanagunas A, Odin P, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease open-label study: interim results. Parkinsonism Relat Disord 2013;19:339–45. [5] Fernandez HH, Standaert DG, Hauser RA, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease: final 12-month, open-label results. Mov Disord 2015;30:500–9. [6] Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 2010;25:2649–85. [7] Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005;64:216–23. [8] Antonini A, Isaias IU, Canesi M, et al. Duodenal levodopa infusion for advanced Parkinson’s disease: 12-month treatment outcome. Mov Disord 2007;22: 1145–9.
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