- Email: [email protected]
Continuous dopaminergic stimulation—From theory to clinical practice
ARTICLE IN PRESS
Parkinsonism and Related Disorders 13 (2007) S24–S28 www.elsevier.com/locate/parkreldis
Continuous dopaminergic stimulation—From theory to clinical practice Angelo Antonini Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy
Abstract Patients with advanced Parkinson’s disease (PD) experience worsening motor fluctuations and dyskinesia. Management options include deep brain stimulation of the subthalamic nucleus (STN-DBS), subcutaneous apomorphine (in combination with oral levodopa) or continuous duodenal levodopa administration. We have used all three therapies at our clinic in Milan and report our experience. Apomorphine infusion reduced daily off time but did not improve dyskinesia; long-term treatment was associated with impulse control disorders. STN-DBS provided motor benefit, but was associated with behavioural changes including attempted suicide. Duodenal levodopa produced significant clinical benefit without behavioural changes and allowed patients to discontinue all other PD medications. Duodenal levodopa should be considered in PD patients with advanced disease. r 2007 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Apomorphine; STN-DBS; Levdopa
1. Introduction Current therapy for Parkinson’s disease (PD) can effectively control motor symptoms for the first few years after diagnosis in many patients. In addition to oral levodopa, the current gold standard treatment, available therapies include dopamine agonists (pramipexole, ropinirole, cabergoline, pergolide), monoamine oxidase B inhibitors (selegiline, rasagiline) and catechol-O-methyltransferase inhibitors (entacapone, tolcapone) [1]. However, as PD progresses and both the dose and number of levodopa administrations are increased, patients begin to experience motor fluctuations and dyskinesia. Management of these motor complications is difficult, even when medications are combined [2]. Results from the recently published ‘‘Lasting effect in Adjunct therapy with Rasagiline Given Once daily (LARGO) study’’, for example, showed that treatment with either rasagiline or entacapone as adjuncts to levodopa resulted in significant reductions in daily off time and significantly increased on time compared with a placebo adjunct [3]. However, in advanced PD with troublesome dyskinesias, the addition of these medications Tel.: +39 02 57993222; fax: +39 02 57993319.
E-mail address: [email protected] 1353-8020/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2007.06.002
to levodopa produced no significant improvements in on time compared with placebo, further highlighting difficulties in managing these patients. Dyskinesia typically develops in patients who take oral levodopa for an extended period of time. Although reducing the levodopa dose can lessen dyskinesia, it will also tend to increase off time. Thus, the therapeutic window for treatment with levodopa becomes extremely narrow and patients with advanced PD are faced with increasing periods of off time with rigidity, bradykinesia and freezing problems [4]. The resulting disability can leave patients unable to perform normal daily activities such as sitting, eating or walking [5]. When patients have reached this stage, there are currently only three treatment options available: deep brain stimulation of the subthalamic nucleus (STN-DBS), subcutaneous apomorphine (in combination with oral levodopa) and continuous duodenal levodopa administration. This paper will discuss experience-treating patients using these therapies at our clinic in Milan. 2. Subcutaneous apomorphine and STN-DBS Apomorphine exerts its antiparkinsonian effect by direct stimulation of striatal presynaptic and postsynaptic dopamine D1 and D2 receptors [6]. When given subcutaneously,
ARTICLE IN PRESS A. Antonini / Parkinsonism and Related Disorders 13 (2007) S24–S28
apomorphine has a rapid onset of action, with effects apparent within 5–15 min. Clinical studies of apomorphine infusion have primarily been open label studies and most examined small numbers of patients. These studies reported an improvement in off time between 50% and 80% [7–9]. Deep brain stimulation involves the surgical implantation of electrodes into the subthalamic nucleus, which are connected by a wire to a pulse generator that controls the level of stimulation. Clinical studies report improvements in both off time and dyskinesia of approximately 50% [10,11]. In a recent study carried out at our clinic, we prospectively examined patients with advanced PD and who had motor fluctuations and dyskinesias that could not be controlled with standard oral treatment [12]. Patients were treated with either subcutaneous apomorphine infusion (n ¼ 13) or STN-DBS (n ¼ 12) and were re-examined 12 months after initiation of treatment to assess both clinical and neuropsychological outcomes. Patients were given the choice between the two treatments and most chose apomorphine infusion due to the long waiting list for the DBS surgical procedure. After 12 months of treatment with apomorphine, patients had a 51% reduction in daily off time and were able to reduce their levodopa dose by 29% (Fig. 1) [12]. However, there was no significant change in the abnormal involuntary movement scale (AIMS) scores, suggesting that apomorphine was not an effective treatment for dyskinesia. Neuropsychiatric testing revealed no significant changes in cognition or behaviour, a finding in agreement with previous studies [13,14]. Among patients who received STN-DBS for 12 months, there was a 76% reduction in off time, a reduction in daily levodopa dose of 62% and an 81% reduction in AIMS scores (Fig. 1). These improvements suggest effects on both off time and dyskinesia. However, the neuropsychological findings were less positive for STN-DBS. There was a significant worsening of the neuropsychiatric inventory (NPI) compared with baseline and at least 50% of patients exhibited behavioural changes
APO
STN-DBS
% Change after 12 months
0 -10 -20 -30 -40
L-dopa dose Off time AIMS
-50 -60 -70 -80 -90
Fig. 1. Changes in levodopa dose, off time and AIMS scores after 6 months treatment with apomorphine or STN-DBS.
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that were not apparent at baseline. Similar changes have been reported previously by other groups [15]. Although both apomorphine and STB-DBS produced significant clinical improvements in our study, both treatments had clear drawbacks. Apomorphine failed to treat dyskinesia and STN-DBS was associated with behavioural problems. Experience in our clinic also points to additional problems with these treatments. During more than 4 years of follow-up with 50 patients receiving apomorphine in our clinic, 22 have dropped out of treatment because they felt that their motor control was insufficient. In addition, patients who use long-term apomorphine (up to 16 h/day for 424 months) can develop impulse control disorders. Five of our patients developed such disorders, including pathological gambling, internet addiction, compulsive eating and increased libido and acute paranoia with attempted suicide. These effects are dopamine mediated and ultimately lead to treatment discontinuation. Among the 150 patients treated with DBS at our clinic, there have been four attempted suicides. This finding is unusual in Italy, which has a low suicide rate, but is in agreement with a number of recent reports of suicides among patients receiving STN-DBS [16,17]. As a result of this and clinical study experience, we are actively looking for other treatment options. 3. Continuous duodenal levodopa administration Continuous delivery represents a more physiologic way to administer levodopa [18], but has been limited in the past by the poor solubility of the drug. The recent introduction of a novel levodopa formulation (Duodopa) has provided a new opportunity for continuous administration by enteral infusion. This technique has been shown to provide more continuous plasma levels than oral administration and has reduced both dyskinesia and off time in clinical studies [19–21]. The levodopa infusion is administered via a permanent catheter implanted into the duodenum via a percutaneous endoscopic gastrostomy (PEG) under local anaesthetic. Administration of the drug is controlled by a pump with an adjustable infusion rate, which allows fine-tuned titration, individual adaptation of dose and also allows administration of extra doses if needed. Seven patients (four men and three women) in our clinic with advanced idiopathic PD, who were experiencing motor fluctuations and dyskinesia, were treated with continuous duodenal infusion of carbidopa/levodopa 5/ 20 mg/ml [22]. Unlike some previous studies of duodenal levodopa infusion, we used strict inclusion criteria in an attempt to make the results more comparable to data from STN-DBS studies. The patients met the Core Assessment Program for Surgical Interventional Therapies (CAPSIT) in PD criteria [23], including Hoehn and Yahr stage 43 and a change in the motor unified Parkinson disease rating scale (UPDRS) score 430% between off and on states.
ARTICLE IN PRESS A. Antonini / Parkinsonism and Related Disorders 13 (2007) S24–S28
Table 1 Rating scale for patients receiving continuous duodenal levodopa administration Rating
Symptoms
Motor state
+3 +2 1, 0, +1 2 3
Severe dyskinesia Dyskinesia Normal Moderate bradykinesia Severe bradykinesia
Hyperkinetic Hyperkinetic On Off Off
Motor state
Baseline +3 +2 +1 0 -1 -2 -3 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Hours
Motor state
1 Week +3 +2 +1 0 -1 -2 -3 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Hours 6 months
Motor state
Patients could not have any atypical features such as falling, gaze abnormalities or autonomic dysfunction. They also had no significant psychiatric disturbances and no cognitive impairment. No age limit was placed on patients. At baseline, patients were aged between 50 and 80 years and had had PD for a mean of 18 years. All patients were taking a combination of oral levodopa and dopamine agonists, including pramipexole, ropinirole, pergolide and cabergoline. In addition, some patients were receiving intermittent subcutaneous apomorphine injections. Both before and during treatment, patients rated their symptoms hourly on a scale from 3 to +3 that recorded off time, on time and dyskinesia [20] (Table 1). Prior to the initiation of continuous duodenal infusion of levodopa, patients reported constant daily fluctuations in their PD state, with off states alternating with dyskinesias throughout the day. Fig. 2 (baseline) illustrates the pattern of daily fluctuation reported by one of our patients before treatment with duodenal levodopa. (The patterns illustrated in Fig. 2 were typical of all seven patients treated in our clinic.) At the end of the 3-day test period, during which patients received duodenal levodopa for 12–14 h per day via a nasogastric tube, motor fluctuations became less pronounced as the dose was titrated. After the test period, the gastrostomy tube was placed in the duodenum and patients had gained considerable stability within 1 week (Fig. 2; 1 week). Six months after the initiation of duodenal levodopa, there was a substantial improvement from baseline in the motor state throughout the day (Fig. 2; 6 months). The few daily fluctuations seen comprised a brief period of off time, which included slight rigidity and bradykinesia. This often occurred after a meal and was treated with a bolus dose of levodopa. Since the pump was turned off at night, an extra levodopa dose was required in the morning. The improvements in daily fluctuations translated to a mean reduction in daily off time from 294 to 40 min, a reduction of 81%. Similarly, the daily time spent with moderate to severe dyskinesia was reduced from 154 to 42 min, a reduction of 70% (Fig. 3). Most dyskinesias reported were related to the administration of bolus doses of levodopa and were of short duration. At 6 months there was a wide variation in the dose of levodopa required by each patient, with a range of 40–120 mg/h (not including bolus doses, which ranged from 100 to 220 mg in the morning) and an average of
+3 +2 +1 0 -1 -2 -3 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Hours
Fig. 2. Treatment with continuous duodenal levodopa infusion: hourly fluctuations in PD state at (A) baseline, (B) 1 week and (C) 6 months. Points are based on the rating scale shown in Table 1.
350 300 Time per day (minutes)
S26
294
250 Baseline 6 months
200
154 150 100 50
40
42
0 Off time
Dyskinesia
Fig. 3. Improvements in off time and dyskinesia in patients treated with continuous duodenal levodopa.
ARTICLE IN PRESS A. Antonini / Parkinsonism and Related Disorders 13 (2007) S24–S28
1365 mg/day. Compared with baseline, this represented a non-significant increase of 18%, which is similar to previous reports using this method [20,21]. Importantly, patients were able to discontinue all other PD medications. Treatment with duodenal levodopa was also associated with significant increases in quality of life according to the PD Questionnaire (PDQ-39), an instrument designed to measure aspects of health that are relevant to patients with PD [24]. The PDQ-39 is scored on a scale of 0–100, where lower scores indicate a better-perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. The results are presented as eight discrete domain scores. Significant improvements (Po0.05) from baseline were seen in the domains of mobility (27 vs. 19), activities of daily living (24 vs. 17) and bodily discomfort (19 vs. 12). There were some complications associated with this treatment. Three of the seven patients had obstructions in their gastrostomy tube during the 6-month follow up. This problem could be resolved, but remains an issue for some patients. Recent technical improvements in the delivery system may reduce the incidence of obstructions. Although one of our patients developed peritonitis following placement of the gastrostomy tube, treatment was halted and then restarted 3 weeks later. The patient is now being treated successfully. Similar to experience with oral levodopa, there was no evidence of any cognitive or behavioural abnormalities with continuous duodenal administration. 4. Continuous duodenal levodopa: open issues Despite the success with continuous duodenal levodopa administration at our institution, some issues remain to be clarified. Although we used strict CAPSIT inclusion criteria for patients, standard inclusion criteria have yet to be determined. It may be useful to include patients who are likely to benefit the most, i.e., those with long disease duration and a long life expectancy. It is also unclear whether or not a test period with a nasoduodenal tube prior to placement of the gastrostomy tube is necessary. Although we used a test period, it may not be indicated since patients who are levodopa responsive are likely to respond well to this treatment. We are also planning to study increasing the continuous infusion from 16 to 24 h because the benefit on sleeping at night appears to be variable with the interrupted infusion. There are also some technical issues that have yet to be resolved, including the size and weight of the pump. Some patients are relatively frail women aged up to 80 years and the pump is relatively cumbersome and heavy for them to carry. In our experience, patients requested a lighter, more portable pump. Another important issue is the need for an efficient hospital team to carry out the procedure. However, it is likely that as this treatment becomes more widespread, improvements will be made to equipment and hospital teams will become familiar with the procedure.
S27
5. Conclusion Apomorphine infusion is easy to perform and the pump that supplies the subcutaneous infusion is light and easy to use. However, the effectiveness of apomorphine has been demonstrated only in open-label studies and it does not appear to improve dyskinesia. In addition, patients must still continue to take oral levodopa. Both continuous duodenal levodopa administration and STN-DBS provide significant motor benefit, but DBS is more invasive and evidence is accumulating that the behavioural and cognitive changes associated with DBS may not be reversible. In contrast, duodenal levodopa administration in this group of patients produced no abnormal changes in behaviour or cognition. In addition, our 6-month follow-up results show that levodopa infusion can lead to significant clinical benefit and that a therapeutic window can be identified even in complicated PD patients. According to our experience, duodenal levodopa infusion should be considered in PD patients with advanced disease and motor complications that cannot be controlled with standard oral treatment. Conflict of interest The author has declared no conflict of interest. References [1] Jankovic J. An update on the treatment of Parkinson’s disease. Mt Sinai J Med 2006;73(4):682–9. [2] Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, BronteStewart H, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2006;66(7):983–95. [3] Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W, Stocchi F, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, lasting effect in adjunct therapy with Rasagiline given once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365(9463):947–54. [4] Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16(3):448–58. [5] Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 2005;20(2):224–30. [6] Deleu D, Hanssens Y, Northway MG. Subcutaneous apomorphine: an evidence-based review of its use in Parkinson’s disease. Drugs Aging 2004;21(11):687–709. [7] Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up. J Neurol Neurosurg Psychiatry 1998;65(5):709–16. [8] 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 followup. Mov Disord 2002;17(1):188–91. [9] Stibe CM, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in parkinsonian on–off oscillations. Lancet 1988; 1(8582):403–6.
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[10] Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 2001; 345(13):956–63. [11] Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pollak P, Rehncrona S, et al. Bilateral deep brain stimulation in Parkinson’s disease: a multicentre study with 4 years follow-up. Brain 2005;128 (Pt 10):2240–9. [12] DeGaspari D, Siri C, Landi A, Cilia R, Bonetti A, Natuzzi F, et al. Clinical and neuropsychological follow up at 12 months in patients with complicated Parkinson’s disease treated with subcutaneous apomorphine infusion or deep brain stimulation of the subthalamic nucleus. J Neurol Neurosurg Psychiatry 2006;77(4):450–3. [13] Di Rosa AE, Epifanio A, Antonini A, Stocchi F, Martino G, Di BL, et al. Continuous apomorphine infusion and neuropsychiatric disorders: a controlled study in patients with advanced Parkinson’s disease. Neurol Sci 2003;24(3):174–5. [14] Morgante L, Basile G, Epifanio A, Spina E, Antonini A, Stocchi F, et al. Continuous apomorphine infusion (CAI) and neuropsychiatric disorders in patients with advanced Parkinson’s disease: a follow-up of two years. Arch Gerontol Geriatr Suppl 2004(9):291–6. [15] Voon V, Saint-Cyr J, Lozano AM, Moro E, Poon YY, Lang AE. Psychiatric symptoms in patients with Parkinson disease presenting for deep brain stimulation surgery. J Neurosurg 2005;103(2):246–51. [16] Burkhard PR, Vingerhoets FJ, Berney A, Bogousslavsky J, Villemure JG, Ghika J. Suicide after successful deep brain stimulation for movement disorders. Neurology 2004;63(11):2170–2.
[17] Doshi PK, Chhaya N, Bhatt MH. Depression leading to attempted suicide after bilateral subthalamic nucleus stimulation for Parkinson’s disease. Mov Disord 2002;17(5):1084–5. [18] Chase TN. The significance of continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Drugs 1998;55(Suppl 1):1–9. [19] Kurth MC, Tetrud JW, Tanner CM, Irwin I, Stebbins GT, Goetz CG, et al. Double-blind, placebo-controlled, crossover study of duodenal infusion of levodopa/carbidopa in Parkinson’s disease patients with ‘on–off’ fluctuations. Neurology 1993;43(9):1698–703. [20] Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infusion in Parkinson’s disease—long-term experience. Acta Neurol Scand 2001;104(6):343–8. [21] 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. [22] Antonini A, Isaias I, Zibetti M, Canesi M, Lopiano L, Pezzoli G. Continuous duodenal levodopa/carbidopa infusion in advanced Parkinson’s disease: clinical and quality of life changes after 6months. Mov Disord 2006;21(Suppl 15):S550. [23] Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 1999;14(4):572–84. [24] Peto V, Jenkinson C, Fitzpatrick R, Greenhall R. The development and validation of a short measure of functioning and well being for individuals with Parkinson’s disease. Qual Life Res 1995;4(3):241–8.
Parkinsonism and Related Disorders 13 (2007) S24–S28 www.elsevier.com/locate/parkreldis
Continuous dopaminergic stimulation—From theory to clinical practice Angelo Antonini Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy
Abstract Patients with advanced Parkinson’s disease (PD) experience worsening motor fluctuations and dyskinesia. Management options include deep brain stimulation of the subthalamic nucleus (STN-DBS), subcutaneous apomorphine (in combination with oral levodopa) or continuous duodenal levodopa administration. We have used all three therapies at our clinic in Milan and report our experience. Apomorphine infusion reduced daily off time but did not improve dyskinesia; long-term treatment was associated with impulse control disorders. STN-DBS provided motor benefit, but was associated with behavioural changes including attempted suicide. Duodenal levodopa produced significant clinical benefit without behavioural changes and allowed patients to discontinue all other PD medications. Duodenal levodopa should be considered in PD patients with advanced disease. r 2007 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Apomorphine; STN-DBS; Levdopa
1. Introduction Current therapy for Parkinson’s disease (PD) can effectively control motor symptoms for the first few years after diagnosis in many patients. In addition to oral levodopa, the current gold standard treatment, available therapies include dopamine agonists (pramipexole, ropinirole, cabergoline, pergolide), monoamine oxidase B inhibitors (selegiline, rasagiline) and catechol-O-methyltransferase inhibitors (entacapone, tolcapone) [1]. However, as PD progresses and both the dose and number of levodopa administrations are increased, patients begin to experience motor fluctuations and dyskinesia. Management of these motor complications is difficult, even when medications are combined [2]. Results from the recently published ‘‘Lasting effect in Adjunct therapy with Rasagiline Given Once daily (LARGO) study’’, for example, showed that treatment with either rasagiline or entacapone as adjuncts to levodopa resulted in significant reductions in daily off time and significantly increased on time compared with a placebo adjunct [3]. However, in advanced PD with troublesome dyskinesias, the addition of these medications Tel.: +39 02 57993222; fax: +39 02 57993319.
E-mail address: [email protected] 1353-8020/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2007.06.002
to levodopa produced no significant improvements in on time compared with placebo, further highlighting difficulties in managing these patients. Dyskinesia typically develops in patients who take oral levodopa for an extended period of time. Although reducing the levodopa dose can lessen dyskinesia, it will also tend to increase off time. Thus, the therapeutic window for treatment with levodopa becomes extremely narrow and patients with advanced PD are faced with increasing periods of off time with rigidity, bradykinesia and freezing problems [4]. The resulting disability can leave patients unable to perform normal daily activities such as sitting, eating or walking [5]. When patients have reached this stage, there are currently only three treatment options available: deep brain stimulation of the subthalamic nucleus (STN-DBS), subcutaneous apomorphine (in combination with oral levodopa) and continuous duodenal levodopa administration. This paper will discuss experience-treating patients using these therapies at our clinic in Milan. 2. Subcutaneous apomorphine and STN-DBS Apomorphine exerts its antiparkinsonian effect by direct stimulation of striatal presynaptic and postsynaptic dopamine D1 and D2 receptors [6]. When given subcutaneously,
ARTICLE IN PRESS A. Antonini / Parkinsonism and Related Disorders 13 (2007) S24–S28
apomorphine has a rapid onset of action, with effects apparent within 5–15 min. Clinical studies of apomorphine infusion have primarily been open label studies and most examined small numbers of patients. These studies reported an improvement in off time between 50% and 80% [7–9]. Deep brain stimulation involves the surgical implantation of electrodes into the subthalamic nucleus, which are connected by a wire to a pulse generator that controls the level of stimulation. Clinical studies report improvements in both off time and dyskinesia of approximately 50% [10,11]. In a recent study carried out at our clinic, we prospectively examined patients with advanced PD and who had motor fluctuations and dyskinesias that could not be controlled with standard oral treatment [12]. Patients were treated with either subcutaneous apomorphine infusion (n ¼ 13) or STN-DBS (n ¼ 12) and were re-examined 12 months after initiation of treatment to assess both clinical and neuropsychological outcomes. Patients were given the choice between the two treatments and most chose apomorphine infusion due to the long waiting list for the DBS surgical procedure. After 12 months of treatment with apomorphine, patients had a 51% reduction in daily off time and were able to reduce their levodopa dose by 29% (Fig. 1) [12]. However, there was no significant change in the abnormal involuntary movement scale (AIMS) scores, suggesting that apomorphine was not an effective treatment for dyskinesia. Neuropsychiatric testing revealed no significant changes in cognition or behaviour, a finding in agreement with previous studies [13,14]. Among patients who received STN-DBS for 12 months, there was a 76% reduction in off time, a reduction in daily levodopa dose of 62% and an 81% reduction in AIMS scores (Fig. 1). These improvements suggest effects on both off time and dyskinesia. However, the neuropsychological findings were less positive for STN-DBS. There was a significant worsening of the neuropsychiatric inventory (NPI) compared with baseline and at least 50% of patients exhibited behavioural changes
APO
STN-DBS
% Change after 12 months
0 -10 -20 -30 -40
L-dopa dose Off time AIMS
-50 -60 -70 -80 -90
Fig. 1. Changes in levodopa dose, off time and AIMS scores after 6 months treatment with apomorphine or STN-DBS.
S25
that were not apparent at baseline. Similar changes have been reported previously by other groups [15]. Although both apomorphine and STB-DBS produced significant clinical improvements in our study, both treatments had clear drawbacks. Apomorphine failed to treat dyskinesia and STN-DBS was associated with behavioural problems. Experience in our clinic also points to additional problems with these treatments. During more than 4 years of follow-up with 50 patients receiving apomorphine in our clinic, 22 have dropped out of treatment because they felt that their motor control was insufficient. In addition, patients who use long-term apomorphine (up to 16 h/day for 424 months) can develop impulse control disorders. Five of our patients developed such disorders, including pathological gambling, internet addiction, compulsive eating and increased libido and acute paranoia with attempted suicide. These effects are dopamine mediated and ultimately lead to treatment discontinuation. Among the 150 patients treated with DBS at our clinic, there have been four attempted suicides. This finding is unusual in Italy, which has a low suicide rate, but is in agreement with a number of recent reports of suicides among patients receiving STN-DBS [16,17]. As a result of this and clinical study experience, we are actively looking for other treatment options. 3. Continuous duodenal levodopa administration Continuous delivery represents a more physiologic way to administer levodopa [18], but has been limited in the past by the poor solubility of the drug. The recent introduction of a novel levodopa formulation (Duodopa) has provided a new opportunity for continuous administration by enteral infusion. This technique has been shown to provide more continuous plasma levels than oral administration and has reduced both dyskinesia and off time in clinical studies [19–21]. The levodopa infusion is administered via a permanent catheter implanted into the duodenum via a percutaneous endoscopic gastrostomy (PEG) under local anaesthetic. Administration of the drug is controlled by a pump with an adjustable infusion rate, which allows fine-tuned titration, individual adaptation of dose and also allows administration of extra doses if needed. Seven patients (four men and three women) in our clinic with advanced idiopathic PD, who were experiencing motor fluctuations and dyskinesia, were treated with continuous duodenal infusion of carbidopa/levodopa 5/ 20 mg/ml [22]. Unlike some previous studies of duodenal levodopa infusion, we used strict inclusion criteria in an attempt to make the results more comparable to data from STN-DBS studies. The patients met the Core Assessment Program for Surgical Interventional Therapies (CAPSIT) in PD criteria [23], including Hoehn and Yahr stage 43 and a change in the motor unified Parkinson disease rating scale (UPDRS) score 430% between off and on states.
ARTICLE IN PRESS A. Antonini / Parkinsonism and Related Disorders 13 (2007) S24–S28
Table 1 Rating scale for patients receiving continuous duodenal levodopa administration Rating
Symptoms
Motor state
+3 +2 1, 0, +1 2 3
Severe dyskinesia Dyskinesia Normal Moderate bradykinesia Severe bradykinesia
Hyperkinetic Hyperkinetic On Off Off
Motor state
Baseline +3 +2 +1 0 -1 -2 -3 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Hours
Motor state
1 Week +3 +2 +1 0 -1 -2 -3 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Hours 6 months
Motor state
Patients could not have any atypical features such as falling, gaze abnormalities or autonomic dysfunction. They also had no significant psychiatric disturbances and no cognitive impairment. No age limit was placed on patients. At baseline, patients were aged between 50 and 80 years and had had PD for a mean of 18 years. All patients were taking a combination of oral levodopa and dopamine agonists, including pramipexole, ropinirole, pergolide and cabergoline. In addition, some patients were receiving intermittent subcutaneous apomorphine injections. Both before and during treatment, patients rated their symptoms hourly on a scale from 3 to +3 that recorded off time, on time and dyskinesia [20] (Table 1). Prior to the initiation of continuous duodenal infusion of levodopa, patients reported constant daily fluctuations in their PD state, with off states alternating with dyskinesias throughout the day. Fig. 2 (baseline) illustrates the pattern of daily fluctuation reported by one of our patients before treatment with duodenal levodopa. (The patterns illustrated in Fig. 2 were typical of all seven patients treated in our clinic.) At the end of the 3-day test period, during which patients received duodenal levodopa for 12–14 h per day via a nasogastric tube, motor fluctuations became less pronounced as the dose was titrated. After the test period, the gastrostomy tube was placed in the duodenum and patients had gained considerable stability within 1 week (Fig. 2; 1 week). Six months after the initiation of duodenal levodopa, there was a substantial improvement from baseline in the motor state throughout the day (Fig. 2; 6 months). The few daily fluctuations seen comprised a brief period of off time, which included slight rigidity and bradykinesia. This often occurred after a meal and was treated with a bolus dose of levodopa. Since the pump was turned off at night, an extra levodopa dose was required in the morning. The improvements in daily fluctuations translated to a mean reduction in daily off time from 294 to 40 min, a reduction of 81%. Similarly, the daily time spent with moderate to severe dyskinesia was reduced from 154 to 42 min, a reduction of 70% (Fig. 3). Most dyskinesias reported were related to the administration of bolus doses of levodopa and were of short duration. At 6 months there was a wide variation in the dose of levodopa required by each patient, with a range of 40–120 mg/h (not including bolus doses, which ranged from 100 to 220 mg in the morning) and an average of
+3 +2 +1 0 -1 -2 -3 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Hours
Fig. 2. Treatment with continuous duodenal levodopa infusion: hourly fluctuations in PD state at (A) baseline, (B) 1 week and (C) 6 months. Points are based on the rating scale shown in Table 1.
350 300 Time per day (minutes)
S26
294
250 Baseline 6 months
200
154 150 100 50
40
42
0 Off time
Dyskinesia
Fig. 3. Improvements in off time and dyskinesia in patients treated with continuous duodenal levodopa.
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1365 mg/day. Compared with baseline, this represented a non-significant increase of 18%, which is similar to previous reports using this method [20,21]. Importantly, patients were able to discontinue all other PD medications. Treatment with duodenal levodopa was also associated with significant increases in quality of life according to the PD Questionnaire (PDQ-39), an instrument designed to measure aspects of health that are relevant to patients with PD [24]. The PDQ-39 is scored on a scale of 0–100, where lower scores indicate a better-perceived health status. Higher scores are consistently associated with the more severe symptoms of the disease such as tremor and stiffness. The results are presented as eight discrete domain scores. Significant improvements (Po0.05) from baseline were seen in the domains of mobility (27 vs. 19), activities of daily living (24 vs. 17) and bodily discomfort (19 vs. 12). There were some complications associated with this treatment. Three of the seven patients had obstructions in their gastrostomy tube during the 6-month follow up. This problem could be resolved, but remains an issue for some patients. Recent technical improvements in the delivery system may reduce the incidence of obstructions. Although one of our patients developed peritonitis following placement of the gastrostomy tube, treatment was halted and then restarted 3 weeks later. The patient is now being treated successfully. Similar to experience with oral levodopa, there was no evidence of any cognitive or behavioural abnormalities with continuous duodenal administration. 4. Continuous duodenal levodopa: open issues Despite the success with continuous duodenal levodopa administration at our institution, some issues remain to be clarified. Although we used strict CAPSIT inclusion criteria for patients, standard inclusion criteria have yet to be determined. It may be useful to include patients who are likely to benefit the most, i.e., those with long disease duration and a long life expectancy. It is also unclear whether or not a test period with a nasoduodenal tube prior to placement of the gastrostomy tube is necessary. Although we used a test period, it may not be indicated since patients who are levodopa responsive are likely to respond well to this treatment. We are also planning to study increasing the continuous infusion from 16 to 24 h because the benefit on sleeping at night appears to be variable with the interrupted infusion. There are also some technical issues that have yet to be resolved, including the size and weight of the pump. Some patients are relatively frail women aged up to 80 years and the pump is relatively cumbersome and heavy for them to carry. In our experience, patients requested a lighter, more portable pump. Another important issue is the need for an efficient hospital team to carry out the procedure. However, it is likely that as this treatment becomes more widespread, improvements will be made to equipment and hospital teams will become familiar with the procedure.
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5. Conclusion Apomorphine infusion is easy to perform and the pump that supplies the subcutaneous infusion is light and easy to use. However, the effectiveness of apomorphine has been demonstrated only in open-label studies and it does not appear to improve dyskinesia. In addition, patients must still continue to take oral levodopa. Both continuous duodenal levodopa administration and STN-DBS provide significant motor benefit, but DBS is more invasive and evidence is accumulating that the behavioural and cognitive changes associated with DBS may not be reversible. In contrast, duodenal levodopa administration in this group of patients produced no abnormal changes in behaviour or cognition. In addition, our 6-month follow-up results show that levodopa infusion can lead to significant clinical benefit and that a therapeutic window can be identified even in complicated PD patients. According to our experience, duodenal levodopa infusion should be considered in PD patients with advanced disease and motor complications that cannot be controlled with standard oral treatment. Conflict of interest The author has declared no conflict of interest. References [1] Jankovic J. An update on the treatment of Parkinson’s disease. Mt Sinai J Med 2006;73(4):682–9. [2] Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, BronteStewart H, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2006;66(7):983–95. [3] Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W, Stocchi F, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, lasting effect in adjunct therapy with Rasagiline given once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365(9463):947–54. [4] Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16(3):448–58. [5] Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 2005;20(2):224–30. [6] Deleu D, Hanssens Y, Northway MG. Subcutaneous apomorphine: an evidence-based review of its use in Parkinson’s disease. Drugs Aging 2004;21(11):687–709. [7] Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up. J Neurol Neurosurg Psychiatry 1998;65(5):709–16. [8] 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 followup. Mov Disord 2002;17(1):188–91. [9] Stibe CM, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in parkinsonian on–off oscillations. Lancet 1988; 1(8582):403–6.
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