Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson's disease

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Parkinsonism and Related Disorders 13 (2007) S18–S23 www.elsevier.com/locate/parkreldis

Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson’s disease Erik Ch Wolters Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands

Abstract Patients receiving oral levodopa, the standard treatment for Parkinson’s disease (PD), eventually develop motor fluctuations and dyskinesias. Treatment options for patients with these symptoms include high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) or continuous dopaminergic stimulation (CDS). STN-DBS is the prevalent surgical therapy for PD and has shown efficacy, but behavioural disorders, including cognitive problems, depression and suicidality have been reported. CDS can be achieved with oral dopamine agonists with a long half-life, transdermal or subcutaneous delivery of dopamine agonists, or intestinal levodopa infusion. Of these, duodenal levodopa infusion appears to be the most promising option in terms of both efficacy and safety. r 2007 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Treatment options; Deep brain stimulation; Continuous dopaminergic stimulation

1. Introduction Parkinson’s disease (PD) is caused by a progressive synucleinopathy starting in the lower brainstem and expanding via the mesencephalon into the neocortex [1]. Motor symptoms of the disease including bradykinesia, hypokinesia, rigidity and tremor, and non-motor symptoms such as sensory, mood, cognition and thought disorders are caused by disintegration of brainstemlocalized neurotransmitter systems [2]. In PD, motor parkinsonism is the clinical manifestation of a significant striatal dopaminergic denervation, caused by degeneration of the nigral dopamine-producing cells. Current treatment of PD is focused on the symptomatic relief of motor parkinsonism. The dopamine precursor levodopa effectively treats motor, and to some extent nonmotor, symptoms of the disease and has been the standard of treatment since its introduction more than 35 years ago [3]. The nausea and vomiting that can be induced by levodopa is reduced by coadministration of peripheral decarboxylase inhibitors, allowing more efficient delivery of levodopa to the brain. Tel.: +31 20 4444444; fax: +31 20 4442800.

E-mail address: [email protected] 1353-8020/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2007.06.006

Among patients who have taken levodopa for 5 years, approximately half begin to suffer from motor fluctuations and dyskinesia [4,5]. After 9 years of treatment, up to 70% of patients may be affected [6]. Motor fluctuations include a shortening of the period of dose effectiveness with early recurrence of symptoms (wearing off), sudden, unpredictable motor symptoms that occur before the expected wearing-off effect (on–off phenomenon) and increases in the period of time before the levodopa dose becomes active (delayed on). The involuntary movements of dyskinesia typically occur when the levodopa dose is at its peak. The wearing-off effect is usually the first motor fluctuation to manifest and is postulated to be related to the loss of levodopa buffering capacity as striatal dopaminergic terminals continue to degenerate [7]. As a result, patients have to take levodopa more frequently and the therapeutic effect becomes increasingly dependent on plasma levels of the drug. Instead of normal physiological activity-related dopaminergic stimulation of the postsynaptic dopamine receptors, there will be a gradually increasing discontinuous and pulsatile, non-physiological but levodopa dosingrelated stimulation [8–10] with fluctuations due to unavoidable low plasma levels. Probably due to this process, gradually neuroplastic changes in the striatal output neurons, with sensitization and/or tolerance, may

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occur, which manifest with pharmacodynamic, levodopa dose-related dyskinesia. Treatment of patients with advanced, levodopa-responsive PD, who have developed motor fluctuations and dyskinesias, remains difficult. These complications can cause significant disability and reduce the patient’s quality of life [11]. Treatment options for patients who have reached this stage theoretically include high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) or continuous (tonic) dopaminergic stimulation (CDS). This paper will discuss these treatment choices and assess their relative importance. 2. Deep brain stimulation Since 1993, high-frequency STN-DBS has been the prevalent surgical therapy for PD. The rationale for DBS is that PD-related striatal dopamine deficiency leads to abnormal neural transmission from the STN-DBS [12]. STN-DBS interrupts this abnormal activity and thus improves motor symptoms of PD. The procedure involves implanting electrodes into the brain, which are connected to a pulse generator that is externally programmed. DBS not only reduces the need for levodopa, but it may also bring down the incidence of related motor complications and dyskinesias. As a rule, STN-DBS improves motor parkinsonism and reduces dyskinesia by at least 50% and overall improvement is sustained at least for 4 to 5 years [13–16]. There is conflicting evidence, though, on the effect of DBS on PD progression. Ostergaard et al. [14] reported a reduction in off time (67%) and motor fluctuations (90%) with a stable clinical off condition in 22 fluctuating patients who received 48 months of DBS, suggesting that DBS may slow disease progression. In contrast, however, Hilker et al. [17] recently reported more direct evidence of continued disease progression during the first 16 months after successful DBS surgery in 30 patients with advanced PD. Using serial 18F-fluorodopa positron emission tomography, they reported annual progression rates relative to baseline of up to 12% in the caudate and up to 13% in the putamen. These percentages are within the range of previously reported data from longitudinal imaging studies studying the rate of progression in PD [18]. Although DBS produces symptomatic improvements, it is not without risk. DBS is associated with complications related to the surgical procedure, the hardware, and the stimulation itself. Surgery-related complications include transient adverse events that occur at a rate of approximately 15–25% and include delirium, hypomania, hemiparesis, intracerebral haemorrhages and infections like abscess, cellulitis and meningitis [16,19]. Hardware-related problems include electrode migration, lead fracture and device failure [20]. Estimations of the frequency of all these problems vary from group to group based on surgical procedure and experience [21,22]. Problems related to the stimulation itself include poor and non-responders,

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behavioural disorders, dysarthria, eye-lid apraxia and weight gain [12,16]. Among patients complaining of suboptimal results following DBS, one study has reported persistently poor outcomes in 34% of patients despite maximal intervention to correct problems [23]. Behavioural disorders, including cognitive, mood and thought disorders, are commonly reported in patients following STN-DBS and appear to depend on the site of stimulation, pre-existing psychiatric vulnerability, disease progression and the DBS-related decrease in the need for levodopa [16,19,24]. A recent systematic review of 1398 patients with a total cumulative follow-up period of 1480 patient-years reported behavioural changes in about 50% of patients who received DBS to the STN-DBS [24]. The most common changes were cognitive problems, depression, (hypo)mania and anxiety disorders (Table 1). Other symptoms, such as personality changes, hypersexuality, apathy, anxiety and aggressiveness were less common. Both dramatic and delayed mood changes have also been reported. In one case, an acute DBS-induced transient depression disappeared 90 s after stimulation stopped [25], while two studies have reported mood changes leading to transient suicidal behaviour [26] or attempted suicide [27]. In fact, several studies have reported that patients who received successful STN-DBS actually committed suicide [28,29]. One study reported a high suicide rate of 4.3% during the 9-year follow-up of 140 patients who received DBS [28]. Five of these six patients had mood disorders prior to DBS, and all had experienced significant improvement in their motor function following surgery. The authors note that the finding is unusual because a relatively low overall suicide rate has been reported in PD patients compared with the general population [30]. Foncke et al. [29] also reported four suicides (among them only one with pre-existent depression) in 122 patients following DBS surgery. So, in view of the risks associated with STN-DBS, screening for pre-existing psychiatric vulnerability should be a prerequisite in the selection of DBS patients. However, given the high prevalence of psychiatric symptoms in patients with PD, this may result in an increase in relative contra-indications for DBS. Depression has been shown to

Table 1 Incidence of cognitive and behavioural problems associated with STNDBS (n ¼ 1398) [24] Problem

Incidence (%)

Cognitive problems Depression (Hypo)mania Anxiety disorders Personality changes Hypersexuality Apathy Anxiety Aggressiveness

41 8 4 o2 o0.5 o0.5 o0.5 o0.5 o0.5

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occur more often in patients with PD than in age-matched individuals [31], and in a recent pre-surgery screening program 78% of patients presenting for DBS surgery had at least one psychiatric diagnosis: depression was found in 60% of patients, psychosis in 35% and anxiety in 40% [32]. Therefore, patients should be evaluated carefully prior to DBS procedures and then monitored postoperatively if surgery is indicated. In addition, caregivers should be aware of the extent of possible behavioural changes, and a risk/benefit evaluation should be performed for individual patients. 3. Continuous dopaminergic stimulation As described above, the motor fluctuations and dyskinesias typically found in patients taking long-term levodopa are thought to be related to non-physiological, levodopa dose-related, pulsatile stimulation of dopaminergic receptors. Consequently, therapies that offer more continuous, non-pulsatile stimulation that mimics the physiological state have the potential to prevent and/or alleviate these conditions. In addition to improving the motor fluctuations and dyskinesia associated with long-term oral levodopa treatment, CDS also has the potential to treat other PD-related symptoms. These include restless leg syndrome and sleep disorders, which are caused by offrelated motor and non-motor Parkinsonism [33,34]. Other off-related symptoms include fatigue, daytime sleepiness and decreased functioning in the morning [33,35], distress and depression [36] and cognitive impairment (inattention, poor memory and predisposition to accidents) [34,36,37]. Several different therapies have been examined with the potential to provide CDS (Table 2), including oral dopamine agonists with a long half-life, continuous transdermal or subcutaneous delivery of dopamine agonists, and intestinal levodopa infusion. 4. Pergolide and cabergoline The long-acting dopamine agonists, pergolide and cabergoline, are recommended as adjuncts to levodopa to Table 2 Potential therapies for continuous dopaminergic stimulation Drug

Pharmacokinetics T1/2 (h) a

Pergolide Cabergolinea Rotigotine patchesb Lisuride patchesb Apomorphine infusionc Levodopa/carbidopa a

Fibrotic valvular heart complications. Limited clinical experience. c Subcutaneous necrosis. b

15–27 100 Continuous Continuous Continuous Continuous

transdermal transdermal subcutaneous duodenal

reduce off time in patients with motor fluctuations and dyskinesia [38]. However, neither agent provides true continuous stimulation of dopamine receptors. Patients with advanced PD who received pergolide as an adjunct to levodopa in one double-blind, placebo-controlled study experienced improvements in off time compared with the control group, reflecting the longer half-life of the drug. However, 62% of patients also had new onset or worsening dyskinesia [39]. Cabergoline as an adjunct to levodopa has also shown efficacy for advanced PD in clinical trials [40,41]. Both pergolide and cabergoline, though, have been associated with serious fibrosis in the chest cavity and heart valves, making them less attractive therapeutical tools [42].

5. Transdermal rotigotine and lisuride There is currently limited clinical experience with transdermal formulations of the dopamine agonists, rotigotine and lisuride. A daily transdermal formulation rotigotine was given to patients with advanced PD in two double-blind, placebo-controlled clinical trails that each included more than 200 patients but have appeared only as abstracts [43,44]. All patients received levodopa. One trial had a large placebo effect resulting in no significant difference in off time between rotigotine and placebo [44], while the other reported an improvement [43]. Application site reactions were common in all studies with transdermal rotigotine, with an incidence of approximately 60% at the highest dose [45]. Lisuride is currently under investigation as the active ingredient in a 7-day patch. As of yet, no data are available dealing with the effect of both drugs on dyskinesia.

6. Subcutaneous apomorphine Apomorphine is one of the most potent short-acting dopamine agonists. Continuous application of subcutaneous apomorphine has been examined in a number of long-term clinical studies in advanced PD, but all were small, open-label and uncontrolled. Overall, these trials included 233 patients and reported decreases in off time, reductions in levodopa requirements and improvements in dyskinesia relative to baseline [46]. However, in a recent comparative trial, subcutaneous apomorphine was found to be less effective at reducing off-time (51% vs. 76%), dyskinesia (0% vs. 81%) and dopaminergic medications (30% vs. 63%) than STN-DBS [47]. Unfortunately, apomorphine is also associated with psychiatric complications [48]. Following apomorphine injection, 15 of 19 patients in one trial also developed abdominal cutaneous nodules at the needle site and four developed abdominal wall scarring with ulceration [49]. Overall, subcutaneous nodules have been reported in approximately 70% of patients receiving continuous apomorphine [46].

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7. Continuous duodenal levodopa infusion Despite the development of a range of new medications for PD, levodopa remains the gold standard treatment. When combined with decarboxylation inhibitors, gastrointestinal side effects are minimised and delivery to the brain is facilitated. The only serious drawback to oral levodopa therapy is the inevitable development of motor fluctuations and dyskinesia after long-term use. Since these adverse events are now thought to result from the noncontinuous, pulsatile stimulation of dopamine receptors

Fig. 1. Continuous duodenal delivery of levodopa. After an initial test period with a nasogastric tube, the drug is delivered to the duodenum via a gastrostomy tube and controlled with a portable pump [51].

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that occurs when levodopa, due to its short half-life, is ingested intermittently, it might be postulated that they should be alleviated if the plasma concentration of levodopa is maintained at a constant level. This can be provided by duodenal levodopa infusion. Continuous duodenal levodopa infusion involves the use of a programmable external pump to deliver a levodopa/ carbidopa gel directly into the duodenum via a gastrostomy tube (Fig. 1). The tube is inserted through the abdominal wall during a minor surgical procedure. Insertion of the tube into the duodenum avoids absorption problems that may be encountered in the stomach due to delayed gastric emptying, which is common in PD and may contribute to drug response fluctuations [50]. The most common adverse events with this technique mainly involve displacement of the inner tube and sporadic tube blockages, which are readily resolved [51]. A displaced tube can be repositioned under radiographic control, while blockages can be removed by flushing the tube with water. Clinical experience with continuous duodenal levodopa infusion has demonstrated that patients have more stable plasma levels of levodopa compared with oral doses and that low plasma levels can be avoided [52]. Patients also experienced significant improvements in off time, on time without dyskinesia and dyskinesia severity compared with oral levodopa [53–55]. Long-term use of this technique for up to 10 years has demonstrated continuing reductions in off time and dyskinesia [55,56]. In addition, patients reported a higher quality of life and greater satisfaction with their motor functioning when treated with the enteral formulation compared with an individualised oral drug

Table 3 Comparison between deep brain stimulation and continuous duodenal levodopa infusion [12–14,16,20,24,51,54,56,57]

Treatment Procedure Treatment control Titration Clinical efficacy

Adverse events

Technical issues

STN-DBS

Duodenal levodopa/carbidopa

High-frequency, pulsatile mono or bipolar electrical stimulation of the brain Neurosurgical placement of electrodes in the subthalamic nucleus Battery-operated pulse generator subcutaneously implanted near the clavicle Frequent adjustments over initial 3-month period; optimal programming can take up to a year Improved control of bradykinesia, dyskinesia and motor fluctuations Other PD treatments required to alleviate uncontrolled symptoms, including oral levodopa Some patients are poor or non responders Surgery-related complications, including infection, haemorrhage, delirium and hypomania Behavioural and cognitive impairment, including suicidality Weight gain Dysarthria, diplopia and paraesthesia The battery in the pulse generator must be replaced after 3–8 years, requiring re-implantation of the unit Other magnetic devices (e.g. security scanners, refrigerators) may interfere with the functioning of the neurostimulator Electrode migration, lead fracture and device failure

Continuous duodenal delivery of carbidopa/levodopa gel Percutaneous endoscopic gastrostomy for placement of small tube into the duodenum Pump worn outside the body Titration to optimal dose achievable within 1 week Improved control of bradykinesia, dyskinesia and motor fluctuations Other PD treatments can be eliminated

Complications related to the central pharmacological activity of dopamine (avoidable by reducing levodopa dosage) Skin inflammation around the stoma

Pump may be cumbersome for some patients Sporadic blockages of tubes Displacement of the inner tube requiring repositioning Leakage in tube conections

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combination [57]. As enteric levodopa infusions did not permit a reduction of the foregoing daily oral levodopa loading, it might be argued that the reduction of dyskinesia is not the consequence of a levodopa-sparing effect [10] (as suggested by the fact that levodopa-sparing strategies with dopamine agonists also come with a reduction of dyskinesia), and thus might be rather considered the consequence of an effect on neural plasticity. Compared with STN-DBS, continuous duodenal levodopa infusion requires a less invasive surgical technique and reaches optimal clinical efficacy more quickly (Table 3). Unlike DBS, there are no significant contra-indications for CDS treatment with duodenal levodopa and, due to its more physiological dopamine receptor stimulating profile, it is not to be expected that it will cause significant adverse effects and/or mental changes. In fact, analysis of clinical data demonstrates that patients with more severe symptoms at baseline were most improved after infusion [58]. Clinical studies with duodenal levodopa infusion are ongoing.

[6]

[7]

[8] [9]

[10] [11]

[12]

[13]

[14]

8. Conclusions Of the treatment options available for advanced PD, CDS appears to hold the most promise. Although DBS has provided clinical efficacy in terms of reduced off time, there is increasing concern that patients with existing psychiatric diagnoses may not be suitable candidates for this therapy. Since depression and other psychiatric conditions are present in the majority of PD patients, DBS may be contra-indicated in all but a minority of patients. In the other patients, CDS can provide symptomatic relief and does not appear to have any major contra-indications. Of the available techniques that provide CDS, continuous duodenal levodopa infusion appears to be the most promising in terms of both efficacy and safety. Further experience with these various novel strategies however, should reveal their relative efficacy and safety compared with DBS. Conflict of Interest

[15]

[16]

[17]

[18]

[19]

[20]

E. Ch Wolters only received lecture fees and does not have any other potential conflict of interest.

[21]

References

[22]

[1] Cookson MR. The biochemistry of Parkinson’s disease. Ann Rev Biochem 2005;74:29–52. [2] Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363(9423):1783–93. [3] Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs. later L-DOPA. Arch Neurol 1999; 56(5):529–35. [4] Poewe WH, Lees AJ, Stern GM. Dystonia in Parkinson’s disease: clinical and pharmacological features. Ann Neurol 1988;23(1):73–8. [5] Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with

[23]

[24]

early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342(20):1484–91. 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. Jankovic J. Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord 2005;20(Suppl 11): S11–6. Chase TN. The significance of continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Drugs 1998;55(Suppl 1):1–9. Abercrombie ED, Bonatz AE, Zigmond MJ. Effects of L-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats. Brain Res 1990;525(1):36–44. Nutt JG. Continuous dopaminergic stimulation: is it the answer to the motor complications of Levodopa? Mov Disord 2006. 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. Ashkan K, Wallace B, Bell BA, Benabid AL. Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease 1993–2003: where are we 10 years on? Br J Neurosurg 2004;18(1):19–34. 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. Ostergaard K, Sunde N, Dupont E. Effects of bilateral stimulation of the subthalamic nucleus in patients with severe Parkinson’s disease and motor fluctuations. Mov Disord 2002;17(4):693–700. 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. Schupbach WM, Chastan N, Welter ML, Houeto JL, Mesnage V, Bonnet AM, et al. Stimulation of the subthalamic nucleus in Parkinson’s disease: a 5 year follow up. J Neurol Neurosurg Psychiatry 2005;76(12):1640–4. Hilker R, Portman AT, Voges J, Staal MJ, Burghaus L, van LT, et al. Disease progression continues in patients with advanced Parkinson’s disease and effective subthalamic nucleus stimulation. J Neurol Neurosurg Psychiatry 2005;76(9):1217–21. Winogrodzka A, Booij J, Wolters EC. Disease-related and druginduced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson’s disease. Parkinsonism Relat Disord 2005;11(8): 475–84. De Almeida AN, Olivier A, Quesney F, Dubeau F, Savard G, Andermann F. Efficacy of and morbidity associated with stereoelectroencephalography using computerized tomography or magnetic resonance imaging-guided electrode implantation. J Neurosurg 2006;104(4):483–7. Joint C, Nandi D, Parkin S, Gregory R, Aziz T. Hardware-related problems of deep brain stimulation. Mov Disord 2002;17(Suppl 3):S175–80. Amirnovin R, Williams ZM, Cosgrove GR, Eskandar EN. Experience with microelectrode guided subthalamic nucleus deep brain stimulation. Neurosurgery 2006;58(1 Suppl):ONS96–ONS102. Voges J, Waerzeggers Y, Maarouf M, Lehrke R, Koulousakis A, Lenartz D, et al. Deep-brain stimulation: long-term analysis of complications caused by hardware and surgery—experiences from a single centre. J Neurol Neurosurg Psychiatry 2006;77(7): 868–72. Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, et al. Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. Arch Neurol 2005;62(8):1250–5. Temel Y, Kessels A, Tan S, Topdag A, Boon P, Visser-Vandewalle V. Behavioural changes after bilateral subthalamic stimulation in advanced Parkinson disease: a systematic review. Parkinsonism Relat Disord 2006;12(5):265–72.

ARTICLE IN PRESS E. Ch Wolters / Parkinsonism and Related Disorders 13 (2007) S18–S23 [25] Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, et al. Transient acute depression induced by high-frequency deepbrain stimulation. N Engl J Med 1999;340(19):1476–80. [26] Berney A, Vingerhoets F, Perrin A, Guex P, Villemure JG, Burkhard PR, et al. Effect on mood of subthalamic DBS for Parkinson’s disease: a consecutive series of 24 patients. Neurology 2002;59(9): 1427–9. [27] 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. [28] 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. [29] Foncke E, Colle H, Alessi G, Verlinden C. Diepe hersenstimulatie bij bewegingsstoornissen: chronische stimulatie gerelateerde complicaties als uitgangspunt voor toekomstige onderzoeksprojecten. PBF Nederland: Bewegingsstoornissen in de lage landen; 2003. [30] Myslobodsky M, Lalonde FM, Hicks L. Are patients with Parkinson’s disease suicidal? J Geriatr Psychiatry Neurol 2001;14(3): 120–4. [31] Ehmann TS, Beninger RJ, Gawel MJ, Riopelle RJ. Depressive symptoms in Parkinson’s disease: a comparison with disabled control subjects. J Geriatr Psychiatry Neurol 1990;3(1):3–9. [32] 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. [33] Lees AJ, Blackburn NA, Campbell VL. The nighttime problems of Parkinson’s disease. Clin Neuropharmacol 1988;11(6):512–9. [34] Chaudhuri KR, Pal S, Bridgman K, Trenkwalder C. Achieving 24-hour control of Parkinson’s disease symptoms: use of objective measures to improve nocturnal disability. Eur Neurol 2001;46(Suppl 1):3–10. [35] Tandberg E, Larsen JP, Karlsen K. Excessive daytime sleepiness and sleep benefit in Parkinson’s disease: a community-based study. Mov Disord 1999;14(6):922–7. [36] Karlsen K, Larsen JP, Tandberg E, Jorgensen K. Fatigue in patients with Parkinson’s disease. Mov Disord 1999;14(2):237–41. [37] Ondo WG, Dat VK, Khan H, Atassi F, Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology 2001;57(8):1392–6. [38] 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. [39] Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig H, Stern M, et al. A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson’s disease. Mov Disord 1994;9(1):40–7. [40] Hutton JT, Koller WC, Ahlskog JE, Pahwa R, Hurtig HI, Stern MB, et al. Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson’s disease. Neurology 1996; 46(4):1062–5. [41] Ahlskog JE, Wright KF, Muenter MD, Adler CH. Adjunctive cabergoline therapy of Parkinson’s disease: comparison with placebo and assessment of dose responses and duration of effect. Clin Neuropharmacol 1996;19(3):202–12. [42] Peralta C, Wolf E, Alber H, Seppi K, Muller S, Bosch S, et al. Valvular heart disease in Parkinson’s disease vs. controls: an echocardiographic study. Mov Disord 2006;21(8):1109–13.

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[43] LeWitt P, Chang F-L, Fazzini E. Rotigotine transdermal system in treatment of patients with advanced-stage Parkinson’s disease. In: Ninth Congress of the European Federation of Neurological Societies, 17–20 September. 2005. [44] Quinn NP. Rotigotine transdermal delivery system (TDS) (SPM 962)a multicenter, double blind, randomized, placebo-controlled trial to asses the safety and efficacy of rotigotine TDS in patients with advanced Parkinson’s disease. Parkinsonism Relat Disord 2001; 7(Suppl 1):S66. [45] Reynolds NA, Wellington K, Easthope SE. Rotigotine: in Parkinson’s disease. CNS Drugs 2005;19(11):973–81. [46] 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. [47] De GD, 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. [48] 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. [49] Colzi A, Turner K, Lees AJ. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998;64(5):573–6. [50] Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2003;2(2):107–16. [51] Odin P, Russmann A, Aquilonius SM. [Pump-driven continuous duodenal delivery of levodopa: a new therapy for patients with advance Parkinson’s Disease]. Psychopharmakotherapie 2005;12(6): 223–8. [52] Stocchi F, Vacca L, Ruggieri S, Olanow CW. Intermittent vs. continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 2005;62(6):905–10. [53] Stocchi F, Vacca L, Ruggieri S, Olanow CW. Intermittent vs. continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 2005;62(6):905–10. [54] 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. [55] Syed N, Murphy J, Zimmerman Jr. T, Mark MH, Sage JI. Ten years’ experience with enteral levodopa infusions for motor fluctuations in Parkinson’s disease. Mov Disord 1998;13(2):336–8. [56] Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infusion in Parkinson’s disease—long-term experience. Acta Neurol Scand 2001;104(6):343–8. [57] 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. [58] Westin J, Nyholm D, Groth T, Dougherty MS, Yerramsetty PK, Palhagen SE. Outcome prediction of enteral levodopa/carbidopa infusion in advanced Parkinson’s disease. Parkinsonism Relat Disord 2006;12(8):509–13.