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Parkinson's Disease
Volume 2011 (2011), Article ID 485063, 6 pages
http://dx.doi.org/10.4061/2011/485063
Review Article

Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease

1Department of Neurology, The Ohio State University, Columbus, OH 43210, USA
2Division of Neurology, Duke University Medical Center, Durham, NC 27705, USA

Received 15 October 2010; Accepted 14 February 2011

Academic Editor: Irena Rektorova

Copyright © 2011 Ariane Park and Mark Stacy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease.

1. Neuropsychiatric

Hallucinations and psychosis have long been known to be associated with dopaminergic therapy. Psychosis in PD refers to the combination of chronic hallucinations and delusions occurring in the setting of otherwise clear senses. Hallucinations can involve various sensory modalities; however, visual hallucinations are the most common. Some may be benign and nonbothersome, while others can be terribly frightening to patients. Risk factors for developing hallucinations include older age, longer duration of PD, history of sleep disorder, depression, and coexisting cognitive impairment [1, 2]. Interestingly, there has been no evidence that increased dose or specific dopaminergic drug class (agonists versus L-dopa) is related to this problem [1, 3], and it is clear that hallucinations and psychosis are not just mere side effects of treatment. The likely pathogenesis is multifactorial involving pharmacologic mechanisms in conjunction with disease-related elements. Treatment for chronic hallucinations includes reduction of dopaminergic medications and discontinuation of anticholinergics or other drugs. If needed, antipsychotic medications may be used. Clozapine has demonstrated efficacy in a double-blind placebo-controlled trial [4]; however, in clinical practice quetiapine is preferred, despite the fact that, it has not been proven more effective than placebo in clinical trials [57].

Dopaminergic medications, particularly dopamine agonists [8], are known to be associated with impulse control disorders, with no differences seen between specific drugs [9, 10]. The prevalence of any ICD in PD patients on dopamine agonists ranges from 13.7 to 17.1% [11]. The formal definition for impulse control disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) is a group of psychiatric disorders characterized five stages of symptomatic behavior. Essential to this is “a failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others.” Patients feel an increasing sense of tension or arousal before the act, experience pleasure, gratification, or relief while committing the act, and finally feel a sense of relief from the urge after the act. Individuals may or may not feel regret, self-reproach, or guilt about these activities [12]. Pathological gambling (PG) is the most extensively studied ICD in PD, first noted in 2003 by Driver-Dunckley et al. [13] in a retrospective study of 1,884 patients. The essential feature of pathological gambling is that it is a “persistent and recurrent maladaptive gambling behavior that disrupts personal, family, or vocational pursuits” [12]. A recent prospective study of 200 PD patients reported a prevalence of PG to be as high as 7% [14]. Compulsive sexual behavior or hypersexuality as well as compulsive buying are not formally defined in the DSM-IV-TR. However, they are easily identified problems once patients cross the threshold of reasonable urge into compulsions leading to personal, familial, and/or occupational suffering and consequences. Hypersexuality can include not only increased libido, but also exhibitionism, excessive masturbation, phone/internet sex, use of prostitutes, and new sexual orientations. More seriously, criminal behaviors such as rape, pedophilia, and incest have been reported [15]. Hypersexuality can be seen in up to 4% of PD patients [16]. Compulsive buying of items that are unnecessary and go unused (i.e., shirts, shoes, jewelry) has been reported in up to 5.7% of PD patients [17] and often leads to financial distress. These patients tend to have traits of both obsessive-compulsive and impulse control disorders [18]. Binge eating is a proposed diagnosis in the DSM-IV-TR as an eating disorder marked by “uncontrolled eating of food that is larger in amount than most people would eat in a similar period of time under similar circumstances, without emesis or laxative abuse” [12]. Patients have a sense of lack of control over eating during the episode, and some report nocturnal awakening with an extreme sweet craving, eating excessive amounts. This has been reported in 4.3% of PD patients [17]. Punding refers to stereotypic, complex, and repetitive behavior involving meaningless activities (i.e., examining, sorting, collecting, arranging, dismantling objects) sometimes to the point of ignoring basic needs such as eating and sleeping. Patient may be irritable when interrupted, and this behavior can lead to social avoidance and isolation. Interestingly, participating in these activities may or may not be enjoyable for patients. One study involved demonstrated a punding prevalence of 1.4% in an ambulatory PD population [19], but it has been reported to be as high as 14% [20].

Dopamine dysregulation syndrome (DDS), also known as hedonistic homeostatic dysregulation (HHD), is a neuropsychiatric disorder characterized by addiction, self-medication, and escalation of antiparkinsonian medication. It is thought to have a prevalence of approximately 3.4% [21]. Not all patients with DDS have an ICD, although the majority of patients with DDS also exhibit punding [22]. Unlike ICD, DDS is typically associated with levodopa or short-acting dopamine agonist medications (i.e., subcutaneous apomorphine) [23], although it has been described with ergot- and nonergot-derived dopamine agonists as well [24]. These patients often do not have insight into the problem and will often take larger- than-recommended total daily doses, far beyond what is necessary for their motor disabilities. Unfortunately, they do not recognize the harm it is causing to themselves and their loved ones and demand increasing quantities of medication despite the development of complications (i.e., dyskinesia, “off” state dysphoria). Attempts to reduce the dose are met with great resistance, making management quite difficult.

DDS behaviors can be viewed as both a substance dependence disorder and an addiction. In fact, the term hedonic homeostatic dysregulation was coined based on the addiction model that addicts take drugs not only for pleasure but also to avoid unpleasant withdrawal symptoms [25, 26]. Other theories of psychostimulant addiction including pleasure seeking, habit models, and chronic neuroadaptations induced in the ventral striatum and nucleus accumbens may help to explain DDS [24]. Supportive of addiction theories, one study utilizing positron emission tomography (PET) showed that PD patients with DDS had enhanced levodopa-induced ventral striatal dopamine release, perhaps due to sensitization, compared with levodopa-treated patients with PD who did not have DDS [27]. In fact, it has been theorized that the pulsatile stimulation of striatal dopamine receptors inherent in the oral delivery of dopamine may cause changes in the basal ganglia circuitry leading to sensitization [28], leading to motor fluctuations, dyskinesia, and possibly even DDS. Interestingly, patients without PD but treated with dopaminergic therapy for restless legs syndrome have also been reported to have DDS, indicating that drug exposure itself plays a physiologic role, perhaps in triggering these behaviors [13, 29].

Treatment for these impulse control disorders starts with recognizing that they exist. It is important for physicians to be aware of these neuropsychiatric side effects of dopaminergic therapy and to actively screen for them, as patients often do not volunteer the information either because they do not have insight into these issues, they are in denial, or they are embarrassed. This is where family/caregiver input can be particularly helpful. One study found that only 25% of PD patients with an active ICD were identified clinically [9]. The risk factor profile of these patients includes male gender, early-onset PD, novelty-seeking personality, history of substance dependence, history of depression, high alcohol intake, and early emergence of dyskinesia [3032]. Once identified, a thorough review of the patient’s mediations is warranted, followed by a systematic reduction or cessation of dopaminergic treatment. For ICDs, this would involve dopamine agonists. If parkinsonism worsens, it may be prudent to concomitantly increase levodopa. In DDS, the strategy is reversed and levodopa is the initial agent to wean, with a subsequent increase in dopamine agonist treatment. However, as previously mentioned, patients with DDS often are not complaint with this, and therefore counseling with both the patients and their families/caregivers is important. As far as additional pharmacologic options, antidepressants for obsessive thoughts and antiandrogens to help decrease hypersexuality may be considered. A recent study found amantadine to be effective in the treatment of pathological gambling in PD [33]. Deep brain stimulation to the subthalamic nucleus may allow dopaminergic drug reduction and therefore improvement in these symptoms [34, 35] although DDS and ICDs may worsen or develop for the first time after DBS surgery [36].

2. Autonomic

Nausea is very commonly associated with dopamineric therapy. It is thought to result from stimulation of the area postrema [37]. Orthostatic hypotension and constipation may be intrinsic to neurodegenerative changes related to PD, but these can clearly worsen with dopaminergic therapy. Higher rates of constipation and nausea have been seen in patients treated with dopamine agonists versus levodopa [38], suggesting that the different pharmacodynamic properties of the various dopamine formulation may contribute to adverse effects. Autonomic symptoms in PD are attributed to the involvement of the central and peripheral postganglionic autonomic nervous system. Constipation in PD may be attributed to Lewy body pathology in the myenteric plexus and colonic sympathetic denervation. These symptoms are exceedingly common. One study found that 60% of patients had orthostatic hypotension early in the course of the disease [39], and 58% of PD patients may experience constipation [40].

In the vast majority of cases, nausea subsides with a slow titration up on dosage, with the addition of carbidopa or domperidone, a peripheral dopamine receptor blocking agent, or taking dopaminergic medications with food.

Conservative measures for the treatment of orthostatic hypotension include increasing salt and fluid intake, elevating the head of the bed (>30 degree incline), and the use of thigh and abdominal compression bands. Patients should be advised to avoid Valsalva maneuvers, warm temperatures, and meals rich in carbohydrates and alcohol, as these may be triggers. Pharmacologic treatments include fludrocortisone, a salt-retaining mineralocorticoid, midodrine, a selective peripherally acting α-adrenergic agent, and droxidopa, an orally active synthetic precursor of norepinephrine [41]. Pyridostigmine has been found to be effective in neurogenic orthostatic hypotension but has not been formally tested in PD [42]. Reduction in dopaminergic medication may be warranted if these medications are not tolerated or if orthostatic hypotension is severe.

Nonpharmacologic treatments for constipation include regular exercise, adequate water intake, and diet including symbiotic yogurts containing Bifidobacterium, fructoligosaccharide, and bulking agents (fibers, psyllium, and polycarbophil). A dietary herb extract, Dai-kenchu-to, has been found to ameliorate PD-related constipation [43]. Osmotic laxatives including magnesium sulfate and polyethylene glycol can be effective. Other laxatives include lubiprostone [44] and macrogol [45]. Serotonergic agents such as cisapride [46], mosapride citrate [47], tegaserod [48], and pyridostigmine [49], an acetylcholinesterase inhibitor, have been shown to be beneficial as well. Constipation in PD may be associated with focal dystonia of the puborectalis muscle, and botulinum toxin A injections to the puborectalis muscle have demonstrated clinical benefit [50]. Sacral nerve stimulation has shown some promise [51]; however, it has not been extensively studied and is not widely used. Reduction of dopaminergic medications, amantadine, and anticholinergics should also be considered. Highlighting the complexity of the pathophysiology involved in PD-related constipation, some dopaminergic agents such as apomorphine [52] and intrajejunal continuous infusion of levodopa [53] can improve constipation and bowel dysfunction.

3. Sleep

Sleep dysfunction is very common in PD, seen in 60–98% of patients [54], and if severe enough can lead to decreased quality of life, impaired function, and caregiver burden. Many sleep problems, are intrinsic to PD, such as fragmented sleep, nighttime sleep problems and daytime sleepiness. Complicating matters, all of these symptoms can be associated with dopaminergic medications [55], and these effects are dose related [56]. Dopaminergic medication is thought to have a desynchronizing effect on sleep architecture that causes disruption of sleep continuity [57]. Low-dose dopamine agonists have been associated with insomnia, whereas higher doses can lead to excessive daytime sleepiness (EDS). EDS has been defined as those patients who are experiencing unusually severe sleepiness during the day, sleeping more than 2 hours in the daytime, or falling asleep three or more times a day [58]. “Sleep attacks,” sudden transitions from wakefulness to sleep without a prodrome, were first described in patients treated with pramipexole or ropinirole [59]. Sleep attacks may be a severe form of excessive daytime sleepiness, and the prevalence in patients treated with dopaminergic medications has been reported to be as high as 43% [60]. While initially associated with dopamine agonists, they can be induced by levodopa as well. One study showed that levodopa monotherapy carries the lowest risk, and combination therapy with levodopa and dopamine agonists has the highest risk [61] of sleep attacks. Drugs that are not associated with excessive daytime sleepiness/sleep attacks include selegiline, amantadine, and entacapone. Selegiline and amantadine have stimulating properties and therefore can induce problems with sleep initiation. Sleep attacks are important to be aware of because these abrupt sleep episodes can have dangerous implications, particularly when driving; thus, it is important to continuously monitor for this side effect.

Management of these sleep issues first begins with education regarding healthy sleep hygiene. Patients should try to maintain regular sleep/wake schedules, exercise regularly, and minimize the use of alcohol and caffeine. Some PD patients have coexisting sleep disorders, including sleep apnea and restless legs syndrome (RLS), and in these cases, a referral to a sleep specialist may be necessary. Physicians should carefully review medication lists and remove those that may be contributing to sleepiness. Medications that may be stimulating should be given earlier in the day. Dopaminergic medication may need to be reduced or discontinued, particularly in cases involving sleep attacks. The use of prolonged release dopamine agonists should be considered, as a recent study using ropinirole prolonged release demonstrated improved subjective quality of sleep, reduced daytime sleepiness, and disappearance of sleep attacks in some PD patients [62]. Possible pharmacologic therapies for daytime sleepiness that have demonstrated benefit in PD patients include methylphenidate [63], modafinil [64], and sodium oxybate [65]. For fragmented sleep and sleep initiation, melatonin, a neurohormone produced in the pineal gland at night, has been shown to improve sleep quality and daytime sleepiness [66]. Patients who have undergone deep brain stimulation (DBS) of the subthalamic nucleus (STN) have reported improvements in nocturnal sleep [67]; however, it is not clear how DBS affects daytime sleepiness.

4. Conclusion

The management of dopamine-induced nonmotor symptoms of PD can be challenging, especially as treatment strategies often involve tapering off of these drugs, and such changes to therapy can worsen motor symptoms (Table 1). However, these effects of dopaminergic therapy are important to recognize given the impact they can have on patients’ quality of life. Hallucinations and psychosis can be frightening to both patients and their loved ones. ICD and DDS can lead to serious personal, social, and financial consequences, and autonomic and sleep symptoms can often be more debilitating than PD motor symptoms themselves. Thus, it is important to exercise sound clinical judgment when initiating and titrating medication and closely monitor patients with the involvement of family and caregivers.

tab1
Table 1: Dopamine-induced nonmotor symptoms of Parkinson’s disease.

References

  1. G. Fénelon, F. Mahieux, R. Huon, and M. Ziégler, “Hallucinations in Parkinson's disease. Prevalence, phenomenology and risk factors,” Brain, vol. 123, part 4, pp. 733–745, 2000. View at Scopus
  2. J. R. Sanchez-Ramos, R. Ortoll, and G. W. Paulson, “Visual hallucinations associated with Parkinson disease,” Archives of Neurology, vol. 53, no. 12, pp. 1265–1268, 1996. View at Scopus
  3. K. M. Biglan, R. G. Holloway Jr., M. P. McDermott, and I. H. Richard, “Risk factors for somnolence, edema, and hallucinations in early Parkinson disease,” Neurology, vol. 69, no. 2, pp. 187–195, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. P. Pollak, F. Tison, O. Rascol et al., “Clozapine in drug induced psychosis in Parkinson's disease: a randomised, placebo controlled study with open follow up,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 75, no. 5, pp. 689–695, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. W. G. Ondo, R. Tintner, K. D. Voung, D. Lai, and G. Ringholz, “Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease,” Movement Disorders, vol. 20, no. 8, pp. 958–963, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. T. A. Zesiewicz, K. L. Sullivan, I. Arnulf et al., “Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology,” Neurology, vol. 74, no. 11, pp. 924–931, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. J. M. Miyasaki, K. Shannon, V. Voon et al., “Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology,” Neurology, vol. 66, no. 7, pp. 996–1002, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. D. Weintraub, J. Koester, M. N. Potenza et al., “Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients,” Archives of Neurology, vol. 67, no. 5, pp. 589–595, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. D. Weintraub, A. D. Siderowf, M. N. Potenza et al., “Association of dopamine agonist use with impulse control disorders in Parkinson disease,” Archives of Neurology, vol. 63, no. 7, pp. 969–973, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. V. Voon, K. Hassan, M. Zurowski et al., “Prospective prevalence of pathologic gambling and medication association in Parkinson disease,” Neurology, vol. 66, no. 11, pp. 1750–1752, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. A. Antonini, E. Tolosa, Y. Mizuno, M. Yamamoto, and W. H. Poewe, “A reassessment of risks and benefits of dopamine agonists in Parkinson's disease,” The Lancet Neurology, vol. 8, no. 10, pp. 929–937, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. American Psychiatric Association, Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders : DSM-IV-TR, vol. 37, American Psychiatric Association, Washington, DC, USA, 4th edition, 2000.
  13. E. Driver-Dunckley, J. Samanta, and M. Stacy, “Pathological gambling associated with dopamine agonist therapy in Parkinson's disease,” Neurology, vol. 61, no. 3, pp. 422–423, 2003. View at Scopus
  14. C. Lu, A. Bharmal, and O. Suchowersky, “Gambling and Parkinson disease,” Archives of Neurology, vol. 63, no. 2, p. 298, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. A. Cannas, P. Solla, G. L. Floris, G. Serra, P. Tacconi, and M. G. Marrosu, “Aberrant sexual behaviours in Parkinson's disease during dopaminergic treatment,” Journal of Neurology, vol. 254, no. 1, pp. 110–112, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. R. Ceravolo, D. Frosini, C. Rossi, and U. Bonuccelli, “Impulse control disorders in Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management,” Parkinsonism and Related Disorders, vol. 15, supplement 4, pp. S111–S115, 2009. View at Publisher · View at Google Scholar
  17. D. Weintraub, “Impulse control disorders in Parkinson's disease: prevalence and possible risk factors,” Parkinsonism and Related Disorders, vol. 15, supplement 3, pp. S110–S113, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. G. A. Christenson, R. J. Faber, M. De Zwaan et al., “Compulsive buying: descriptive characteristics and psychiatric comorbidity,” Journal of Clinical Psychiatry, vol. 55, no. 1, pp. 5–11, 1994. View at Scopus
  19. J. M. Miyasaki, K. Al Hassan, A. E. Lang, and V. Voon, “Punding prevalence in Parkinson's disease,” Movement Disorders, vol. 22, no. 8, pp. 1179–1181, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. A. H. Evans, A. P. Strafella, D. Weintraub, and M. Stacy, “Impulsive and compulsive behaviors in Parkinson's disease,” Movement Disorders, vol. 24, no. 11, pp. 1561–1570, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. F. R. Pezzella, C. Colosimo, N. Vanacore, et al., “Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson's disease,” Movement Disorders, vol. 20, no. 1, pp. 77–81, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. A. H. Evans, R. Katzenschlager, D. Paviour et al., “Punding in Parkinson's disease: its relation to the dopamine dysregulation syndrome,” Movement Disorders, vol. 19, no. 4, pp. 397–405, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. D. A. Gallagher, S. S. O'Sullivan, A. H. Evans, A. J. Lees, and A. Schrag, “Pathological gambling in Parkinson's disease: risk factors and differences from dopamine dysregulation. An analysis of published case series,” Movement Disorders, vol. 22, no. 12, pp. 1757–1763, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. A. D. Lawrence, A. H. Evans, and A. J. Lees, “Compulsive use of dopamine replacement therapy in Parkinson's disease: reward systems gone awry?” Lancet Neurology, vol. 2, no. 10, pp. 595–604, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. G. F. Koob and M. Le Moal, “Drug addiction, dysregulation of reward, and allostasis,” Neuropsychopharmacology, vol. 24, no. 2, pp. 97–129, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. G. Giovannoni, J. D. O'Sullivan, K. Turner, A. J. Manson, and A. J. L. Lees, “Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies,” Journal of Neurology Neurosurgery and Psychiatry, vol. 68, no. 4, pp. 423–428, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. A. H. Evans, N. Pavese, A. D. Lawrence et al., “Compulsive drug use linked to sensitized ventral striatal dopamine transmission,” Annals of Neurology, vol. 59, no. 5, pp. 852–858, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. J. G. Nutt, “Continuous dopaminergic stimulation: is it the answer to the motor complications of levodopa?” Movement Disorders, vol. 22, no. 1, pp. 1–9, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. S. Leu-Semenescu, E. Karroum, A. Brion, E. Konofal, and I. Arnulf, “Dopamine dysregulation syndrome in a patient with restless legs syndrome,” Sleep Medicine, vol. 10, no. 4, pp. 494–496, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. A. H. Evans, A. D. Lawrence, J. Potts, S. Appel, and A. J. Lees, “Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson disease,” Neurology, vol. 65, no. 10, pp. 1570–1574, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. V. Voon, T. Thomsen, J. M. Miyasaki et al., “Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease,” Archives of Neurology, vol. 64, no. 2, pp. 212–216, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. L. Silveira-Moriyama, A. H. Evans, R. Katzenschlager, and A. J. Lees, “Punding and dyskinesias,” Movement Disorders, vol. 21, no. 12, pp. 2214–2217, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. A. Thomas, L. Bonanni, F. Gambi, A. Di Iorio, and M. Onofrj, “Pathological gambling in parkinson disease is reduced by amantadine,” Annals of Neurology, vol. 68, no. 3, pp. 400–404, 2010. View at Publisher · View at Google Scholar · View at PubMed
  34. C. Ardouin, V. Voon, Y. Worbe et al., “Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation,” Movement Disorders, vol. 21, no. 11, pp. 1941–1946, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. F. Bandini, A. Primavera, M. Pizzorno, and L. Cocito, “Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson's disease,” Parkinsonism and Related Disorders, vol. 13, no. 6, pp. 369–371, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. S. Y. Lim, S. S. O'Sullivan, K. Kotschet et al., “Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease,” Journal of Clinical Neuroscience, vol. 16, no. 9, pp. 1148–1152, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. M. Stacy, “Managing late complications of Parkinson's disease,” Medical Clinics of North America, vol. 83, no. 2, pp. 469–481, 1999. View at Publisher · View at Google Scholar · View at Scopus
  38. R. L. Stowe, N. J. Ives, C. Clarke et al., “Dopamine agonist therapy in early Parkinson's disease,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD006564, 2008.
  39. D. S. Goldstein, “Orthostatic hypotension as an early finding in Parkinson's disease,” Clinical Autonomic Research, vol. 16, no. 1, pp. 46–54, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. C. Magerkurth, R. Schnitzer, and S. Braune, “Symptoms of autonomic failure in Parkinson's disease: prevalence and impact on daily life,” Clinical Autonomic Research, vol. 15, no. 2, pp. 76–82, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. G. Mostile and J. Jankovic, “Treatment of dysautonomia associated with Parkinson's disease,” Parkinsonism and Related Disorders, vol. 15, no. 3, pp. S224–S232, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. W. Singer, P. Sandroni, T. L. Opfer-Gehrking et al., “Pyridostigmine treatment trial in neurogenic orthostatic hypotension,” Archives of Neurology, vol. 63, no. 4, pp. 513–518, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. R. Sakakibara, T. Odaka, Z. Lui et al., “Dietary herb extract dai-kenchu-to ameliorates constipation in parkinsonian patients (Parkinson's disease and multiple system atrophy),” Movement Disorders, vol. 20, no. 2, pp. 261–262, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. J. F. Johanson and R. Ueno, “Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety,” Alimentary Pharmacology and Therapeutics, vol. 25, no. 11, pp. 1351–1361, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. R. Zangaglia, E. Martignoni, M. Glorioso et al., “Macrogol for the treatment of constipation in Parkinson's disease. A randomized placebo-controlled study,” Movement Disorders, vol. 22, no. 9, pp. 1239–1244, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. W. H. Jost and K. Schimrigk, “Long-term results with cisapride in Parkinson's disease,” Movement Disorders, vol. 12, no. 3, pp. 423–425, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. Z. Liu, R. Sakakibara, T. Odaka et al., “Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, amerliorates constipation in Parkinsonian patients,” Movement Disorders, vol. 20, no. 6, pp. 680–686, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. K. L. Sullivan, J. F. Staffetti, R. A. Hauser, P. B. Dunne, and T. A. Zesiewicz, “Tegaserod (Zelnorm) for the treatment of constipation in Parkinson's disease,” Movement Disorders, vol. 21, no. 1, pp. 115–116, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. K. Sadjadpour, “Pyridostigmine bromide and constipation in Parkinson's disease,” Journal of the American Medical Association, vol. 249, no. 9, pp. 1148–1149, 1983. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Albanese, G. Maria, A. Bentivoglio, G. Brisinda, E. Cassetta, and P. Tonali, “Severe constipation in Parkinson's disease relieved by botulinum toxin,” Movement Disorders, vol. 12, no. 5, pp. 764–766, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. R. A. Pinto and D. R. Sands, “Surgery and sacral nerve stimulation for constipation and fecal incontinence,” Gastrointestinal Endoscopy Clinics of North America, vol. 19, no. 1, pp. 83–116, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. L. L. Edwards, E. M. M. Quigley, R. K. Harned, R. Hofman, and R. F. Pfeiffer, “Defecatory function in Parkinson's disease: response to apomorphine,” Annals of Neurology, vol. 33, no. 5, pp. 490–493, 1993. View at Scopus
  53. H. Honig, A. Antonini, P. Martinez-Martin et al., “Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life,” Movement Disorders, vol. 24, no. 10, pp. 1468–1474, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. M. Stacy, “Sleep disorders in Parkinson's disease: epidemiology and management,” Drugs and Aging, vol. 19, no. 10, pp. 733–739, 2002. View at Scopus
  55. C. L. Comella, “Sleep disturbances in Parkinson's disease,” Current Neurology and Neuroscience Reports, vol. 3, no. 2, pp. 173–180, 2003. View at Scopus
  56. D. Verbaan, S. M. Van Rooden, M. Visser, J. Marinus, and J. J. Van Hilten, “Nighttime sleep problems and daytime sleepiness in Parkinson's disease,” Movement Disorders, vol. 23, no. 1, pp. 35–41, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. H. Brunner, T. C. Wetter, B. Hoegl, A. Yassouridis, C. Trenkwalder, and E. Friess, “Microstructure of the non-rapid eye movement sleep electroencephalogram in patients with newly diagnosed Parkinson's disease: effects of dopaminergic treatment,” Movement Disorders, vol. 17, no. 5, pp. 928–933, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. M. D. Gjerstad, G. Alves, T. Wentzel-Larsen, D. Aarsland, and J. P. Larsen, “Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease?” Neurology, vol. 67, no. 5, pp. 853–858, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. S. Frucht, J. D. Rogers, P. E. Greene, M. F. Gordon, and S. Fahn, “Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole,” Neurology, vol. 52, no. 9, pp. 1908–1910, 1999. View at Scopus
  60. R. Manni, M. Terzaghi, I. Sartori, F. Mancini, and C. Pacchetti, “Dopamine agonists and sleepiness in PD: review of the literature and personal findings,” Sleep Medicine, vol. 5, no. 2, pp. 189–193, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. S. Paus, H. M. Brecht, J. Köster, G. Seeger, T. Klockgether, and U. Wüllner, “Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson's disease,” Movement Disorders, vol. 18, no. 6, pp. 659–667, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. P. Dušek, J. Bušková, E. Růžička, et al., “Effects of ropinirole prolonged-release on sleep disturbances and daytime sleepiness in parkinson disease,” Clinical Neuropharmacology, vol. 33, no. 4, pp. 186–190, 2010. View at Publisher · View at Google Scholar · View at PubMed
  63. E. Miller and H. A. Nieburg, “Amphetamines. Valuable adjunct in treatment of Parkinsonism,” New York State Journal of Medicine, vol. 73, no. 22, pp. 2657–2661, 1973. View at Scopus
  64. C. H. Adler, J. N. Caviness, J. G. Hentz, M. Lind, and J. Tiede, “Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease,” Movement Disorders, vol. 18, no. 3, pp. 287–293, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. W. G. Ondo, T. Perkins, T. Swick et al., “Sodium oxybate for excessive daytime sleepiness in Parkinson disease: an open-label polysomnographic study,” Archives of Neurology, vol. 65, no. 10, pp. 1337–1340, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. G. A. Dowling, J. Mastick, E. Colling, J. H. Carter, C. M. Singer, and M. J. Aminoff, “Melatonin for sleep disturbances in Parkinson's disease,” Sleep Medicine, vol. 6, no. 5, pp. 459–466, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. N. Hjort, K. Øtergaard, and E. Dupont, “Improvement of sleep quality in patients with advanced Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus,” Movement Disorders, vol. 19, no. 2, pp. 196–199, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus