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Neurol Clin 26 (2008) S65S83

Adverse Events from the Treatment of Parkinsons Disease


Kelvin L. Chou, MD
Department of Neurology, University of Michigan Medical School, 1500 East Medical Center Drive, 1914 Taubman Center, Ann Arbor, MI 48109-5316, USA

Parkinsons disease (PD) is a neurodegenerative disorder characterized clinically by resting tremor, rigidity, bradykinesia, and postural instability. Eective medications exist to treat these motor symptoms but can be associated with adverse eects. When severe, these adverse eects can interfere with a patients quality of life. In this article, the most common adverse events from PD treatment are discussed, including nausea, dyskinesias, somnolence, compulsive behaviors, psychosis, and peripheral edema. Additionally, melanoma and weight loss, two conditions that have been variably linked to PD treatment, are reviewed. Nausea/vomiting Nausea is one of the most common side eects of PD treatment with a dopaminergic agent, although 16% of patients who have PD and are not on dopaminergic agents may experience nausea [1]. Although nausea may occur with all dopaminergic agents, vomiting is rare. When the rst levodopa trials were conducted, patients experienced marked nausea and vomiting. This was because levodopa was predominantly metabolized to dopamine by peripheral decarboxylase. Dopamine does not cross the blood-brain barrier, but circulating dopamine can induce nausea by stimulating the chemoreceptive trigger zone in the area postrema of the brainstem, one of the few brain structures without a blood-brain barrier. Adding a peripheral decarboxylase inhibitor, such as carbidopa or benserazide, to levodopa signicantly reduces nausea and allows more levodopa to cross the blood-brain barrier. All levodopa preparations now are coupled with a peripheral decarboxylase inhibitor. Carbidopa is approved for use
This work is supported by a grant from Teva Neuroscience. E-mail address: http://klchou@med.umich.edu 0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2008.05.003 neurologic.theclinics.com

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within the United States, whereas benserazide is used in countries throughout Europe. Patients commonly experience nausea when starting a dopaminergic agent or when increasing their dosage of dopaminergic agent. The nausea often is mild, and patients tend to develop a tolerance over time. Taking the medication with food also may reduce nausea, although this is not often recommended, as co-administration with food leads to poorer absorption and variable plasma levels, which may contribute to motor uctuations. If nausea occurs with a carbidopa/levodopa preparation, administering additional carbidopa may be benecial because inhibition of peripheral decarboxylase may be incomplete in some patients. As much as 200 to 300 mg per day of additional carbidopa may be needed to achieve complete inhibition [2]. If nausea occurs with a dopamine agonist, using a slower titration or switching to another agonist may be helpful. If a patient continues to experience nausea despite these measures, an antiemetic, such as domperidone or trimethobenzamide, may be given. Not all antiemetics may be used in patients who have PD. Medications, such as metoclopramide and prochlorperazine, commonly are prescribed for nausea, but both block dopamine receptors and worsen PD. Domperidone is a dopamine antagonist that does not cross the blood-brain barrier and thus is safe to use in patients who have PD. Two small, double-blind, randomized trials have demonstrated that domperidone is better than placebo at preventing nausea in patients who have PD treated with bromocriptine [3,4]. More importantly, domperidone did not cause worsening of motor symptoms. In one single-blind trial, domperidone was equivalent to carbidopa in preventing nausea/vomiting associated with levodopa treatment [5]. Domperidone is not approved for use in the United States, so trimethobenzamide may be substituted. Although there are no specic trials of trimethobenzamide for nausea related to dopaminergic drugs, it is commonly used in the United States to prevent nausea and vomiting associated with apomorphine [6]. Dyskinesias Dyskinesias, along with motor uctuations, are the main motor complications of levodopa therapy. A retrospective analysis of studies investigating incidence of dyskinesias with levodopa treatment estimated that slightly more than one third of patients who had PD had dyskinesias after 4 to 6 years [7]. Early-onset PD and higher doses of levodopa are the biggest risk factors for the development of dyskinesias [8,9]. Dyskinesias may aect any part of the body and can be choreic or dystonic. They may manifest when plasma levodopa levels are at their peak (peak-dose dyskinesias), as plasma levodopa levels are rising and falling (diphasic dyskinesias), or when plasma levodopa levels are low (o-state dystonia). Dyskinesias typically are mild but may interfere with quality of life when painful or

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severe, as seen in advanced PD [10]. Current evidence regarding dyskinesia prevention strategies are described elsewhere in this journal supplement and are not discussed here. One way of treating dyskinesias is to modify the antiparkinsonian regimen. Peak-dose dyskinesias are related directly to the amount of levodopa given per dose, so decreasing individual doses generally reduces dyskinesias. The amount of clinical benet to motor symptoms in PD may decline, however, and patients may experience increasing o periods. Thus, a decrease in individual doses of levodopa often has to be combined with more frequent administration, a practice termed dose fractionation. There are signicant limitations to this approach, however, which are detailed in the article by Dewey elsewhere in this issue. Discontinuing catechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase (MAO)-B inhibitors also may be helpful in reducing peak-dose dyskinesias. Sustained-release formulations in theory could reduce dyskinesias, as they are released slowly throughout the day. In practice, however, they tend to prolong the duration of dyskinesias and increase the severity of dyskinesias in the late afternoon or early evening [11]. Patients who have dyskinesias and are on sustained-release levodopa formulations may benet from switching to immediate-release levodopa. Diphasic dyskinesias can be dicult to treat. The same strategies (discussed previously) can be tried, but there are no data to support one strategy over the other. Other options include overlapping the doses of levodopa to prevent trough plasma levodopa levels until late in the evening or administering very small doses of levodopa frequently (such as 50 mg of levodopa given hourly while awake) [12]. Strategies for treating o-state dystonias are similar to strategies to reduce motor uctuations in PD and may include changing the levodopa dosing schedule or adding dopamine agonists, COMT inhibitors, or MAO-B inhibitors (discussed in the article by Dewey elsewhere this supplement). Recent evidence-based reviews recommend amantadine for treating dyskinesias in PD [13,14]. Amantadine is believed to have an antidyskinetic eect through its action at the N-methyl-D-aspartate receptor. Amantadine can reduce dyskinesias between 24% and 60% [1519]. In one study, the eect of amantadine was maintained for up to a year. Some patients, however, are reported to have had rebound dyskinesias when amantadine was discontinued [18]. Side eects include confusion, peripheral edema, and livedo reticularis. A double-blind, placebo-controlled trial of clozapine demonstrates an increase in on time without dyskinesias with a corresponding decrease in on time with dyskinesias [20]. The potential for agranulocytosis and the frequent blood monitoring required make it an unattractive agent, however. Buspirone is reported eective in one small crossover trial of 10 patients [21], but only seven patients completed the trial, and there are no other large randomized studies. Clinical trials of other drugs reported

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to be helpful for treating dyskinesias were uncontrolled or failed to show ecacy in large double-blind trials [12,22]. Although pallidotomy commonly was used as a surgical intervention for dyskinesias with good results [14], most surgical centers have turned to deep brain stimulation (DBS) to treat patients who have motor uctuations and dyskinesias. There are two main targets for DBS in patients who have PD: the globus pallidus interna (GPi) and the subthalamic nucleus (STN). Although DBS of the GPi reduces dyskinesias in open-label reports and blinded evaluations of patients on and o stimulation [23,24], a recent practice parameter determined that there was insucient evidence to determine the ecacy of GPi DBS for dyskinesias [13]. Part of this lack of evidence is because most centers prefer to place electrodes in the STN DBS. In a metaanalysis of outcomes, STN DBS reduced dyskinesias in patients who had PD by an average of 69.1% [25]. This occurs along with a reduction in levodopa dosage, which is mainly responsible for the improvement in dyskinesias. Based on existing studies, STN DBS is considered possibly eective for reducing motor uctuations, dyskinesias, and antiparkinsonian medications in PD [13]. Adverse eects from DBS surgery may include surgical complications, such as hemorrhage, stroke, infection of the device, seizures, delirium, and stimulation-related eects, such as dystonia, confusion, paresthesias, dysarthria, and diplopia, depending on the stimulation site. Somnolence Excessive daytime somnolence (EDS) is a common problem in PD [2628], and its prevalence ranges from 33% to 76% [2931]. There is controversy as to whether or not sleepiness in PD is related to the disease itself or drug treatment [3234] but likely it is due to both. Other contributors to EDS in PD include sleep fragmentation, depression, dementia, psychosis, and dopaminergic treatment [33,3539]. Diculty sleeping at night may be the result of problems falling asleep (sleep-onset insomnia) or staying asleep (sleep-maintenance insomnia). Many factors may have an impact on a PD patients ability to fall asleep, including less than optimal control of motor symptoms causing tremor, rigidity, dystonia, or pain. Furthermore, patients who have EDS may take frequent daytime naps and consequently are not tired at night. Akathisia and restless legs syndrome (RLS) also may be present, causing patients to pace all night or forcing them to fall asleep in reclining chairs. Oral selegiline is a MAO-B inhibitor that has an amphetamine metabolite. Patients who take this medication late in the day may have increased wakefulness and sleep-onset insomnia [40]. There are several reasons why patients who have PD may have diculty maintaining sleep, including nocturia, diculty turning over in bed, leg cramps, vivid dreams or nightmares, and pain [41,42]. Such problems may wax and wane over time, but poor sleep related to turning over in bed or vivid

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dreams tends to worsen over time [39]. Periodic limb movements of sleep (PLMS), often associated with RLS, also may contribute to nocturnal awakenings. Estimates of the prevalence of PLMS in patients who have PD range from 30% to 80% [43]. Rapid eye movement sleep behavior disorder (RBD) also frequently is present in PD, resulting in vocalizations and acting out of dreams. This may cause patients to wake up in the middle of the night and have diculty falling back asleep. EDS in PD also may be caused by sleepdisordered breathing; although the prevalence of sleep apnea syndrome in PD is unclear, a recent case-control study diagnosed sleep apnea in 43% of patients who had PD and were referred for polysomnography [44]. Depression can occur in up to 50% of patients who have PD [45,46] and commonly is associated with early morning awakening. Dementia is another common feature of PD, with the prevalence estimated as high as 41% [47]. If dementia is present, sundowning may occur, with resulting confusion and disorientation preventing a restful sleep. Dementia also is a risk factor for psychosis [48], and the hallucinations and delusions that occur may contribute to sleep-onset insomnia. The medications used to treat PD may aect sleep, and the biggest oenders are the dopamine agonists [38], although levodopa also can cause sedation. Large trials in patients who have de novo PD show that somnolence occurs in approximately 30% of patients treated with dopamine agonists [4951]. These patients often report feeling sleepy for a short period of time after taking their dose, as opposed to a chronic sleepiness. There also are reports of dopamine agonists causing sleep attacks, dened as sudden, irresistible, overwhelming sleepiness without awareness of falling asleep [52]. Since 1999, when this phenomenon was rst reported by Frucht and colleagues [52], many studies have been published debating whether or not these episodes of sudden onset of sleep (SOS) truly occur. The wealth of evidence suggests that SOS is uncommon, that patients who have SOS also tend to have EDS, and that dopaminergic medications in general are the main inuencing factors [35,5356]. EDS and SOS episodes can be a hazard for patients who have PD who drive and they should be warned about this potential problem. When treating EDS in PD, stressing good sleep hygiene is important. Patients should try to avoid naps and increase daytime physical activity so sleep can be consolidated into one long block at night. Avoiding stimulants at bedtime and sedating medications during the day also is essential. Treating other factors contributing to sleep-onset or sleep-maintenance insomnia also may help. For example, if patients experience discomfort in bed due to rigidity or pain, adjustment of dopaminergic medications may allow them to feel more comfortable. A sustained-release formulation of levodopa and a peripheral decarboxylase inhibitor at bedtime may prevent wearing-o symptoms overnight [57]. In patients who have continuing motor uctuations and dyskinesias despite optimal medical management, DBS STN may improve sleep [58]. Decreasing uid intake in the evening,

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emptying the bladder before bed, and using a bedside commode overnight are useful strategies for combating nocturia. If nocturia is the result of bladder hyperactivity, an anticholinergic medication, such as oxybutinin or tolteridone, can be prescribed. Any other sleep disorders, such as obstructive sleep apnea, RBD, or RLS, should be addressed and treated. If patients continue to experience daytime somnolence despite these measures, reducing the dose of dopaminergic medications may help. This often is not possible, however, as patients may have intolerable declines in motor function. Stimulants, such as methylphenidate, caeine, and amphetamines, often are used to treat EDS in PD, but there are scant data supporting their use. Modanil, a wake-promoting agent, may be eective for some patients, although the available data are mixed. Two double-blind, placebocontrolled crossover studies of modanil using small numbers of patients determined that subjective sleepiness (using the Epworth Sleepiness Scale) improved signicantly in those patients on the medication [59,60]. One of these crossover studies used an objective measure, the Maintenance of Wakefulness Test, which was no dierent in the modanil and placebo groups [59]. A recent double-blind, placebo-controlled, parallel trial involving 40 patients who had PD, however, showed no dierence in ESS scores or in Multiple Sleep Latency Test (an objective measure of sleep) results with modanil compared with placebo [61]. Modanil seems well tolerated with minimal side eects. Compulsive behaviors Several complex behaviors are reported to occur in patients who have PD, including pathologic gambling, hypersexuality, punding, and compulsive shopping, eating, or medication use [62]. These behaviors are referred to as impulse control disorders, or compulsive or repetitive behaviors in the literature. In general, compulsive behaviors consist of rewardbased, unrestrained, and often unplanned actions and behaviors that ultimately result in negative consequences. These actions and behaviors seem related to dopaminergic medication use [6365]. It can be argued that punding, a form of behavior where patients perform repetitive, purposeless movements [66], is not a reward-based action but often it is included among these behaviors due to its repetitive nature. A recent survey of 297 patients who had PD estimated the lifetime prevalence of pathologic gambling, hypersexuality, and compulsive shopping to be 6.1% [64]. In patients taking dopamine agonists, the lifetime prevalence of these behaviors increased to 13.7%. Prevalence for pathologic gambling and hypersexuality falls generally in the 3% to 8% range [64,65,6769] and seems more common than compulsive shopping [64,69]. Punding estimates vary greatly, reportedly occurring between 1.4% and 14% of patients who have PD [70,71]. Compulsive medication use occurs in approximately 4% of patients [72,73], whereas the prevalence of uncontrolled eating is unknown.

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The mechanism for development of these behaviors is not well understood, but several factors likely contribute to repetitive behaviors in PD, including use of dopamine agonists and individual susceptibility [62]. Dopamine is a key neurotransmitter in the reward system of the brain [74], and many of these compulsive behaviors, especially pathologic gambling, are attributed mostly to the dopamine agonists [65,69], as opposed to levodopa, a precursor to dopamine. The nonergot agonists have a higher anity for the dopamine D3 receptor, which is found primarily in the mesolimbic pathways responsible for reward behaviors, and this may be what dierentiates the agonists from levodopa in terms of causing compulsive behaviors [75,76]. This theory is supported by the fact that several patients who have RLS have developed pathologic gambling while being treated with dopamine agonists [7780]. Alternatively, excessive use of levodopa, as seen in compulsive medication use, or tonic stimulation of the postsynaptic dopamine receptor by agonists could interfere with signaling involved with reward learning in the brain [62]. Certain clinical features also may increase susceptibility to compulsive behaviors, including younger age at onset [76,81], male gender [76], a history of repetitive behaviors [69], novelty seeking behavior [70,81], and a history of substance or alcohol abuse [81]. Patients should be counseled about the possibility of developing these types of behaviors before initiating dopamine agonists. Once patients start agonist treatment, the identication of compulsive behaviors may be dicult, as they rarely are volunteered. Clinicians, therefore, should question all patients specically about such behavior. Even when patients report such behaviors, they tend to be minimized. Often, corroborating patient accounts with other family members is necessary. There are little data on the treatment of compulsive behaviors in patients who have PD. In one study, 15 subjects were contacted for a telephone interview a mean of 29.2 months after developing compulsive behaviors on a dopamine agonist [82]. The investigators found that overall, patients had decreased their agonist use and increased their levodopa dosage amount but had similar levodopa equivalent dosages to baseline. Ten of these patients no longer met criteria for an impulse control disorder, suggesting that discontinuing or reducing the dopamine agonists may be helpful. Switching patients to a dierent agonist may be helpful in some cases [83] but not consistently. Antidepressants and antipsychotics may be tried, but compulsive behaviors seen in PD do not seem to respond to these agents as eectively as typical obsessive-compulsive disorders do [70,84,85]. Pathologic gambling and compulsive medication use may resolve with DBS, but whether this is due to stimulation itself or medication reduction is unknown [86,87]. Psychosis Psychosis occurs in up to 40% of patients who have PD [8890] and likely is related to a combination of drug treatment, advanced disease, and

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cognitive impairment. Although currently there is no uniform way to diagnose psychosis in PD, a group of experts recently proposed diagnostic criteria [91], with the key components being the presence of hallucinations, delusions, illusions, or a sense of presence that occurs for at least 1 month after the onset of PD motor symptoms. Hallucinations are abnormal perceptions that can occur in any sensory modality without a physical stimulus and are dierent from illusions, which are real sensory perceptions that are distorted. A sense of presence occurs when a patient feels that someone else is present even though no one is there. Delusions are false, irrational beliefs that are maintained even though they have no basis in reality. Visual hallucinations are the most common manifestation of psychosis in PD, but auditory, olfactory, and gustatory hallucinations also may occur [88,90,92,93]. Hallucinations in nonvisual modalities, however, tend to occur in conjunction with visual hallucinations [9295]. Delusions are less common than visual hallucinations and occur in approximately 5% to 10% of patients [96,97]. Risk factors for psychosis include advanced stages of PD, dementia, antiparkinsonian medications, and impaired vision [48,90]. PD psychosis is associated with higher levels of caregiver stress [98], nursing home placement [99,100], and mortality [101,102]. After ruling out potential infectious or metabolic factors, reducing the dosages of antiparkinsonian medications is the rst step in treating PD psychosis. When hallucinations or delusions are severe, however, it may be necessary to add an atypical antipsychotic immediately in conjunction with reducing PD drugs. The recommended order for discontinuing these medications is (1) anticholinergic agents, (2) MAO inhibitors, (3) amantadine, (4) dopamine agonists, (5) COMT inhibitors, and nally (6) levodopa [103]. Although in some cases, discontinuing or reducing medications can be helpful in ameliorating psychotic symptoms, patients may not be able to tolerate them because of worsening motor function. If psychosis persists despite decreasing antiparkinsonian agents to the lowest possible level, then an atypical (or second-generation) antipsychotic should be initiated. In a recent practice parameter, the American Academy of Neurology (AAN) recommended clozapine (level B evidence) for the treatment of PD psychosis [104]. This recommendation was based on two well-designed, double-blind, placebo-controlled trials, one conducted by the Parkinson Study Group (PSG) in the United States [105] and the other by the French Clozapine Parkinson Study Group [106]. Both trials were similar in design and reported that low-dose clozapine improved psychosis in PD without causing motor decline. In the PSG trial, patients took a mean dosage of 25 mg per day, whereas in the French study, patients were on a mean dosage of 37 mg per day. Despite the ecacy data, clozapine has not enjoyed widespread use, mainly because of the potential for agranulocytosis, which necessitates frequent blood monitoring. Clozapine also may cause sedation, sialorrhea, and weight gain.

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Quetiapine is considered the next best option for controlling psychosis in PD. Large open-label reports suggest that most patients experienced improved psychosis with minimal motor decline on this medication [107,108]. In addition, two separate blinded-rater trials comparing quetiapine to clozapine demonstrated that both drugs were equally eective for psychosis without worsening parkinsonism [109,110]. Two recent doubleblind, placebo-controlled trials, however, reported no dierence between quetiapine and placebo on PD psychotic symptoms [111,112]. Because of these results, future double-blind studies with larger numbers of subjects clearly are needed. Nevertheless, the AAN practice parameter states, quetiapine may be considered (Level C) for patients who have PD and psychosis [104]. The major side eect of quetiapine is sedation. The AAN practice parameter recommends against using olanzapine for psychosis in PD [104]. This recommendation is based on several randomized trials. Two parallel trials, one in the United States and the other in Europe, comparing olanzapine to placebo, demonstrated no benet of olanzapine on psychosis in PD and unequivocal worsening of parkinsonism [113]. A separate trial comparing olanzapine to clozapine was aborted early because the patients who had PD and were on olanzapine suered signicant motor problems not seen in the clozapine group [114]. There are open-label data only on the other three atypical antipsychotics, risperidone, ziprasidone, and aripiprazole, for the treatment of psychosis in PD; thus, they cannot be recommended at this point. Small studies of risperidone [115119] and aripiprazole [120,121], however, suggest that these agents worsen parkinsonian signs in patients who have PD. In a large trial of 410 patients who had PD and mildmoderate dementia, rivastigmine improved psychotic symptoms as measured by the Neuropsychiatric Inventory [122]. Whether or not this agent would help psychosis in patients who have PD and who do not have dementia remains to be seen. Peripheral edema Peripheral edema is a recognized complication of amantadine therapy [123] but also is associated with use of the dopamine agonists. Although originally believed related to the ergot properties of bromocriptine [124] and pergolide [125,126], evidence now suggests that peripheral edema is an agonist class eect [127129]. Peripheral edema is reported to occur in 6.4% of patients treated with ropinirole [130] and approximately 15% of patients on pramipexole [128,131]. Risk factors for the development of peripheral edema reported in pramipexole studies include female gender, older age, cardiac disease, and diabetes [127,128]. The development of edema does not seem related to dosage [127,128]. The underlying pathophysiology is unclear, although dopamine clearly has eects on the sympathetic nervous system. Peripheral edema resulting from PD therapy does not always need to be treated, especially if mild. Patients can have trouble tting into their shoes,

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however, and some may even have diculty walking [129]. Fortunately, it disappears on discontinuation of the oending medication [129]. Because the phenomenon is not dose dependent, reducing the dosage usually does not help. Many clinicians use diuretics if patients cannot tolerate other PD medications, but there are no data to support or refute their use in this population. Melanoma It is a well-established observation that there is a higher rate of melanoma in patients who have PD [132136]. A large epidemiologic study of 14,088 patients who had PD identied from a national registry found 44 cases of melanoma, with a standardized incidence ratio (compared with a normal population) of 1.95 (95% CI, 1.42.6) [133]. Why patients who have higher rates in PD compared to the general population is unclear, but treatment with levodopa has been implicated since the 1970s, when Skibba and colleagues [137] reported a case of a patient who had PD and had melanoma. Although in this case, the patient was diagnosed before levodopa treatment, several case reports followed, with some reporting melanoma occurrence after levodopa was started and some reporting melanoma before levodopa treatment [134]. Because levodopa is a substrate for tyrosine hydroxylase, which converts levodopa to melanin, the association between levodopa use and melanoma in patients who have PD seemed reasonable, if not conclusive. Levodopa then was found to be toxic to melanoma cells in vitro, however [138]. Despite the lack of understanding of how levodopa may increase the risk for melanoma, the Food and Drug Administration added the warning of melanoma to the levodopa prescribing instructions and lists a history of melanoma as a contraindication to levodopa use. Several lines of evidence demonstrate, however, that the link between levodopa usage and melanoma in PD is not causal. Reviews of existing case reports on levodopa, melanoma and PD have shown that melanoma occurred before levodopa treatment in many instances [134,139,140]. An analysis of the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study found no dierence in melanoma incidence rates before and after treatment with levodopa [141]. Olsen and colleagues [132] conducted a large population-based study that found an increased prevalence of melanoma in patients who had PD (0.57%) compared with controls (0.40%) (odds ratio 1.44; 95% CI, 1.032.01) before the date of rst hospital contact and presumably levodopa treatment. Finally, a separate nested case-control study conducted by the same investigators found no relationship between the occurrence of melanoma and the amount of levodopa received by the patients before the diagnosis of melanoma [142]. These ndings suggest that a common environmental or genetic factor likely is responsible for the development of melanoma and PD in the same patient. One possible consideration is social class. Patients who have PD tend to be in a higher socioeconomic class [143], and higher

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socioeconomic status is predictive of melanoma [144], presumably because of more opportunities for sun exposure. Driver and colleagues [145], however, found a strong relationship between PD and melanoma incidence, despite controlling for socioeconomic factors, supporting the theory that PD and melanoma share a common genetic trait. Because patients who have PD are at higher risk for melanoma, they should be warned about this and instructed to watch for suspicious-looking moles or skin lesions. Limiting activities in the sun also is a reasonable precaution, but if outside activities are necessary, patients should be aware of how to protect their skin. Finally, regular visits to a dermatologist for a comprehensive skin examination should be encouraged so that abnormal skin lesions are identied and treated early. Weight loss Weight loss is a common comorbidity in PD that may be related to use of dopaminergic medications. It is estimated that approximately half of patients who have PD experience weight loss [146]. The weight loss occurs throughout the course of the disease [147149], more so as parkinsonism progresses [148,150152], but even may precede the diagnosis [147]. In addition to severity of motor symptoms, the presence of dyskinesia, female gender, older age, hallucinations, and dementia are implicated as risk factors for weight loss in PD [148,149,151,152]. The decreasing weight seems due more to loss of fat than muscle [146,149,152]. The exact reasons for weight loss in PD are unclear. Patients who have PD often have problems that could contribute to decreased energy intake, including decreased olfaction, dysphagia, nausea, anorexia, and poor gastrointestinal motility and absorption. A few reports have demonstrated that patients who have PD continue to lose weight despite increased caloric intake [147,153], suggesting that increased energy expenditure is the more likely reason for weight loss in PD. This has been supported by several studies demonstrating increased resting energy expenditure in patients who have PD [152,154,155], but one study found no change in daily resting energy expenditure and a lower daily total energy expenditure in patients who had PD as a result of decreased physical activity [156], arguing against this hypothesis. Potential reasons for increased resting energy expenditure in PD include the presence of muscle rigidity, tremor, dyskinesias, and autonomic dysfunction. Markus and colleagues concluded that increased muscle rigidity and dyskinesias likely resulted in weight loss in their patients [154]. This claim seems to be supported by patients commonly gaining weight after pallidotomy and bilateral STN DBS.There is no clear correlation, however, between amelioration of dyskinesias and weight gain in the pallidotomy [157159] or DBS literature [160]. More research is needed into the underlying basis for weight loss in PD. Only then can evidence-based recommendations to treat this condition be

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made. In the meantime, clinicians should monitor the weight of their patients closely and use strategies to optimize caloric intake. The reduced body mass and increased risk for falls as PD becomes more advanced puts patients at risk for hip fractures, so supplementation with vitamin D and calcium also is a sensible recommendation. Summary Several adverse eects result from the treatment of PD. Some have been recognized for a long time (nausea and dyskinesias) whereas some are just being increasingly recognized (peripheral edema and compulsive behaviors). Although discontinuation of an oending medication is the proper way to manage drug-induced symptoms, this may not always be possible in patients who have PD because of intolerable motor decline. Furthermore, some medications used to treat the side eects of dopaminergic medications also can worsen PD. This is seen with some of the antinausea agents (metoclopramide and prochlorperazine) and most of the antipsychotic medications, with the exception of clozapine and possibly quetiapine. Further research focusing on investigating other agents or strategies to manage adverse eects of PD treatment is needed to aect patient outcomes in PD positively. Note added in proof Rotigotine transdermal system (Neupro) recently has been recalled in the United States because of a manufacturing problem leading to the formation of crystals in the patch matrix, which impede absorption of rotigotine into the skin. It currently is unknown if this problem can or will be solved by the maker of rotigotine transdermal system, but currently the drug is not expected to be available in United States pharmacies after April 2008, unless re-introduced by the manufacturer at a later date. References
[1] Edwards LL, Pfeier RF, Quigley EM, et al. Gastrointestinal symptoms in Parkinsons disease. Mov Disord 1991;6:1516. [2] Koller WC, Rueda MG. Mechanism of action of dopaminergic agents in Parkinsons disease. Neurology 1998;50:S114 [discussion: S448]. [3] Agid Y, Pollak P, Bonnet AM, et al. Bromocriptine associated with a peripheral dopamine blocking agent in treatment of Parkinsons disease. Lancet 1979;1:5702. [4] Pollak P, Gaio JM, Hommel M, et al. [Acute study of the association of bromocriptine and domperidone in parkinsonism (authors transl)]. Therapie 1981;36:6716 [in French]. [5] Langdon N, Malcolm PN, Parkes JD. Comparison of levodopa with carbidopa, and levodopa with domperidone in Parkinsons disease. Clin Neuropharmacol 1986;9:4407. [6] Kolls BJ, Stacy M. Apomorphine: a rapid rescue agent for the management of motor uctuations in advanced Parkinson disease. Clin Neuropharmacol 2006;29:292301.

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[7] Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor uctuations as estimated from the cumulative literature. Mov Disord 2001;16:44858. [8] Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol 2006;5:35563. [9] Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinsons disease. J Neurol 1999;246:112733. [10] Pechevis M, Clarke CE, Vieregge P, et al. Eects of dyskinesias in Parkinsons disease on quality of life and health-related costs: a prospective European study. Eur J Neurol 2005; 12:95663. [11] Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa-induced dyskinesias. Mov Disord 2007;22:137989, quiz 1523. [12] Muenter MD. Patterns of dystonia in response to L-Dopa therapy for Parkinsons disease. Mayo Clin Proc 1977;52:16374. [13] Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor uctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66: 98395. [14] Goetz CG, Poewe W, Rascol O, et al. Evidence-based medical review update: pharmacological and surgical treatments of Parkinsons disease: 2001 to 2004. Mov Disord 2005;20: 52339. [15] Luginger E, Wenning GK, Bosch S, et al. Benecial eects of amantadine on L-dopa-induced dyskinesias in Parkinsons disease. Mov Disord 2000;15:8738. [16] Metman LV, Del Dotto P, LePoole K, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999;56:13836. [17] Snow BJ, Macdonald L, McAuley D, et al. The eect of amantadine on levodopa-induced dyskinesias in Parkinsons disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000;23:825. [18] Thomas A, Iacono D, Luciano AL, et al. Duration of amantadine benet on dyskinesia of severe Parkinsons disease. J Neurol Neurosurg Psychiatry 2004;75:1413. [19] Verhagen Metman L, Del Dotto P, van den Munckhof P, et al. Amantadine as treatment for dyskinesias and motor uctuations in Parkinsons disease. Neurology 1998;50:13236. [20] Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology 2004;62:3818. [21] Bonifati V, Fabrizio E, Cipriani R, et al. Buspirone in levodopa-induced dyskinesias. Clin Neuropharmacol 1994;17:7382. [22] Goetz CG, Damier P, Hicking C, et al. Sarizotan as a treatment for dyskinesias in Parkinsons disease: a double-blind placebo-controlled trial. Mov Disord 2007;22:17986. [23] Deep Brain Stimulation for Parkinsons Disease Study Group. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinsons disease. N Engl J Med 2001;345:95663. [24] Visser-Vandewalle V, Van der Linden C, Temel Y, et al. Long-term motor eect of unilateral pallidal stimulation in 26 patients with advanced Parkinson disease. J Neurosurg 2003; 99:7017. [25] Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord 2006;21(Suppl 14):S290304. [26] Arnulf I, Bonnet AM, Damier P, et al. Hallucinations, REM sleep, and Parkinsons disease: a medical hypothesis. Neurology 2000;55:2818. [27] Factor SA, McAlarney T, Sanchez-Ramos JR, et al. Sleep disorders and sleep eect in Parkinsons disease. Mov Disord 1990;5:2805. [28] Van Hilten JJ, Weggeman M, van der Velde EA, et al. Sleep, excessive daytime sleepiness and fatigue in Parkinsons disease. J Neural Transm Park Dis Dement Sect 1993;5:23544. [29] Brodsky MA, Godbold J, Roth T, et al. Sleepiness in Parkinsons disease: a controlled study. Mov Disord 2003;18:66872.

S78

CHOU

[30] Henderson JM, Lu Y, Wang S, et al. Olfactory decits and sleep disturbances in Parkinsons disease: a case control survey. J Neurol Neurosurg Psychiatry 2003;74:9568. [31] Hogl B, Seppi K, Brandauer E, et al. Increased daytime sleepiness in Parkinsons disease: a questionnaire survey. Mov Disord 2003;18:31923. [32] Arnulf I, Konofal E, Merino-Andreu M, et al. Parkinsons disease and sleepiness: an integral part of PD. Neurology 2002;58:101924. [33] Fabbrini G, Barbanti P, Aurilia C, et al. Excessive daytime sleepiness in de novo and treated Parkinsons disease. Mov Disord 2002;17:102630. [34] OSuilleabhain PE, Dewey RB Jr. Contributions of dopaminergic drugs and disease severity to daytime sleepiness in Parkinson disease. Arch Neurol 2002;59:9869. [35] Hobson DE, Lang AE, Martin WR, et al. Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA 2002;287:45563. [36] Razmy A, Lang AE, Shapiro CM. Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine agonists. Arch Neurol. 2004;61:97102. [37] Avorn J, Schneeweiss S, Sudarsky LR, et al. Sudden uncontrollable somnolence and medication use in Parkinson disease. Arch Neurol 2005;62:12428. [38] Gjerstad MD, Alves G, Wentzel-Larsen T, et al. Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease? Neurology 2006;67:8538. [39] Gjerstad MD, Wentzel-Larsen T, Aarsland D, et al. Insomnia in Parkinsons disease: frequency and progression over time. J Neurol Neurosurg Psychiatry. 2007;78:4769. [40] Thornton C, Dore CJ, Elsworth JD, et al. The eect of deprenyl, a selective monoamine oxidase B inhibitor, on sleep and mood in man. Psychopharmacology (Berl) 1980;70: 1636. [41] Dhawan V, Dhoat S, Williams AJ, et al. The range and nature of sleep dysfunction in untreated Parkinsons disease (PD). A comparative controlled clinical study using the Parkinsons disease sleep scale and selective polysomnography. J Neurol Sci 2006;248: 15862. [42] Kumar S, Bhatia M, Behari M. Sleep disorders in Parkinsons disease. Mov Disord 2002;17: 77581. [43] Poewe W, Hogl B. Akathisia, restless legs and periodic limb movements in sleep in Parkinsons disease. Neurology 2004;63:S126. [44] Diederich NJ, Vaillant M, Leischen M, et al. Sleep apnea syndrome in Parkinsons disease. A case-control study in 49 patients. Mov Disord 2005;20:14138. [45] Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinsons disease. J Neurol Neurosurg Psychiatry 1999;67:4926. [46] Tandberg E, Larsen JP, Aarsland D, et al. The occurrence of depression in Parkinsons disease. A community-based study. Arch Neurol 1996;53:1759. [47] Mayeux R, Denaro J, Hemenegildo N, et al. A population-based investigation of Parkinsons disease with and without dementia. Relationship to age and gender. Arch Neurol 1992;49:4927. [48] Aarsland D, Larsen JP, Cummins JL, et al. Prevalence and clinical correlates of psychotic symptoms in Parkinson disease: a community-based study. Arch Neurol 1999;56:595601. [49] Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000;284:19318. [50] Rascol O, Brooks DJ, Korczyn AD, et al. A ve-year study of the incidence of dyskinesia in patients with early Parkinsons disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342:148491. [51] Watts RL, Jankovic J, Waters C, et al. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 2007;68:2726. [52] Frucht S, Rogers JD, Greene PE, et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999;52:190810.

ADVERSE EVENTS FROM TREATMENT

S79

[53] Homann CN, Wenzel K, Suppan K, et al. Sleep attacks in patients taking dopamine agonists: review. BMJ 2002;324:14837. [54] Olanow CW, Schapira AH, Roth T. Waking up to sleep episodes in Parkinsons disease. Mov Disord 2000;15:2125. [55] Paus S, Brecht HM, Koster J, et al. Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinsons disease. Mov Disord 2003;18:65967. [56] Meindorfner C, Korner Y, Moller JC, et al. Driving in Parkinsons disease: mobility, accidents, and sudden onset of sleep at the wheel. Mov Disord 2005;20:83242. [57] Van den Kerchove M, Jacquy J, Gonce M, et al. Sustained-release levodopa in parkinsonian patients with nocturnal disabilities. Acta Neurol Belg 1993;93:329. [58] Hjort N, Ostergaard K, Dupont E. Improvement of sleep quality in patients with advanced Parkinsons disease treated with deep brain stimulation of the subthalamic nucleus. Mov Disord 2004;19:1969. [59] Adler CH, Caviness JN, Hentz JG, et al. Randomized trial of modanil for treating subjective daytime sleepiness in patients with Parkinsons disease. Mov Disord 2003;18: 28793. [60] Hogl B, Saletu M, Brandauer E, et al. Modanil for the treatment of daytime sleepiness in Parkinsons disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002;25:9059. [61] Ondo WG, Fayle R, Atassi F, et al. Modanil for daytime somnolence in Parkinsons disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 2005; 76:16369. [62] Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 2007;64:108996. [63] Klos KJ, Bower JH, Josephs KA, et al. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinsons disease and multiple system atrophy. Parkinsonism Relat Disord 2005;11:3816. [64] Voon V, Hassan K, Zurowski M, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006;67:12547. [65] Voon V, Hassan K, Zurowski M, et al. Prospective prevalence of pathologic gambling and medication association in Parkinson disease. Neurology 2006;66:17502. [66] Friedman JH. Punding on levodopa. Biol Psychiatry 1994;36:3501. [67] Avanzi M, Baratti M, Cabrini S, et al. Prevalence of pathological gambling in patients with Parkinsons disease. Mov Disord 2006;21:206872. [68] Grosset KA, Macphee G, Pal G, et al. Problematic gambling on dopamine agonists: Not such a rarity. Mov Disord 2006;21:22068. [69] Weintraub D, Siderowf AD, Potenza MN, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006;63:96973. [70] Evans AH, Katzenschlager R, Paviour D, et al. Punding in Parkinsons disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004;19:397405. [71] Miyasaki JM, Al Hassan K, Lang AE, et al. Punding prevalence in Parkinsons disease. Mov Disord 2007;22:117981. [72] Giovannoni G, OSullivan JD, Turner K, et al. Hedonistic homeostatic dysregulation in patients with Parkinsons disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000;68:4238. [73] Pezzella FR, Colosimo C, Vanacore N, et al. Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinsons disease. Mov Disord 2005;20:7781. [74] Young AM, Moran PM, Joseph MH. The role of dopamine in conditioning and latent inhibition: what, when, where and how? Neurosci Biobehav Rev 2005;29:96376. [75] Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005;62:137781. [76] Giladi N, Weitzman N, Schreiber S, et al. New onset heightened interest or drive for gambling, shopping, eating or sexual activity in patients with Parkinsons disease: the role of

S80

CHOU

[77]

[78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92]

[93] [94] [95] [96] [97] [98]

[99] [100]

dopamine agonist treatment and age at motor symptoms onset. J Psychopharmacol 2007; 21:5016. Driver-Dunckley ED, Noble BN, Hentz JG, et al. Gambling and increased sexual desire with dopaminergic medications in restless legs syndrome. Clin Neuropharmacol 2007;30: 24955. Evans AH, Butzkueven H. Dopamine agonist-induced pathological gambling in restless legs syndrome due to multiple sclerosis. Mov Disord 2007;22:5901. Quickfall J, Suchowersky O. Pathological gambling associated with dopamine agonist use in restless legs syndrome. Parkinsonism Relat Disord 2007;13:5356. Tippmann-Peikert M, Park JG, Boeve BF, et al. Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists. Neurology 2007;68:3013. Voon V, Thomsen T, Miyasaki JM, et al. Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease. Arch Neurol 2007;64:2126. Mamikonyan E, Siderowf AD, Duda JE, et al. Long-term follow-up of impulse control disorders in Parkinsons disease. Mov Disord 2008;23(1):7580. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinsons disease. Neurology 2003;61:4223. Kurlan R. Disabling repetitive behaviors in Parkinsons disease. Mov Disord 2004;19: 4337. Miwa H, Morita S, Nakanishi I, et al. Stereotyped behaviors or punding after quetiapine administration in Parkinsons disease. Parkinsonism Relat Disord 2004;10:17780. Ardouin C, Voon V, Worbe Y, et al. Pathological gambling in Parkinsons disease improves on chronic subthalamic nucleus stimulation. Mov Disord 2006;21:19416. Witjas T, Baunez C, Henry JM, et al. Addiction in Parkinsons disease: impact of subthalamic nucleus deep brain stimulation. Mov Disord 2005;20:10525. Fenelon G, Mahieux F, Huon R, et al. Hallucinations in Parkinsons disease: prevalence, phenomenology and risk factors. Brain 2000;123(Pt 4):73345. Holroyd S, Currie L, Wooten GF. Prospective study of hallucinations and delusions in Parkinsons disease. J Neurol Neurosurg Psychiatry. 2001;70:7348. Sanchez-Ramos JR, Ortoll R, Paulson GW. Visual hallucinations associated with Parkinson disease. Arch Neurol 1996;53:12658. Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria for psychosis in Parkinsons disease: report of an NINDS, NIMH work group. Mov Disord 2007;22:10618. Chou KL, Messing S, Oakes D, et al. Drug-induced psychosis in parkinson disease: phenomenology and correlations among psychosis rating instruments. Clin Neuropharmacol 2005;28:2159. Inzelberg R, Kipervasser S, Korczyn AD. Auditory hallucinations in Parkinsons disease. J Neurol Neurosurg Psychiatry 1998;64:5335. Goetz CG, Wuu J, Curgian LM, et al. Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 2005;64:816. Marsh L, Williams JR, Rocco M, et al. Psychiatric comorbidities in patients with Parkinson disease and psychosis. Neurology 2004;63:293300. Dewey RB Jr, OSuilleabhain PE. Treatment of drug-induced psychosis with quetiapine and clozapine in Parkinsons disease. Neurology 2000;55:17534. Factor SA, Molho ES, Podskalny GD, et al. Parkinsons disease: drug-induced psychiatric states. Adv Neurol 1995;65:11538. Schrag A, Hovris A, Morley D, et al. Caregiver-burden in parkinsons disease is closely associated with psychiatric symptoms, falls, and disability. Parkinsonism Relat Disord 2006; 12:3541. Aarsland D, Larsen JP, Tandberg E, et al. Predictors of nursing home placement in Parkinsons disease: a population-based, prospective study. J Am Geriatr Soc 2000;48:93842. Goetz CG, Stebbins GT. Risk factors for nursing home placement in advanced Parkinsons disease. Neurology 1993;43:22279.

ADVERSE EVENTS FROM TREATMENT

S81

[101] Factor SA, Feustel PJ, Friedman JH, et al. Longitudinal outcome of Parkinsons disease patients with psychosis. Neurology 2003;60:175661. [102] Goetz CG, Stebbins GT. Mortality and hallucinations in nursing home patients with advanced Parkinsons disease. Neurology 1995;45:66971. [103] Chou KL, Fernandez HH. Combating psychosis in Parkinsons disease patients: the use of antipsychotic drugs. Expert Opin Investig Drugs 2006;15:33949. [104] Miyasaki JM, Shannon K, Voon V, et al. Practice parameter: evaluation and treatment of depression, psychosis and dementia in Parkinsons disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:9961002. [105] Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinsons disease. N Engl J Med 1999;340:75763. [106] Pollak P, Tison F, Rascol O, et al. Clozapine in drug induced psychosis in Parkinsons disease: a randomized, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry 2004;75:68995. [107] Fernandez HH, Trieschmann ME, Burke MA, et al. Long-term outcome of quetiapine use for psychosis among Parkinsonian patients. Mov Disord 2003;18:5104. [108] Reddy S, Factor SA, Molho ES, et al. The eect of quetiapine on psychosis and motor function in parkinsonian patients with and without dementia. Mov Disord 2002;17:67681. [109] Merims D, Balas M, Peretz C, et al. Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinsons disease psychosis. Clin Neuropharmacol 2006;29:3317. [110] Morgante L, Epifanio A, Spine E, et al. Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis. Clin Neuropharmacol 2004;27:1536. [111] Ondo WG, Tintner R, Voung KD, et al. Double-blinded, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinsons disease. Mov Disord 2006;20:95863. [112] Rabey JM, Prokhorov T, Miniovitz A, et al. Eect of quetiapine in psychotic Parkinsons disease patients; a double-blinded labeled study of 3 months duration. Mov Disord 2007; 22:3138. [113] Breier A, Sutton VK, Feldman PD, et al. Olanzapine in the treatment of Dopamimeticinduced psychosis in patients with Parkinsons disease. Biol Psychiatry 2002;52:43845. [114] Goetz CG, Blasucci LM, Leurgans S, et al. Olanzapine and clozapine: comparative eects on motor function in hallucination PD patients. Neurology 2000;55:78994. [115] Ford B, Lynch T, Greene P. Risperidone in Parkinsons disease. Lancet 1994;344(8923): 681. [116] Rich SS, Friedman JH, Ott BR. Risperidone versus clozapine in the treatment of psychosis in six patients with Parkinsons disease and other akinetic-rigid syndromes. J Clin Psychiatry 1995;56(12):5569. [117] Meco G, Alessandri A, Giustini P, et al. Risperidone in levodopa-induced psychosis in advanced Parkinsons disease: an open-label, long-term study. Mov Disord 1997;12(4):6102. [118] Leopold NA. Risperidone treatment of drug-related psychosis in patients with Parkinsonism. Mov Disord 2000;15(2):3014. [119] Mohr E, Mendis T, Hildebrand K, et al. Risperidone in the treatment of dopamine-induced psychosis in Parkinsons disease: an open pilot trial. Mov Disord 2000;15(6):12307. [120] Fernandez HH, Trieschmann ME, Friedman JH. Aripiprazole for drug-induced psychosis in Parkinson disease: preliminary experience. Clin Neuropharmacol 2004;27(1):45. [121] Friedman JH, Berman RM, Goetz CG, et al. Open-label exible dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinsons disease. Mov Disord 2006;21(12):207881. [122] Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinsons disease. N Engl J Med 2004;351:250918. [123] Pearce LA, Waterbury LD, Green HD. Amantadine hydrochloride: alteration in peripheral circulation. Neurology 1974;24:468.

S82

CHOU

[124] Blackard WG. Edemaan infrequently recognized complication of bromocriptine and other ergot dopaminergic drugs. Am J Med 1993;94:445. [125] Bianchi M, Castiglioni MG. Refractory generalized edema: an infrequent complication of long-term pergolide treatment for Parkinson disease. Clin Neuropharmacol 2005;28:2456. [126] Varsano S, Gershman M, Hamaoui E. Pergolide-induced dyspnea, bilateral pleural eusion and peripheral edema. Respiration 2000;67:5802. [127] Biglan KM, Holloway RG Jr, McDermott MP, et al. Risk factors for somnolence, edema, and hallucinations in early Parkinson disease. Neurology 2007;69:18795. [128] Kleiner-Fisman G, Fisman DN. Risk factors for the development of pedal edema in patients using pramipexole. Arch Neurol 2007;64:8204. [129] Tan EK, Ondo W. Clinical characteristics of pramipexole-induced peripheral edema. Arch Neurol 2000;57:72932. [130] Schrag AE, Brooks DJ, Brunt E, et al. The safety of ropinirole, a selective nonergoline dopamine agonist, in patients with Parkinsons disease. Clin Neuropharmacol 1998;21: 16975. [131] Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004;61:104453. [132] Olsen JH, Friis S, Frederiksen K. Malignant melanoma and other types of cancer preceding Parkinson disease. Epidemiology 2006;17:5827. [133] Olsen JH, Friis S, Frederiksen K, et al. Atypical cancer pattern in patients with Parkinsons disease. Br J Cancer 2005;92:2015. [134] Zanetti R, Loria D, Rosso S. Melanoma, Parkinsons disease and levodopa: causal or spurious link? A review of the literature. Melanoma Res 2006;16:2016. [135] Jansson B, Jankovic J. Low cancer rates among patients with Parkinsons disease. Ann Neurol 1985;17:5059. [136] Moller H, Mellemkjaer L, McLaughlin JK, et al. Occurrence of dierent cancers in patients with Parkinsons disease. BMJ 1995;310:15001. [137] Skibba JL, Pinckley J, Gilbert EF, et al. Multiple primary melanoma following administration of levodopa. Arch Pathol 1972;93:55661. [138] Kable EP, Favier D, Parsons PG. Sensitivity of human melanoma cells to L-dopa and DL-buthionine (S,R)-sulfoximine. Cancer Res 1989;49:232731. [139] Fiala KH, Whetteckey J, Manyam BV. Malignant melanoma and levodopa in Parkinsons disease: causality or coincidence? Parkinsonism Relat Disord 2003;9:3217. [140] Siple JF, Schneider DC, Wanlass WA, et al. Levodopa therapy and the risk of malignant melanoma. Ann Pharmacother 2000;34:3825. [141] Constantinescu R, Romer M, Kieburtz K. Malignant melanoma in early Parkinsons disease: the DATATOP trial. Mov Disord 2007;22:7202. [142] Olsen JH, Tangerud K, Wermuth L, et al. Treatment with levodopa and risk for malignant melanoma. Mov Disord 2007;22:12527. [143] Frigerio R, Elbaz A, Sanft KR, et al. Education and occupations preceding Parkinson disease: a population-based case-control study. Neurology 2005;65:157583. [144] Elwood JM, Whitehead SM, Davison J, et al. Malignant melanoma in England: risks associated with naevi, freckles, social class, hair colour, and sunburn. Int J Epidemiol 1990;19: 80110. [145] Driver JA, Logroscino G, Buring JE, et al. A prospective cohort study of cancer incidence following the diagnosis of Parkinsons disease. Cancer Epidemiol Biomarkers Prev 2007;16: 12605. [146] Abbott RA, Cox M, Markus H, et al. Diet, body size and micronutrient status in Parkinsons disease. Eur J Clin Nutr 1992;46:87984. [147] Chen H, Zhang SM, Hernan MA, et al. Weight loss in Parkinsons disease. Ann Neurol 2003;53:6769. [148] Uc EY, Struck LK, Rodnitzky RL, et al. Predictors of weight loss in Parkinsons disease. Mov Disord 2006;21:9306.

ADVERSE EVENTS FROM TREATMENT

S83

[149] Beyer PL, Palarino MY, Michalek D, et al. Weight change and body composition in patients with Parkinsons disease. J Am Diet Assoc 1995;95:97983. [150] Vardi J, Oberman Z, Rabey I, et al. Weight loss in patients treated long-term with levodopa. Metabolic aspects. J Neurol Sci 1976;30:3340. [151] Lorefalt B, Ganowiak W, Palhagen S, et al. Factors of importance for weight loss in elderly patients with Parkinsons disease. Acta Neurol Scand 2004;110:1807. [152] Markus HS, Tomkins AM, Stern GM. Increased prevalence of undernutrition in Parkinsons disease and its relationship to clinical disease parameters. J Neural Transm Park Dis Dement Sect 1993;5:11725. [153] Davies KN, King D, Davies H. A study of the nutritional status of elderly patients with Parkinsons disease. Age Ageing 1994;23:1425. [154] Markus HS, Cox M, Tomkins AM. Raised resting energy expenditure in Parkinsons disease and its relationship to muscle rigidity. Clin Sci (Lond). 1992;83:199204. [155] Levi S, Cox M, Lugon M, et al. Increased energy expenditure in Parkinsons disease. BMJ 1990;301:12567. [156] Toth MJ, Fishman PS, Poehlman ET. Free-living daily energy expenditure in patients with Parkinsons disease. Neurology 1997;48:8891. [157] Lang AE, Lozano A, Tasker R, et al. Neuropsychological and behavioral changes and weight gain after medial pallidotomy. Ann Neurol 1997;41:8346. [158] Ondo WG, Ben-Aire L, Jankovic J, et al. Weight gain following unilateral pallidotomy in Parkinsons disease. Acta Neurol Scand 2000;101:7984. [159] Vitek JL, Bakay RA, Freeman A, et al. Randomized trial of pallidotomy versus medical therapy for Parkinsons disease. Ann Neurol 2003;53:55869. [160] Moro E, Scerrati M, Romito LM, et al. Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinsons disease. Neurology 1999;53:8590.