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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: 0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2008.05.003



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



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



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



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,



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.



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



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.



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,



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



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



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
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