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Motor fluctuations and dyskinesia in Parkinson's disease
Parkinsonism & Related Disorders Parkinsonism and Related Disorders 8 (2001) 101±108
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Motor ¯uctuations and dyskinesia in Parkinson's disease John G. Nutt* Departments of Neurology, and Physiology and Pharmacology, School of Medicine, Oregon Health Sciences University, Portland, OR 97201-3098, USA
Abstract Motor ¯uctuations and dyskinesia are common complications of long-term levodopa therapy. The neural and molecular mechanisms underlying their development are partially understood. A variety of clinical strategies may reduce the unpredictability of motor ¯uctuations and reduce their impact. Prevention of these complications remains an elusive goal. q 2001 Published by Elsevier Science Ltd. Keywords: Parkinson's disease; Levodopa; Motor ¯uctuations; Levodopa-induced dyskinesia
1. Introduction Motor ¯uctuations are an important contributor to the disability of PD. Fluctuations interrupt patients activities and are associated with other ¯uctuating phenomena such as mood, sensory and autonomic symptoms that add to the distress of motor ¯uctuations. Dyskinesia, a frequent accompaniment of motor ¯uctuations further compounds the problems. Motor ¯uctuations are not only important to patients who experience ¯uctuations; the threat of motor ¯uctuations dictates how patients are treated in early stages of the disease. Finally, motor ¯uctuations challenge our understanding of how the dopaminergic system functions and our concept of neurotransmitter replacement therapy for central nervous system diseases.
2. Prevalence of ¯uctuations and dyskinesia Motor ¯uctuations are generally seen as an inevitable consequence of long-term levodopa therapy. Sweet and McDowell found that 47% of the patients still alive and taking levodopa after 5 years had motor ¯uctuations and 49% had dyskinesia [1]. Barbeau found that 55% of his study group had motor ¯uctuations and 55% had dyskinesia after 6 years of treatment [2]. It should be noted that these early studies, shortly after the introduction of levodopa, very likely included patients with more severe disease than would be true in studies today that follow subjects from the initiation of levodopa therapy. Also, higher doses of levodopa were frequently used than is the practice today. * Tel.: 11-503-494-7231; fax: 11-503-494-7242. E-mail address: [email protected] (J.G. Nutt). 1353-8020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd. PII: S 1353-802 0(01)00024-4
Poewe et al. found that with low dose levodopa (less than 500 mg/day with decarboxylase inhibitor) after 6 years, 52% of the patients had motor ¯uctuations and 54% dyskinesia. With maximally tolerated doses at 6 years the prevalence of motor ¯uctuations was 80% and of dyskinesia was 88% [3]. Similarly, Heley et al. found that 41% of patients treated for 5 years with low dose levodopa/carbidopa had motor ¯uctuations and 55% had dyskinesia [4]. Age of onset of Parkinson's disease may in¯uence the occurrence of ¯uctuations; 96% of patients with onset of PD before age 40 had ¯uctuations after 5 years of levodopa treatment as opposed to 64% of case-matched patients with disease onset after age 40 [5]. Other studies in young onset PD have also found prevalence in excess of 90% for ¯uctuations and dyskinesia [6,7]. In contrast to these retrospective studies which found prevalence of ¯uctuations and dyskinesia of 40±96% after 5 or 6 years of levodopa therapy, a recent, large, double-blind, prospective study comparing 5 years of treatment with low dose, immediate release levodopa/carbidopa with controlled release levodopa/carbidopa found approximately 20% prevalence of motor ¯uctuations and dyskinesia by patient report or physician observation during out-patient clinic visits [8]. One possible explanation for this low prevalence of motor complications is that subjects with relatively mild parkinsonism were enrolled. A smaller, open, prospective study observed ¯uctuations in 13 of 18 subjects and dyskinesia in 11 subjects of 18 subjects monitored during a dose cycle after the ®rst year of levodopa treatment [9]. However, only six of the subjects reported ¯uctuations and three were aware of dyskinesia [9]. This discrepancy suggests that studies that depend upon patient report to determine prevalence of these complications will underestimate their prevalence and give a different picture of the natural history of these complications. On the other hand, patient reports will
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estimate the prevalence of ¯uctuations and dyskinesia that are clinically signi®cant. In sum, most studies indicate that motor complications are common after 5 years of levodopa therapy. There are hints that severity of disease, age of onset of parkinsonism and levodopa dose may in¯uence the time of onset of these problems. 3. Development of motor ¯uctuations The manner in which motor ¯uctuations develop is important to understanding the pathogenesis of the problem as well as designing therapies for motor ¯uctuations. The clinical impressions of how the response to levodopa changes differ somewhat from the measured changes in motor function that occur during long-term levodopa therapy. Accurately de®ning the natural history of how the response to levodopa changes during long-term therapy is important as the time course of changes may implicate and exclude various pathogenetic mechanisms for ¯uctuations and dyskinesia. Motor ¯uctuations are commonly envisioned to be due to a single effect of levodopa on motor function. However, there is evidence that the motor performance of a levodopa-treated PD patient is the summation of several different responses to levodopa plus contributions from endogenous dopamine [9,10]. There are at least three different motor responses to levodopa. The short-duration response is a motor improvement that roughly parallels the elevation of plasma levodopa after a dose of drug and is therefore measured in minutes to hours. The short-duration response is responsible for the peak motor response, the response that has been the focus of attention in the clinic and in basic and clinical research. The long-duration response, ®rst described by Cotzias [11] and Muenter [12] is a motor improvement that builds up over days and, likewise, decays over days. It has received relatively little attention. A negative or inhibitory response is a worsening of motor function that follows (and may precede) a short-duration response [13±15]. The negative response worsens the off condition for minutes up to an hour and is therefore sometimes termed the `super off'. These three responses to levodopa are superimposed on a diurnal pattern of motor function that is evident in levodopa untreated and treated PD patients. The diurnal motor pattern is characterized by better motor performance in the morning (sleep bene®t [16±18]) and worse function in the evenings. Finally, there is the residual endogenous dopaminergic function that presumably accounts for what motor function remains when a patient has been taken off levodopa for several weeks. This endogenous dopamine production may be virtually nil as indicated by the virtual immobility of severely affected, untreated PD patients. The endogenous dopamine plus the long-duration response are the main determinants of the off motor function. Currently, there is no method to dissociate the contributions of the long-duration levodopa response
and the endogenous dopamine production to motor function without prolonged withdrawal from levodopa which is usually precluded for ethical, medical and logistical reasons. The clinical de®nition of the stable response is a levodopa-induced improvement of motor function in the absence of motor ¯uctuations in a patient taking four or less doses of levodopa/carbidopa per day. The stable response is characteristically observed in patients early in the course of the disease and early in long-term levodopa therapy, the so-called honeymoon period that lasts several years. It is commonly envisioned that the stable response is due to the fact that the short-duration response to each dose of levodopa/carbidopa is suf®ciently long that the effects of each dose overlap with the previous dose to produce a sustained response. However, measurement of motor performance in patients with a stable response suggests that the sustained improvement appears to be largely due to the long-duration response. If patients' motor function is measured in the morning after 12 h without levodopa, or even several days without medication, it can be seen that their motor function is still appreciably better than before they began levodopa [9]. Stable responding subjects do have motor ¯uctuations related to the short-duration response that is superimposed on the long-duration response but the patients are unaware and untroubled by them [9]. The negative response and diurnal variation are usually unimportant at this stage. Motor ¯uctuations ®rst clinically appear as wearing-off, with bradykinesia emerging at the end of dose cycles or after being without levodopa overnight. This is commonly attributed to shortening of the short-duration response. Motor effects no longer seem to last the 4±6 h between doses. The short-duration response is briefer in wearingoff patients [19±22] but there is not a direct correlation with duration of action and presence of ¯uctuations nor are the differences between stable and ¯uctuating patients very great [20,22]. The often ignored characteristic of ¯uctuating patients is that there is a large, clinically appreciable difference in motor function between the on and off motor states [20,22,23]. Thus, another change between ¯uctuating and stable patients is that the short-duration response, generally measurable from the beginning of therapy, becomes larger and clinically more signi®cant. The peak levodopa response does not increase; rather deterioration in the off motor function makes the magnitude of the short-duration response larger. Precisely how much of this deterioration in the off motor function is related to changes in the longduration response and how much is related to further loss of endogenous dopaminergic function is unknown. We do know that a long-duration response is still present in severely affected PD patients [24,25] and is approximately the magnitude of the long-duration response in less severe PD patients. Thus, loss of endogenous dopamine production seems more likely to explain the increasing off motor disability. The negative response may also appear at this time and further augment off disability. Finally, diurnal
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patterns of response become apparent with better function in the morning and poorer response to medications in the afternoon [26,27]. The more marked motor ¯uctuations, termed on±off, are clinically characterized by rapid switches between on and off, seemingly unrelated to oral dosing with levodopa. It occurs in severely affected patients with large differences in on and off motor function who are on complex, frequent dosing regimens. The unpredictable response to oral levodopa is in contrast to the predictable, dose-responsive responses to intravenous boluses or brief infusions in these patients [23,28]. This observation indicates that the unpredictable on±off response is largely pharmacokinetic in origin. Unpredictability is enhanced by administering frequent, small doses of levodopa in the vain hope that this strategy will yield relatively constant plasma levodopa concentrations. 4. Development of levodopa-induced dyskinesia Dyskinesia is almost an invariable component of motor ¯uctuations and a consideration in treating ¯uctuations. Dyskinesia occurring when the patient is on is frequently termed peak-dose dyskinesia. This term is misleading in that dyskinesia is generally present throughout the time the patient is on and is either physically, emotionally or cognitively active (i.e., dyskinesia is brought out by motor activity and any form of stress and conversely, is reduced by relaxation and inactivity). Furthermore, many patients have an increase in dyskinesia at the beginning and end of a dose cycle, a mild form of the so called diphasic dyskinesia [29]. How the dyskinesia dose-response relationship is altered during long-term levodopa therapy should offer clues to the pathogenesis of dyskinesia. The thresholds and time course for dyskinesia and antiparkinsonian effects are reported to be similar in patients with motor ¯uctuations [28,30]. The important question is what happens during the ®rst months of treatment as dyskinesia ®rst appears. There are three hypotheses. One hypothesis is that the threshold for dyskinesia is initially much higher than that for an antiparkinsonian effect and that the dyskinesia threshold is lowered by repeated dosing of levodopa until it approximates the antiparkinsonian effect threshold [28,30]. The threshold is a marker for the initial in¯ection of the dose-response curve or the equivalent of an .effective dose 05 0 (dose producing 5% of the maximum response). Thus, lowering of the dyskinesia threshold would be equivalent to shifting the dose-response curve to the left. The slope of the dyskinesia dose-response curve and the maximum response (Emax) could also change but the essential feature is the leftward shift and reduction of dose required to produce dyskinesia (often expressed as the reduction in ED50, the dose producing two of the maximum response). The problem with this hypothesis is that there
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have been few [28] or no [30] subjects described with newly developed dyskinesia that fall between the subjects who have no dyskinesia at all (and in whom no threshold can be determined because they do not have dyskinesia) and the ¯uctuating subjects with dyskinesia thresholds that are similar to antiparkinsonian thresholds. Thus there are no subjects with dyskinesia in whom to demonstrate the initial high threshold postulated by this model. In conclusion, although intuitively attractive, the leftward shift of the dose-response curve is an unproven model of how dyskinesia develops. A second model is that rather than a leftward shift of the dose-response curve, an increase in Emax from clinically undetectable to clinically apparent explains the development of dyskinesia [31]. This hypothesis is also based on scanty data, three stable patients who exhibited mild dyskinesia at doses of levodopa that were as low or lower than those inducing an antiparkinsonian action in the subjects or dyskinesia in ¯uctuating subjects [23]. The Emax hypothesis would explain the increase in severity of levodopa-induced dyskinesia during long-term levodopa therapy. The third model contradicts both of the above models and suggests that neither the ED50 nor the Emax of the dose (concentration)-response curve for dyskinesia change during levodopa therapy [32]. These conclusions are based on longitudinal studies in 11 Parkinson's disease subjects who had received levodopa for an average of 4 years and had dyskinesia for 1 year upon entry to the study. Concentration (as opposed to dose) response curves were derived from pharmacokinetic±pharmacodynamic modeling. Instead of the dyskinesia concentration±response curve shifting, the antiparkinsonian concentration±response curve shifted to the right. That is, the threshold for the antiparkinsonian action increased during long-term therapy while that for dyskinesia did not change. The severity of dyskinesia (Emax) also did not change over the 3 years of the study although the scale used [33] is relatively insensitive to changes in severity of dyskinesia. It is obvious that more careful observations as dyskinesia initially appears is critical to deciding between these different models of development of dyskinesia. Understanding the clinical course of events will indicate the type and time course of biochemical events that might underlie development of dyskinesia. Two unproven concepts guide treatment of dyskinesia. The ®rst concept is that there are different thresholds for dyskinesia and for antiparkinsonian actions of levodopa. Most studies using single parenteral doses of levodopa ®nd that the thresholds for dyskinesia and antiparkinsonian actions are similar in wearing-off and on±off patients [23,28]. Thus, the concept of dosing to exceed the antiparkinsonian threshold and not the dyskinesia threshold is problematic, particularly, when the short half-life of levodopa is considered. The second concept is that severity of dyskinesia is dose related. Several studies have indicated that severity of
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To effectively treat ¯uctuations, it is important to have a clear picture of what is ¯uctuating and in what pattern. A careful history in the clinic may be suf®cient. If not, having the patient come to the clinic for several hours may allow the clinician to see the on and off states. The clinician should be aware that the response to the ®rst dose cycle may be different from the response to dose cycles later in the day. Home videos are another manner in which to see the on and off manifestations. Home diaries, with the patient, care giver and physician agreeing on what constitutes off and what constitutes on before the diary is ®lled out may yield diurnal patterns of response. It is important to recognize that the motor ¯uctuations are often accompanied by ¯uctuations in anxiety level, mood, autonomic function, and sensation. Anxiety, as part of the off experience, is frequently a major contributor to distress. It may be that therapy needs to be directed at these phenomena rather than to motor ¯uctuations.
netic characteristic of levodopa is the short plasma half-life. This in turn makes the variable absorption and distribution of levodopa very important. The most common cause of unpredictable responses is frequent small doses of levodopa. The duration of response to each dose of levodopa is, like other drugs, proportional to the size of the dose; larger doses give longer responses [35]. Small levodopa doses will give brief periods of motor improvement and thereby increase the motor ¯uctuations. Furthermore, because small doses will produce plasma concentrations that are closer to the threshold for antiparkinsonian effects, delays or reductions in absorption may cause individual doses to fail to reach threshold. Controlled release levodopa preparations are associated with more erratic absorption and consequently erratic responses in many subjects. Because of these considerations, when faced with a patient with seemingly unpredictable response to levodopa, a good strategy is to switch the patient to regular levodopa given at 3±4 h intervals without altering the total daily dose of levodopa. The schedule for administration of other antiparkinsonian agents should be adjusted so they are given with levodopa. This will almost always convert the unpredictable response into a predictable response and provide a starting point for adjusting medications. There is another bene®t of this regimen; a simpler regimen will increase compliance and reduce the variability caused by patients' efforts to titrate their medications with self developed, complex formulas based on response. The short half-life of levodopa (1±2 h) makes it impossible to maintain relatively constant plasma concentrations of levodopa. Further, the absorption of levodopa is largely in the small bowel so that variations in gastric emptying or bowel transit time may alter absorption. Avoiding giving levodopa with meals [36±38] or ferrous sulfate, [39] reconsidering the need for anticholinergics that may slow gastric emptying [40] and possibly adding antacids or domperidone to enhance gastric emptying [41,42] are methods to enhance absorption. Levodopa enters the brain via a saturable large neutral amino acid (LNAA) transporter and levodopa entry may be in¯uenced by plasma concentrations of LNAAs. Increases in LNAA concentrations after meals as well as the tendency for LNAA concentrations to increase during the day underlie some unpredictable motor ¯uctuations [36] and the diurnal pattern of declining response to levodopa during the day [27]. The standard American diet contains about twice the recommended daily amount of protein. Low protein diets will enhance levodopa effects [43] but are dif®cult to implement. Rather than a low protein diet, avoiding meals with very high protein may be the best compromise. A dietician may be very helpful to patients and also avoid protein malnutrition.
5.3. Making responses predictable
5.4. Making responses useable
Unpredictable levodopa responses are generally related to pharmacokinetic causes. The most important pharmacoki-
A predictable response that only lasts for a few minutes is of little use to the patient. The response must be of suf®cient
dyskinesia is not very dose related and more of an all or nothing phenomenon [23,30,34]. The duration of dyskinesia is, however, dose-related [23,30,34]. Thus small doses of levodopa will not necessarily reduce the severity of dyskinesia although they will shorten the time dyskinesia is present. By patient history, dyskinesia tends to have a diurnal pattern; if present, it tends to be more severe in the evening. 5. Treatment of ¯uctuations and dyskinesia 5.1. Aims The strategies for managing PD patients with motor ¯uctuations are dictated by the physicians clinical experience and his or her weighting of clinical studies and their interpretations. What follows is admittedly a personal algorithm and is a mixture of science and style. Several principles guide treating patients with ¯uctuations. First, educate the patient that ¯uctuations generally cannot be eliminated but may be made more bearable. Second, determine what ¯uctuates and what causes disability. Third, make responses predictable by controlling pharmacokinetic factors and administering adequate doses. Fourth, make the response to each dose suf®ciently long that it is useful to the patient. Fifth, reduce off disability. Sixth, avoid drug toxicity and tolerance by limiting cumulative doses of antiparkinsonian agents. Seventh, treat on dyskinesia and off dystonia. These will be considered in the following sections. 5.2. Determining what ¯uctuates
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duration that the patient can accomplish various activities. Methods to prolong the response to each dose of drug include giving larger doses of levodopa [23,34] using controlled release preparations in patients who do not have complicated ¯uctuations, adding dopamine agonists, selegiline, amantadine or COMT inhibitors. Amantadine, which is generally thought of as a drug to use in early PD, may be dramatically helpful in some ¯uctuating patients. There is a tendency to continue to escalate doses of antiparkinsonian agents to lengthen on time but the clinician should be aware that this is a strategy with diminishing returns. The most striking example of this phenomenon in our clinic was a 50-year-old man who had been maintained on carbidopa/levodopa 25/250 every 3 h who, to cope with wearing off at the end of each dose cycle, progressively increased his carbidopa/levodopa to 25/250 every 45 min around the clockÐand still had wearing off. This case and some studies suggest that tolerance develops with continuous therapy [44±48]. For this reason, it is worthwhile to try to limit the total drug intake and to provide some drug free periods, generally overnight. Another limitation to increasing antiparkinsonian medications is an exacerbation of dyskinesia which will be considered later. 5.5. Reducing off disability Dopamine agonists are often considered to reduce off disability although what has been measured in trials is a reduction in off time and off ADLs [49]. Pallidotomy reduces off severity in some investigators hands but not in others [50,51] and it is best to consider an improvement in off disability a bonus and not the indication for pallidotomy. Deep brain stimulation of the pallidum or subthalamic nucleus can reduce off severity [52±54] but is an experimental procedure at this point. Likewise, fetal mesencephalic grafting into the putamen may reduce off disability [55]. Anxiety, panic attacks and depression as off phenomena may be amenable to conventional therapy and thereby reduce the off distress. 5.6. Reducing cumulative drug intake There is a tendency to increase antiparkinsonian drugs during long-term treatment because an increase in levodopa will temporarily reduce off time. However, this bene®t wanes over weeks to months necessitating a further increase in levodopa. I try to keep patients on 1200 mg or less of levodopa per day. Sometimes, it is possible to get as good, if not better, control of ¯uctuations with lower doses of levodopa and with less adverse effects [56]. One strategy is to try to minimize levodopa use during the night and to focus on other methods to give the patient a comfortable night's sleep. Trazadone or benzodiazepines may help with sleep and therapy for restless legs, off dystonia and nocturia may improve sleep.
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5.7. Controlling on dyskinesia The ®rst strategy for reducing dyskinesia is to reduce antiparkinsonian medications that are adjunctive therapy and may contribute to dyskinesia. Selegiline can promote dyskinesia and is the ®rst drug to consider tapering and discontinuing, if possible. Levodopa controlled release preparations may increase dyskinesia and switching to immediate release may reduce dyskinesia and increase the predictability of a motor response. Dopamine agonists rarely cause dyskinesia by themselves, but added to levodopa they may augment dyskinesia. Therefore, stopping agonists may reduce dyskinesia. Levodopa itself may be reduced. As discussed above, trying to prevent dyskinesia by frequent small doses is generally ineffective and leads to short, unpredictable motor responses. A second strategy is to add drugs. Amantadine may have antidyskinetic effects and, paradoxically, may reduce dyskinesia while increasing on time. Buspirone has been reported to reduce dyskinesia [57] but is not dramatic in my experience. Adding dopamine agonists and reducing levodopa may be very effective, particularly if levodopa can be markedly reduced or stopped [58]. A third strategy, for severe, disabling dyskinesia, is pallidotomy contralateral to the most affected side [59,60]. Bilateral pallidotomy is effective at reducing dyskinesia bilaterally but with an unacceptable rate of speech, swallowing and balance problems. Unilateral pallidotomy combined with contralateral pallidal stimulation may, in the future, be a manner to prevent adverse effects of bilateral procedures. 5.8. Reducing off dystonia Off dystonia is a painful posture or cramp, generally occurring in the foot or leg, that appears when plasma levodopa concentrations are low. For this reason, off dystonia is particularly common in the morning before the ®rst morning dose of levodopa. Off dystonia is also frequently brought on by movement, typically walking to the bathroom upon arising. There are several methods to cope with this problem. The easiest is to have the patient take the ®rst dose of levodopa while in bed, perhaps dissolving the tablet in water to hasten absorption, and waiting 15±30 min before arising. A second method is to use a controlled release levodopa preparation at bedtime which will sometimes carry over to the next morning. A third method is to add a dopamine agonist to the antiparkinsonian drug regimen. Antispasticity drugs have been of little use in my experience. Finally, although off dystonia is rarely an indication for pallidotomy by itself, off dystonia, like on dyskinesia, is generally relieved by contralateral pallidotomy. 5.9. Prevention of motor complications The knowledge that levodopa-induced ¯uctuations and dyskinesia will complicate the management of many patients with parkinsonism, is dictating treatment of patients
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early in the course of the disease. As these complications are clearly related to levodopa and are rare to nonexistent with other drugs including the dopamine agonists, one strategy is to delay levodopa use until absolutely necessary to preserve the patient's function and to subsequently reduce levodopa use by combining levodopa with other antiparkinsonian drugs. There is no doubt that initiating dopaminergic treatment with dopamine agonists will delay the need for levodopa by 1±3 years and that the incidence of motor complications during that time will be very low [61]. However, when levodopa is added motor complications will emerge with the same or shortened latency as when levodopa is the ®rst dopaminergic treatment [61]. This may be related to the observation that delaying initiation of levodopa shortens the interval to appearance of motor ¯uctuations [62] probably because emergence of motor complications is related to disease severity [63]. Another strategy for early treatment of parkinsonism is based on the theoretical importance of pulsatile administration of levodopa to the development of motor complications [64]. Attempts to test this theory by comparing immediate release carbidopa/levodopa and controlled release preparations has not shown any difference in motor complications after 5 years of treatment [8]. Controlled release carbidopa/levodopa does not produce constant dopaminergic stimulation and so it may be argued that the failure to show differences is not a test of the theory. However, it is also important to realize that the animal studies supporting this theory are using levodopa doses that could be dif®cult to extrapolate to the clinic situation [65]. In conclusion, there are strong feelings about the proper manner to manage early PD patients but they are based more on interpretation of basic studies rather than proven clinical tenets [66,67]. Because motor ¯uctuations and dyskinesia are related to disease severity, another approach to minimizing ¯uctuations is to reduce the off disability. This means either increasing, or at least maintaining, the long-duration response and preventing or reversing the further loss of the endogenous nigrostriatal dopaminergic system. Neuroprotective strategies arguably are largely theoretical at this point [68]. Deep brain stimulation of pallidum [52,53] and subthalamic nucleus [54,69], fetal mesencephalic grafting [55,70] and perhaps pallidotomy may reduce off disability and thereby ¯uctuations. The mechanism underlying the long-duration response is completely mysterious and, when understood, may offer other strategies to improve function and reduce motor complications. Acknowledgements Preparation of this manuscript is supported in part by the National Parkinson's Foundation and by NIH grant 5 R01 NS21062±14. This manuscript was initially published as a syllabus for the American Academy of Neurology 1999 Annual Meeting.
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www.elsevier.com/locate/parkreldis
Motor ¯uctuations and dyskinesia in Parkinson's disease John G. Nutt* Departments of Neurology, and Physiology and Pharmacology, School of Medicine, Oregon Health Sciences University, Portland, OR 97201-3098, USA
Abstract Motor ¯uctuations and dyskinesia are common complications of long-term levodopa therapy. The neural and molecular mechanisms underlying their development are partially understood. A variety of clinical strategies may reduce the unpredictability of motor ¯uctuations and reduce their impact. Prevention of these complications remains an elusive goal. q 2001 Published by Elsevier Science Ltd. Keywords: Parkinson's disease; Levodopa; Motor ¯uctuations; Levodopa-induced dyskinesia
1. Introduction Motor ¯uctuations are an important contributor to the disability of PD. Fluctuations interrupt patients activities and are associated with other ¯uctuating phenomena such as mood, sensory and autonomic symptoms that add to the distress of motor ¯uctuations. Dyskinesia, a frequent accompaniment of motor ¯uctuations further compounds the problems. Motor ¯uctuations are not only important to patients who experience ¯uctuations; the threat of motor ¯uctuations dictates how patients are treated in early stages of the disease. Finally, motor ¯uctuations challenge our understanding of how the dopaminergic system functions and our concept of neurotransmitter replacement therapy for central nervous system diseases.
2. Prevalence of ¯uctuations and dyskinesia Motor ¯uctuations are generally seen as an inevitable consequence of long-term levodopa therapy. Sweet and McDowell found that 47% of the patients still alive and taking levodopa after 5 years had motor ¯uctuations and 49% had dyskinesia [1]. Barbeau found that 55% of his study group had motor ¯uctuations and 55% had dyskinesia after 6 years of treatment [2]. It should be noted that these early studies, shortly after the introduction of levodopa, very likely included patients with more severe disease than would be true in studies today that follow subjects from the initiation of levodopa therapy. Also, higher doses of levodopa were frequently used than is the practice today. * Tel.: 11-503-494-7231; fax: 11-503-494-7242. E-mail address: [email protected] (J.G. Nutt). 1353-8020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd. PII: S 1353-802 0(01)00024-4
Poewe et al. found that with low dose levodopa (less than 500 mg/day with decarboxylase inhibitor) after 6 years, 52% of the patients had motor ¯uctuations and 54% dyskinesia. With maximally tolerated doses at 6 years the prevalence of motor ¯uctuations was 80% and of dyskinesia was 88% [3]. Similarly, Heley et al. found that 41% of patients treated for 5 years with low dose levodopa/carbidopa had motor ¯uctuations and 55% had dyskinesia [4]. Age of onset of Parkinson's disease may in¯uence the occurrence of ¯uctuations; 96% of patients with onset of PD before age 40 had ¯uctuations after 5 years of levodopa treatment as opposed to 64% of case-matched patients with disease onset after age 40 [5]. Other studies in young onset PD have also found prevalence in excess of 90% for ¯uctuations and dyskinesia [6,7]. In contrast to these retrospective studies which found prevalence of ¯uctuations and dyskinesia of 40±96% after 5 or 6 years of levodopa therapy, a recent, large, double-blind, prospective study comparing 5 years of treatment with low dose, immediate release levodopa/carbidopa with controlled release levodopa/carbidopa found approximately 20% prevalence of motor ¯uctuations and dyskinesia by patient report or physician observation during out-patient clinic visits [8]. One possible explanation for this low prevalence of motor complications is that subjects with relatively mild parkinsonism were enrolled. A smaller, open, prospective study observed ¯uctuations in 13 of 18 subjects and dyskinesia in 11 subjects of 18 subjects monitored during a dose cycle after the ®rst year of levodopa treatment [9]. However, only six of the subjects reported ¯uctuations and three were aware of dyskinesia [9]. This discrepancy suggests that studies that depend upon patient report to determine prevalence of these complications will underestimate their prevalence and give a different picture of the natural history of these complications. On the other hand, patient reports will
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estimate the prevalence of ¯uctuations and dyskinesia that are clinically signi®cant. In sum, most studies indicate that motor complications are common after 5 years of levodopa therapy. There are hints that severity of disease, age of onset of parkinsonism and levodopa dose may in¯uence the time of onset of these problems. 3. Development of motor ¯uctuations The manner in which motor ¯uctuations develop is important to understanding the pathogenesis of the problem as well as designing therapies for motor ¯uctuations. The clinical impressions of how the response to levodopa changes differ somewhat from the measured changes in motor function that occur during long-term levodopa therapy. Accurately de®ning the natural history of how the response to levodopa changes during long-term therapy is important as the time course of changes may implicate and exclude various pathogenetic mechanisms for ¯uctuations and dyskinesia. Motor ¯uctuations are commonly envisioned to be due to a single effect of levodopa on motor function. However, there is evidence that the motor performance of a levodopa-treated PD patient is the summation of several different responses to levodopa plus contributions from endogenous dopamine [9,10]. There are at least three different motor responses to levodopa. The short-duration response is a motor improvement that roughly parallels the elevation of plasma levodopa after a dose of drug and is therefore measured in minutes to hours. The short-duration response is responsible for the peak motor response, the response that has been the focus of attention in the clinic and in basic and clinical research. The long-duration response, ®rst described by Cotzias [11] and Muenter [12] is a motor improvement that builds up over days and, likewise, decays over days. It has received relatively little attention. A negative or inhibitory response is a worsening of motor function that follows (and may precede) a short-duration response [13±15]. The negative response worsens the off condition for minutes up to an hour and is therefore sometimes termed the `super off'. These three responses to levodopa are superimposed on a diurnal pattern of motor function that is evident in levodopa untreated and treated PD patients. The diurnal motor pattern is characterized by better motor performance in the morning (sleep bene®t [16±18]) and worse function in the evenings. Finally, there is the residual endogenous dopaminergic function that presumably accounts for what motor function remains when a patient has been taken off levodopa for several weeks. This endogenous dopamine production may be virtually nil as indicated by the virtual immobility of severely affected, untreated PD patients. The endogenous dopamine plus the long-duration response are the main determinants of the off motor function. Currently, there is no method to dissociate the contributions of the long-duration levodopa response
and the endogenous dopamine production to motor function without prolonged withdrawal from levodopa which is usually precluded for ethical, medical and logistical reasons. The clinical de®nition of the stable response is a levodopa-induced improvement of motor function in the absence of motor ¯uctuations in a patient taking four or less doses of levodopa/carbidopa per day. The stable response is characteristically observed in patients early in the course of the disease and early in long-term levodopa therapy, the so-called honeymoon period that lasts several years. It is commonly envisioned that the stable response is due to the fact that the short-duration response to each dose of levodopa/carbidopa is suf®ciently long that the effects of each dose overlap with the previous dose to produce a sustained response. However, measurement of motor performance in patients with a stable response suggests that the sustained improvement appears to be largely due to the long-duration response. If patients' motor function is measured in the morning after 12 h without levodopa, or even several days without medication, it can be seen that their motor function is still appreciably better than before they began levodopa [9]. Stable responding subjects do have motor ¯uctuations related to the short-duration response that is superimposed on the long-duration response but the patients are unaware and untroubled by them [9]. The negative response and diurnal variation are usually unimportant at this stage. Motor ¯uctuations ®rst clinically appear as wearing-off, with bradykinesia emerging at the end of dose cycles or after being without levodopa overnight. This is commonly attributed to shortening of the short-duration response. Motor effects no longer seem to last the 4±6 h between doses. The short-duration response is briefer in wearingoff patients [19±22] but there is not a direct correlation with duration of action and presence of ¯uctuations nor are the differences between stable and ¯uctuating patients very great [20,22]. The often ignored characteristic of ¯uctuating patients is that there is a large, clinically appreciable difference in motor function between the on and off motor states [20,22,23]. Thus, another change between ¯uctuating and stable patients is that the short-duration response, generally measurable from the beginning of therapy, becomes larger and clinically more signi®cant. The peak levodopa response does not increase; rather deterioration in the off motor function makes the magnitude of the short-duration response larger. Precisely how much of this deterioration in the off motor function is related to changes in the longduration response and how much is related to further loss of endogenous dopaminergic function is unknown. We do know that a long-duration response is still present in severely affected PD patients [24,25] and is approximately the magnitude of the long-duration response in less severe PD patients. Thus, loss of endogenous dopamine production seems more likely to explain the increasing off motor disability. The negative response may also appear at this time and further augment off disability. Finally, diurnal
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patterns of response become apparent with better function in the morning and poorer response to medications in the afternoon [26,27]. The more marked motor ¯uctuations, termed on±off, are clinically characterized by rapid switches between on and off, seemingly unrelated to oral dosing with levodopa. It occurs in severely affected patients with large differences in on and off motor function who are on complex, frequent dosing regimens. The unpredictable response to oral levodopa is in contrast to the predictable, dose-responsive responses to intravenous boluses or brief infusions in these patients [23,28]. This observation indicates that the unpredictable on±off response is largely pharmacokinetic in origin. Unpredictability is enhanced by administering frequent, small doses of levodopa in the vain hope that this strategy will yield relatively constant plasma levodopa concentrations. 4. Development of levodopa-induced dyskinesia Dyskinesia is almost an invariable component of motor ¯uctuations and a consideration in treating ¯uctuations. Dyskinesia occurring when the patient is on is frequently termed peak-dose dyskinesia. This term is misleading in that dyskinesia is generally present throughout the time the patient is on and is either physically, emotionally or cognitively active (i.e., dyskinesia is brought out by motor activity and any form of stress and conversely, is reduced by relaxation and inactivity). Furthermore, many patients have an increase in dyskinesia at the beginning and end of a dose cycle, a mild form of the so called diphasic dyskinesia [29]. How the dyskinesia dose-response relationship is altered during long-term levodopa therapy should offer clues to the pathogenesis of dyskinesia. The thresholds and time course for dyskinesia and antiparkinsonian effects are reported to be similar in patients with motor ¯uctuations [28,30]. The important question is what happens during the ®rst months of treatment as dyskinesia ®rst appears. There are three hypotheses. One hypothesis is that the threshold for dyskinesia is initially much higher than that for an antiparkinsonian effect and that the dyskinesia threshold is lowered by repeated dosing of levodopa until it approximates the antiparkinsonian effect threshold [28,30]. The threshold is a marker for the initial in¯ection of the dose-response curve or the equivalent of an .effective dose 05 0 (dose producing 5% of the maximum response). Thus, lowering of the dyskinesia threshold would be equivalent to shifting the dose-response curve to the left. The slope of the dyskinesia dose-response curve and the maximum response (Emax) could also change but the essential feature is the leftward shift and reduction of dose required to produce dyskinesia (often expressed as the reduction in ED50, the dose producing two of the maximum response). The problem with this hypothesis is that there
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have been few [28] or no [30] subjects described with newly developed dyskinesia that fall between the subjects who have no dyskinesia at all (and in whom no threshold can be determined because they do not have dyskinesia) and the ¯uctuating subjects with dyskinesia thresholds that are similar to antiparkinsonian thresholds. Thus there are no subjects with dyskinesia in whom to demonstrate the initial high threshold postulated by this model. In conclusion, although intuitively attractive, the leftward shift of the dose-response curve is an unproven model of how dyskinesia develops. A second model is that rather than a leftward shift of the dose-response curve, an increase in Emax from clinically undetectable to clinically apparent explains the development of dyskinesia [31]. This hypothesis is also based on scanty data, three stable patients who exhibited mild dyskinesia at doses of levodopa that were as low or lower than those inducing an antiparkinsonian action in the subjects or dyskinesia in ¯uctuating subjects [23]. The Emax hypothesis would explain the increase in severity of levodopa-induced dyskinesia during long-term levodopa therapy. The third model contradicts both of the above models and suggests that neither the ED50 nor the Emax of the dose (concentration)-response curve for dyskinesia change during levodopa therapy [32]. These conclusions are based on longitudinal studies in 11 Parkinson's disease subjects who had received levodopa for an average of 4 years and had dyskinesia for 1 year upon entry to the study. Concentration (as opposed to dose) response curves were derived from pharmacokinetic±pharmacodynamic modeling. Instead of the dyskinesia concentration±response curve shifting, the antiparkinsonian concentration±response curve shifted to the right. That is, the threshold for the antiparkinsonian action increased during long-term therapy while that for dyskinesia did not change. The severity of dyskinesia (Emax) also did not change over the 3 years of the study although the scale used [33] is relatively insensitive to changes in severity of dyskinesia. It is obvious that more careful observations as dyskinesia initially appears is critical to deciding between these different models of development of dyskinesia. Understanding the clinical course of events will indicate the type and time course of biochemical events that might underlie development of dyskinesia. Two unproven concepts guide treatment of dyskinesia. The ®rst concept is that there are different thresholds for dyskinesia and for antiparkinsonian actions of levodopa. Most studies using single parenteral doses of levodopa ®nd that the thresholds for dyskinesia and antiparkinsonian actions are similar in wearing-off and on±off patients [23,28]. Thus, the concept of dosing to exceed the antiparkinsonian threshold and not the dyskinesia threshold is problematic, particularly, when the short half-life of levodopa is considered. The second concept is that severity of dyskinesia is dose related. Several studies have indicated that severity of
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To effectively treat ¯uctuations, it is important to have a clear picture of what is ¯uctuating and in what pattern. A careful history in the clinic may be suf®cient. If not, having the patient come to the clinic for several hours may allow the clinician to see the on and off states. The clinician should be aware that the response to the ®rst dose cycle may be different from the response to dose cycles later in the day. Home videos are another manner in which to see the on and off manifestations. Home diaries, with the patient, care giver and physician agreeing on what constitutes off and what constitutes on before the diary is ®lled out may yield diurnal patterns of response. It is important to recognize that the motor ¯uctuations are often accompanied by ¯uctuations in anxiety level, mood, autonomic function, and sensation. Anxiety, as part of the off experience, is frequently a major contributor to distress. It may be that therapy needs to be directed at these phenomena rather than to motor ¯uctuations.
netic characteristic of levodopa is the short plasma half-life. This in turn makes the variable absorption and distribution of levodopa very important. The most common cause of unpredictable responses is frequent small doses of levodopa. The duration of response to each dose of levodopa is, like other drugs, proportional to the size of the dose; larger doses give longer responses [35]. Small levodopa doses will give brief periods of motor improvement and thereby increase the motor ¯uctuations. Furthermore, because small doses will produce plasma concentrations that are closer to the threshold for antiparkinsonian effects, delays or reductions in absorption may cause individual doses to fail to reach threshold. Controlled release levodopa preparations are associated with more erratic absorption and consequently erratic responses in many subjects. Because of these considerations, when faced with a patient with seemingly unpredictable response to levodopa, a good strategy is to switch the patient to regular levodopa given at 3±4 h intervals without altering the total daily dose of levodopa. The schedule for administration of other antiparkinsonian agents should be adjusted so they are given with levodopa. This will almost always convert the unpredictable response into a predictable response and provide a starting point for adjusting medications. There is another bene®t of this regimen; a simpler regimen will increase compliance and reduce the variability caused by patients' efforts to titrate their medications with self developed, complex formulas based on response. The short half-life of levodopa (1±2 h) makes it impossible to maintain relatively constant plasma concentrations of levodopa. Further, the absorption of levodopa is largely in the small bowel so that variations in gastric emptying or bowel transit time may alter absorption. Avoiding giving levodopa with meals [36±38] or ferrous sulfate, [39] reconsidering the need for anticholinergics that may slow gastric emptying [40] and possibly adding antacids or domperidone to enhance gastric emptying [41,42] are methods to enhance absorption. Levodopa enters the brain via a saturable large neutral amino acid (LNAA) transporter and levodopa entry may be in¯uenced by plasma concentrations of LNAAs. Increases in LNAA concentrations after meals as well as the tendency for LNAA concentrations to increase during the day underlie some unpredictable motor ¯uctuations [36] and the diurnal pattern of declining response to levodopa during the day [27]. The standard American diet contains about twice the recommended daily amount of protein. Low protein diets will enhance levodopa effects [43] but are dif®cult to implement. Rather than a low protein diet, avoiding meals with very high protein may be the best compromise. A dietician may be very helpful to patients and also avoid protein malnutrition.
5.3. Making responses predictable
5.4. Making responses useable
Unpredictable levodopa responses are generally related to pharmacokinetic causes. The most important pharmacoki-
A predictable response that only lasts for a few minutes is of little use to the patient. The response must be of suf®cient
dyskinesia is not very dose related and more of an all or nothing phenomenon [23,30,34]. The duration of dyskinesia is, however, dose-related [23,30,34]. Thus small doses of levodopa will not necessarily reduce the severity of dyskinesia although they will shorten the time dyskinesia is present. By patient history, dyskinesia tends to have a diurnal pattern; if present, it tends to be more severe in the evening. 5. Treatment of ¯uctuations and dyskinesia 5.1. Aims The strategies for managing PD patients with motor ¯uctuations are dictated by the physicians clinical experience and his or her weighting of clinical studies and their interpretations. What follows is admittedly a personal algorithm and is a mixture of science and style. Several principles guide treating patients with ¯uctuations. First, educate the patient that ¯uctuations generally cannot be eliminated but may be made more bearable. Second, determine what ¯uctuates and what causes disability. Third, make responses predictable by controlling pharmacokinetic factors and administering adequate doses. Fourth, make the response to each dose suf®ciently long that it is useful to the patient. Fifth, reduce off disability. Sixth, avoid drug toxicity and tolerance by limiting cumulative doses of antiparkinsonian agents. Seventh, treat on dyskinesia and off dystonia. These will be considered in the following sections. 5.2. Determining what ¯uctuates
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duration that the patient can accomplish various activities. Methods to prolong the response to each dose of drug include giving larger doses of levodopa [23,34] using controlled release preparations in patients who do not have complicated ¯uctuations, adding dopamine agonists, selegiline, amantadine or COMT inhibitors. Amantadine, which is generally thought of as a drug to use in early PD, may be dramatically helpful in some ¯uctuating patients. There is a tendency to continue to escalate doses of antiparkinsonian agents to lengthen on time but the clinician should be aware that this is a strategy with diminishing returns. The most striking example of this phenomenon in our clinic was a 50-year-old man who had been maintained on carbidopa/levodopa 25/250 every 3 h who, to cope with wearing off at the end of each dose cycle, progressively increased his carbidopa/levodopa to 25/250 every 45 min around the clockÐand still had wearing off. This case and some studies suggest that tolerance develops with continuous therapy [44±48]. For this reason, it is worthwhile to try to limit the total drug intake and to provide some drug free periods, generally overnight. Another limitation to increasing antiparkinsonian medications is an exacerbation of dyskinesia which will be considered later. 5.5. Reducing off disability Dopamine agonists are often considered to reduce off disability although what has been measured in trials is a reduction in off time and off ADLs [49]. Pallidotomy reduces off severity in some investigators hands but not in others [50,51] and it is best to consider an improvement in off disability a bonus and not the indication for pallidotomy. Deep brain stimulation of the pallidum or subthalamic nucleus can reduce off severity [52±54] but is an experimental procedure at this point. Likewise, fetal mesencephalic grafting into the putamen may reduce off disability [55]. Anxiety, panic attacks and depression as off phenomena may be amenable to conventional therapy and thereby reduce the off distress. 5.6. Reducing cumulative drug intake There is a tendency to increase antiparkinsonian drugs during long-term treatment because an increase in levodopa will temporarily reduce off time. However, this bene®t wanes over weeks to months necessitating a further increase in levodopa. I try to keep patients on 1200 mg or less of levodopa per day. Sometimes, it is possible to get as good, if not better, control of ¯uctuations with lower doses of levodopa and with less adverse effects [56]. One strategy is to try to minimize levodopa use during the night and to focus on other methods to give the patient a comfortable night's sleep. Trazadone or benzodiazepines may help with sleep and therapy for restless legs, off dystonia and nocturia may improve sleep.
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5.7. Controlling on dyskinesia The ®rst strategy for reducing dyskinesia is to reduce antiparkinsonian medications that are adjunctive therapy and may contribute to dyskinesia. Selegiline can promote dyskinesia and is the ®rst drug to consider tapering and discontinuing, if possible. Levodopa controlled release preparations may increase dyskinesia and switching to immediate release may reduce dyskinesia and increase the predictability of a motor response. Dopamine agonists rarely cause dyskinesia by themselves, but added to levodopa they may augment dyskinesia. Therefore, stopping agonists may reduce dyskinesia. Levodopa itself may be reduced. As discussed above, trying to prevent dyskinesia by frequent small doses is generally ineffective and leads to short, unpredictable motor responses. A second strategy is to add drugs. Amantadine may have antidyskinetic effects and, paradoxically, may reduce dyskinesia while increasing on time. Buspirone has been reported to reduce dyskinesia [57] but is not dramatic in my experience. Adding dopamine agonists and reducing levodopa may be very effective, particularly if levodopa can be markedly reduced or stopped [58]. A third strategy, for severe, disabling dyskinesia, is pallidotomy contralateral to the most affected side [59,60]. Bilateral pallidotomy is effective at reducing dyskinesia bilaterally but with an unacceptable rate of speech, swallowing and balance problems. Unilateral pallidotomy combined with contralateral pallidal stimulation may, in the future, be a manner to prevent adverse effects of bilateral procedures. 5.8. Reducing off dystonia Off dystonia is a painful posture or cramp, generally occurring in the foot or leg, that appears when plasma levodopa concentrations are low. For this reason, off dystonia is particularly common in the morning before the ®rst morning dose of levodopa. Off dystonia is also frequently brought on by movement, typically walking to the bathroom upon arising. There are several methods to cope with this problem. The easiest is to have the patient take the ®rst dose of levodopa while in bed, perhaps dissolving the tablet in water to hasten absorption, and waiting 15±30 min before arising. A second method is to use a controlled release levodopa preparation at bedtime which will sometimes carry over to the next morning. A third method is to add a dopamine agonist to the antiparkinsonian drug regimen. Antispasticity drugs have been of little use in my experience. Finally, although off dystonia is rarely an indication for pallidotomy by itself, off dystonia, like on dyskinesia, is generally relieved by contralateral pallidotomy. 5.9. Prevention of motor complications The knowledge that levodopa-induced ¯uctuations and dyskinesia will complicate the management of many patients with parkinsonism, is dictating treatment of patients
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early in the course of the disease. As these complications are clearly related to levodopa and are rare to nonexistent with other drugs including the dopamine agonists, one strategy is to delay levodopa use until absolutely necessary to preserve the patient's function and to subsequently reduce levodopa use by combining levodopa with other antiparkinsonian drugs. There is no doubt that initiating dopaminergic treatment with dopamine agonists will delay the need for levodopa by 1±3 years and that the incidence of motor complications during that time will be very low [61]. However, when levodopa is added motor complications will emerge with the same or shortened latency as when levodopa is the ®rst dopaminergic treatment [61]. This may be related to the observation that delaying initiation of levodopa shortens the interval to appearance of motor ¯uctuations [62] probably because emergence of motor complications is related to disease severity [63]. Another strategy for early treatment of parkinsonism is based on the theoretical importance of pulsatile administration of levodopa to the development of motor complications [64]. Attempts to test this theory by comparing immediate release carbidopa/levodopa and controlled release preparations has not shown any difference in motor complications after 5 years of treatment [8]. Controlled release carbidopa/levodopa does not produce constant dopaminergic stimulation and so it may be argued that the failure to show differences is not a test of the theory. However, it is also important to realize that the animal studies supporting this theory are using levodopa doses that could be dif®cult to extrapolate to the clinic situation [65]. In conclusion, there are strong feelings about the proper manner to manage early PD patients but they are based more on interpretation of basic studies rather than proven clinical tenets [66,67]. Because motor ¯uctuations and dyskinesia are related to disease severity, another approach to minimizing ¯uctuations is to reduce the off disability. This means either increasing, or at least maintaining, the long-duration response and preventing or reversing the further loss of the endogenous nigrostriatal dopaminergic system. Neuroprotective strategies arguably are largely theoretical at this point [68]. Deep brain stimulation of pallidum [52,53] and subthalamic nucleus [54,69], fetal mesencephalic grafting [55,70] and perhaps pallidotomy may reduce off disability and thereby ¯uctuations. The mechanism underlying the long-duration response is completely mysterious and, when understood, may offer other strategies to improve function and reduce motor complications. Acknowledgements Preparation of this manuscript is supported in part by the National Parkinson's Foundation and by NIH grant 5 R01 NS21062±14. This manuscript was initially published as a syllabus for the American Academy of Neurology 1999 Annual Meeting.
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