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Levodopa, motor complications and disease progression
Journal of the Neurological Sciences 273 (2008) 155–157
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j n s
Letters to the Editor
Levodopa, motor complications and disease progression Dear Sir, I read with great interest the review of Bhidayasiri and Truong on the clinical manifestations and management of motor complications in Parkinson disease [1]. I congratulate the authors for their concise and comprehensive review of this very intricate but still enigmatic matter. I have a few comments though. Firstly, in contrast to general notions, literature data and clinical experience clearly show that motor complications are actually occurring as early as the first few months following the start of levodopa therapy [2,3]. Secondly, the authors correctly state that in the early stage of Parkinson disease, the long-duration response (LDR) to levodopa provides a long-lasting clinical improvement, while the superimposed SDR accounts for the rapid onset and brief duration effects. However unlike suggested, there is little evidence that the loss of levodopa's LDR contributes
significantly to ‘wearing-off’ and that this LDR is related to the capacity of the nigrostriatal dopaminergic neurons to produce, store and tonically release dopamine in the synaptic cleft. Emerging data derived from studies with dopamine agonists [4,5] suggests that LDR to levodopa is mediated through long-lasting effects on postsynaptic membrane excitability or synaptic transmission through the activation of proto-oncogenes (e.g. c-fos) [3]. Last but not least, the authors reviewed the risk factors for the pathogenesis of motor complications but ignored an important issue being the pharmacodynamic alterations to levodopa in the effector compartment related to disease progression. With advancing disease severity, the LDR to levodopa becomes less noticeable and the SDR becomes more prominent, frequently governing the patient's motor status (Fig. 1). Indeed, in the early stage of the disease, levodopa's LDR accounts for a large portion of the ‘on’-time during repetitive levodopa dosing (left panel of Fig. 1) while the impact of levodopa's SDR is almost negligible. With disease progression, the threshold for motor response to levodopa gradually
Fig. 1. Left panel: in the early stage Parkinson disease the LDR to levodopa governs most of the ‘on’ effect. The SDR is superimposed on the LDR but contributes relatively little to the patients' ‘on’ time. Middle panel: in the early advanced stage the SDR becomes more prominent with ‘wearing-off’ phenomenon. Right panel: the late advanced stage is characterized by prominent changes in levodopa's pharmacodynamics resulting in the motor responses observed. Note the gradual increase in threshold for the motor response to levodopa and the lowering of the threshold for dyskinesia associated with disease progression. The magnitude of the SDR is determined by the baseline (disease severity) at each stage. 0022-510X/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
156
Letters to the Editor
increases, while the threshold for dyskinesias gradually decreases, compromizing levodopa's therapeutic window. Furthermore, disease progression is associated with significant alterations in levodopa kinetic-dynamic variables: i) shortening of the levodopa equilibration half-life (t1/2eq) between plasma drug concentration and motor response; ii) increase levodopa concentration in the effector compartment producing 50% of the maximum response (EC50); and iii) an increasing steepness of the levodopa concentration-response curve. The latter in conjunction with a gradual shortened t1/2eq results clinically – in fluctuating compared to stable patients – in a levodopa motor response which has a faster onset and offset (“all-or-nothing” response), as well as a shorter duration, finally accounting for the reduced ‘on’-time in the late advanced stage (right panel of Fig. 1) [6]. The magnitude of the SDR to levodopa remains essentially unchanged, but because of advanced disease severity there is lowering of the baseline (end-of-dose or through performance decline) resulting in a larger increment of improvement. References [1] Bhidayasiri R, Truong D. Motor complications in Parkinson disease: clinical manifestations and management. J Neurol Sci 2008;266:204–15. [2] Nutt JG. Continuous dopaminergic stimulation: is it the answer to the motor complications of Levodopa? Mov Disord 2007;22:1–9. [3] Nutt JG, Carter JH, Van Houten L, Woodward WR. Short- and long-duration responses to levodopa during the first year of levodopa therapy. Ann Neurol 1997;42:349–55. [4] Nutt JG, Carter JH. Apomorphine can sustain the long-duration response to l-dopa in fluctuating PD. Neurology 2000;54:247–50. [5] Barbato L, Stocchi F, Monge A, et al. The long-duration action of levodopa may be due to a post-synaptic effect. Clin Neuropharmacol 1997;20:394–401. [6] Contin M, Riva R, Martinelli P, Albani F, Avoni P, Baruzzi A. Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. Ther Drug Monit 2001;23:621–9.
Dirk Deleu Department of Neurology (Medicine), Hamad Medical Corporation, P.O. Box 3050, Doha, State of Qatar E-mail address: [email protected]. 31 March 2008 doi:10.1016/j.jns.2008.06.001
Reply from the authors: Motor complications in Parkinson disease: Clinical manifestations and management We appreciate the comments made by Dr. Deleu's and his interest in our review article [1]. As noted by Dr. Deleu, although we tried to be as comprehensive as possible in our review, the scope of our article is necessarily limited. Whether motor complications actually occur as early as the first few months following initiation of levodopa therapy is currently not clear [2,3]. Dopaminergic denervation in PD alone is not sufficient to explain levodopa-related motor complications because these problems do not usually occur with the first dose of levodopa, but require continued administration of the drug [4]. In addition to the duration of levodopa exposure, the latency between initiation of levodopa therapy and the appearance of motor complications varies and may be related to other factors, such as the severity of parkinsonism [2,5]. The recent ELLDOPA study demonstrated that motor complications in levodopa-treated patients are dose-related and begin earlier than was previously appreciated, but are not limited to the first few months following the start of levodopa [6]. In this trial, after 9 months of levodopa treatment (200 mg three times daily), 20% of patients experienced wearing off and 16% had dyskinesias [6]. Hence, 80% to 84% of patients in the ELLDOPA study still had not developed motor complications after the study
completion. Lastly, the risk of developing motor complications may also increase in patients with young-onset disease [7,8]. Secondly, we agree with Dr. Deleu that shortening of the LDR does not completely explain the development of the fluctuating response to levodopa. In early PD, intrasynaptic dopamine formed from exogenous levodopa is believed to be largely synthesized and stored in the striatal dopaminergic terminals. Dopamine storage in nerve terminal vesicles explains why the effects of levodopa initially last for several hours despite a much shorter half-life (90 min) [9]. With the progressive degeneration of substantia nigra neurons, less exogenous levodopa enters the striatal terminals. Increasing amounts are taken up and converted to dopamine in other decarboxylase containing cells. Therefore, the newly synthesized amine quickly leaks from these cells into the interstitial space, from which it can diffuse and come into contact with nearby dopamine receptors. Under these circumstances, intrasynaptic dopamine concentrations reflect the broad swings in plasma and cerebral levodopa levels. Since the capacity of dopaminergic terminals to store dopamine decreases, the antiparkinsonian effect of levodopa progressively shortens, partly explaining the occurrence of “wearing-off” symptoms [10]. While a decreased ability to store dopamine in remaining dopaminergic nerve terminals may explain the shortening of the response to each dose of levodopa, the mechanisms of motor complications, which emerge over months to years after levodopa therapy, are much more complex. Tolerance to levodopa may develop with chronic therapy. Increasing evidence also indicates that other factors, such as the effects on postsynaptic membrane excitability, the variation in absorption and distribution of levodopa, or firing pattern of basal ganglia neurons can contribute to the subsequent appearance of motor complications [9,11]. Studies in dopamine-denervated mice, monkeys, and even postmortem brains of PD patients have shown that dysknesia induced by short-acting dopaminergic drugs is associated with altered expression of different genes or proteins, including not only cFos, but also preproenkephalin, preprodynorphin, delta, FosB, JunB, ERK1/2, DARP32 and D1-signalling proteins [12]. Precisely how these molecular and physiological changes lead to dyskinesia is not completely understood. The ways in which the dose–response relationship is altered during long-term levodopa therapy offer clues to the pathogenesis of motor complications. Although different concepts have been proposed, as detailed in Dr. Deleu's comments, no single theory/concept is capable of explaining the full spectrum of motor complications, especially from what happens during the initial months of levodopa treatment. While the concept of different thresholds for dyskinesia and antiparkinsonian actions of levodopa appears to be attractive, it is not supported by studies involving parenteral doses of levodopa, which suggest that the majority of PD patients have a similar threshold for both dyskinesia and motor benefit [13]. Furthermore, the severity of dyskinesia is not dose-related but more of an all-or-nothing phenomenon [14,15]. Therefore, a small decrement of levodopa dose does not usually ameliorate dyskinesia but tends to shorten the duration of dyskinesia. Despite the equivocal evidence, a method of eliminating the peaks and troughs in levodopa concentration by intravenous infusion of certain dopamine agonists or enteric levodopa infusion may lessen or prevent the development of motor complications [16]. Whether continuous dopamine stimulation is desirable requires further study. References [1] Bhidayasiri R, Truong DD. Motor complications in Parkinson disease: clinical manifestations and management. J Neurol Sci 2008;266(1–2):204–15. [2] Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16:448–58. [3] Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47(4 Suppl 1): S2–9 [discussion S9–11.]. [4] Gunzler SA, Nutt JG. Motor fluctuations and dyskinesias. In: Factor SA, Weiner WJ, editors. Parkinson's disease: diagnosis and clinical management. 2nd ed. Demos Medical Publishing; 2007. p. 575–83.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j n s
Letters to the Editor
Levodopa, motor complications and disease progression Dear Sir, I read with great interest the review of Bhidayasiri and Truong on the clinical manifestations and management of motor complications in Parkinson disease [1]. I congratulate the authors for their concise and comprehensive review of this very intricate but still enigmatic matter. I have a few comments though. Firstly, in contrast to general notions, literature data and clinical experience clearly show that motor complications are actually occurring as early as the first few months following the start of levodopa therapy [2,3]. Secondly, the authors correctly state that in the early stage of Parkinson disease, the long-duration response (LDR) to levodopa provides a long-lasting clinical improvement, while the superimposed SDR accounts for the rapid onset and brief duration effects. However unlike suggested, there is little evidence that the loss of levodopa's LDR contributes
significantly to ‘wearing-off’ and that this LDR is related to the capacity of the nigrostriatal dopaminergic neurons to produce, store and tonically release dopamine in the synaptic cleft. Emerging data derived from studies with dopamine agonists [4,5] suggests that LDR to levodopa is mediated through long-lasting effects on postsynaptic membrane excitability or synaptic transmission through the activation of proto-oncogenes (e.g. c-fos) [3]. Last but not least, the authors reviewed the risk factors for the pathogenesis of motor complications but ignored an important issue being the pharmacodynamic alterations to levodopa in the effector compartment related to disease progression. With advancing disease severity, the LDR to levodopa becomes less noticeable and the SDR becomes more prominent, frequently governing the patient's motor status (Fig. 1). Indeed, in the early stage of the disease, levodopa's LDR accounts for a large portion of the ‘on’-time during repetitive levodopa dosing (left panel of Fig. 1) while the impact of levodopa's SDR is almost negligible. With disease progression, the threshold for motor response to levodopa gradually
Fig. 1. Left panel: in the early stage Parkinson disease the LDR to levodopa governs most of the ‘on’ effect. The SDR is superimposed on the LDR but contributes relatively little to the patients' ‘on’ time. Middle panel: in the early advanced stage the SDR becomes more prominent with ‘wearing-off’ phenomenon. Right panel: the late advanced stage is characterized by prominent changes in levodopa's pharmacodynamics resulting in the motor responses observed. Note the gradual increase in threshold for the motor response to levodopa and the lowering of the threshold for dyskinesia associated with disease progression. The magnitude of the SDR is determined by the baseline (disease severity) at each stage. 0022-510X/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
156
Letters to the Editor
increases, while the threshold for dyskinesias gradually decreases, compromizing levodopa's therapeutic window. Furthermore, disease progression is associated with significant alterations in levodopa kinetic-dynamic variables: i) shortening of the levodopa equilibration half-life (t1/2eq) between plasma drug concentration and motor response; ii) increase levodopa concentration in the effector compartment producing 50% of the maximum response (EC50); and iii) an increasing steepness of the levodopa concentration-response curve. The latter in conjunction with a gradual shortened t1/2eq results clinically – in fluctuating compared to stable patients – in a levodopa motor response which has a faster onset and offset (“all-or-nothing” response), as well as a shorter duration, finally accounting for the reduced ‘on’-time in the late advanced stage (right panel of Fig. 1) [6]. The magnitude of the SDR to levodopa remains essentially unchanged, but because of advanced disease severity there is lowering of the baseline (end-of-dose or through performance decline) resulting in a larger increment of improvement. References [1] Bhidayasiri R, Truong D. Motor complications in Parkinson disease: clinical manifestations and management. J Neurol Sci 2008;266:204–15. [2] Nutt JG. Continuous dopaminergic stimulation: is it the answer to the motor complications of Levodopa? Mov Disord 2007;22:1–9. [3] Nutt JG, Carter JH, Van Houten L, Woodward WR. Short- and long-duration responses to levodopa during the first year of levodopa therapy. Ann Neurol 1997;42:349–55. [4] Nutt JG, Carter JH. Apomorphine can sustain the long-duration response to l-dopa in fluctuating PD. Neurology 2000;54:247–50. [5] Barbato L, Stocchi F, Monge A, et al. The long-duration action of levodopa may be due to a post-synaptic effect. Clin Neuropharmacol 1997;20:394–401. [6] Contin M, Riva R, Martinelli P, Albani F, Avoni P, Baruzzi A. Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. Ther Drug Monit 2001;23:621–9.
Dirk Deleu Department of Neurology (Medicine), Hamad Medical Corporation, P.O. Box 3050, Doha, State of Qatar E-mail address: [email protected]. 31 March 2008 doi:10.1016/j.jns.2008.06.001
Reply from the authors: Motor complications in Parkinson disease: Clinical manifestations and management We appreciate the comments made by Dr. Deleu's and his interest in our review article [1]. As noted by Dr. Deleu, although we tried to be as comprehensive as possible in our review, the scope of our article is necessarily limited. Whether motor complications actually occur as early as the first few months following initiation of levodopa therapy is currently not clear [2,3]. Dopaminergic denervation in PD alone is not sufficient to explain levodopa-related motor complications because these problems do not usually occur with the first dose of levodopa, but require continued administration of the drug [4]. In addition to the duration of levodopa exposure, the latency between initiation of levodopa therapy and the appearance of motor complications varies and may be related to other factors, such as the severity of parkinsonism [2,5]. The recent ELLDOPA study demonstrated that motor complications in levodopa-treated patients are dose-related and begin earlier than was previously appreciated, but are not limited to the first few months following the start of levodopa [6]. In this trial, after 9 months of levodopa treatment (200 mg three times daily), 20% of patients experienced wearing off and 16% had dyskinesias [6]. Hence, 80% to 84% of patients in the ELLDOPA study still had not developed motor complications after the study
completion. Lastly, the risk of developing motor complications may also increase in patients with young-onset disease [7,8]. Secondly, we agree with Dr. Deleu that shortening of the LDR does not completely explain the development of the fluctuating response to levodopa. In early PD, intrasynaptic dopamine formed from exogenous levodopa is believed to be largely synthesized and stored in the striatal dopaminergic terminals. Dopamine storage in nerve terminal vesicles explains why the effects of levodopa initially last for several hours despite a much shorter half-life (90 min) [9]. With the progressive degeneration of substantia nigra neurons, less exogenous levodopa enters the striatal terminals. Increasing amounts are taken up and converted to dopamine in other decarboxylase containing cells. Therefore, the newly synthesized amine quickly leaks from these cells into the interstitial space, from which it can diffuse and come into contact with nearby dopamine receptors. Under these circumstances, intrasynaptic dopamine concentrations reflect the broad swings in plasma and cerebral levodopa levels. Since the capacity of dopaminergic terminals to store dopamine decreases, the antiparkinsonian effect of levodopa progressively shortens, partly explaining the occurrence of “wearing-off” symptoms [10]. While a decreased ability to store dopamine in remaining dopaminergic nerve terminals may explain the shortening of the response to each dose of levodopa, the mechanisms of motor complications, which emerge over months to years after levodopa therapy, are much more complex. Tolerance to levodopa may develop with chronic therapy. Increasing evidence also indicates that other factors, such as the effects on postsynaptic membrane excitability, the variation in absorption and distribution of levodopa, or firing pattern of basal ganglia neurons can contribute to the subsequent appearance of motor complications [9,11]. Studies in dopamine-denervated mice, monkeys, and even postmortem brains of PD patients have shown that dysknesia induced by short-acting dopaminergic drugs is associated with altered expression of different genes or proteins, including not only cFos, but also preproenkephalin, preprodynorphin, delta, FosB, JunB, ERK1/2, DARP32 and D1-signalling proteins [12]. Precisely how these molecular and physiological changes lead to dyskinesia is not completely understood. The ways in which the dose–response relationship is altered during long-term levodopa therapy offer clues to the pathogenesis of motor complications. Although different concepts have been proposed, as detailed in Dr. Deleu's comments, no single theory/concept is capable of explaining the full spectrum of motor complications, especially from what happens during the initial months of levodopa treatment. While the concept of different thresholds for dyskinesia and antiparkinsonian actions of levodopa appears to be attractive, it is not supported by studies involving parenteral doses of levodopa, which suggest that the majority of PD patients have a similar threshold for both dyskinesia and motor benefit [13]. Furthermore, the severity of dyskinesia is not dose-related but more of an all-or-nothing phenomenon [14,15]. Therefore, a small decrement of levodopa dose does not usually ameliorate dyskinesia but tends to shorten the duration of dyskinesia. Despite the equivocal evidence, a method of eliminating the peaks and troughs in levodopa concentration by intravenous infusion of certain dopamine agonists or enteric levodopa infusion may lessen or prevent the development of motor complications [16]. Whether continuous dopamine stimulation is desirable requires further study. References [1] Bhidayasiri R, Truong DD. Motor complications in Parkinson disease: clinical manifestations and management. J Neurol Sci 2008;266(1–2):204–15. [2] Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16:448–58. [3] Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47(4 Suppl 1): S2–9 [discussion S9–11.]. [4] Gunzler SA, Nutt JG. Motor fluctuations and dyskinesias. In: Factor SA, Weiner WJ, editors. Parkinson's disease: diagnosis and clinical management. 2nd ed. Demos Medical Publishing; 2007. p. 575–83.