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Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson's disease on l -dopa monotherapy
Parkinsonism and Related Disorders 11 (2005) 151–155 www.elsevier.com/locate/parkreldis
Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson’s disease on L-dopa monotherapy L. Mazzellaa,b, M.D. Yahrd,1, L. Marinellia,b, N. Huangc, E. Moshierd, A. Di Roccoa,* a
Department of Neurology, Beth Israel Medical Center—Albert Einstein College of Medicine, PACC-10 Union Square East #5K, New York, NY 10003, USA b Dipartimento di Neuroscienze, Oftalmologia e Genetica, Universita` di Genova, Genova, Italy c The Parkinson’s Institute, Sunnyvale, CA, USA d Mount Sinai School of Medicine, New York, NY, USA Received 14 October 2003; revised 6 October 2004; accepted 13 October 2004
Abstract The aim of the study was to investigate the relationship between dyskinesias and motor fluctuations in patients with Parkinson’s disease on monotherapy. We identified 116 patients on L-dopa monotherapy treated between 1965 and 1992 and followed until death. Dyskinesias occurred in 102 patients. Of these, 48 only developed dyskinesias while 54 had both dyskinesias and motor fluctuations. Among patients with both complications, 49 developed dyskinesias before fluctuations, and only five had dyskinesias after the onset of fluctuations. Our findings suggest that dyskinesias predict the onset of motor fluctuations, and may share a common pathophysiological mechanism. q 2004 Published by Elsevier Ltd. L-dopa
Keywords: Parkinson’s disease; Dyskinesias; Motor fluctuations; L-dopa; Risk factors
1. Introduction Dyskinesias and motor response fluctuations are very common and potentially disabling complications of chronic L-dopa treatment for Parkinson’s disease (PD) [1]. After 5–6 years of L-dopa therapy, the combined frequency of motor complication has been estimated to range between 20% to more than 90% [2,3]. Such different rates in prevalence probably reflect the lack of uniform definition criteria and the wide heterogeneity of L-dopa dosage, severity of disease and concomitant use of other antiparkinsonian drugs [4]. There have been a number of longitudinal studies reporting the cumulative incidence of dyskinesias and motor fluctuations and the risk factors of each motor complication [2,3,5–12]. There is however, very little data on whether in individual patients the onset of one motor complication predicts the development of the other. * Corresponding author. Tel.: C1 212 844 8362; fax: C1 212 844 8707. E-mail address: [email protected] (A. Di Rocco). 1 Deceased. 1353-8020/$ - see front matter q 2004 Published by Elsevier Ltd. doi:10.1016/j.parkreldis.2004.10.002
It is also unknown whether dyskinesias and motor fluctuations are due to a common mechanism or are related to different pathogenic events. A better clinical and pathophysiological understanding of the relationship between these motor complications may thus have important clinical implication and may influence therapeutic strategies. We reviewed the clinical records of a large PD population treated with L-dopa monotherapy to determine whether either motor complication would predict the onset of the other and to assess relative risk factors for each of the complications.
2. Patients and methods 2.1. Study population We examined the records of 325 patients treated by one of the investigators (MDY) between 1965 and 1992 at the Department of Neurology, Mount Sinai School of Medicine and followed till death. The diagnosis of PD was established
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when two of the three following signs: bradykinesia, resting tremor, and rigidity, were present for more then 6 months. The patients were seen at regular intervals (1–3 months) and followed for at least 7 years. At every follow-up visit, the treating neurologist routinely assessed for the presence of any change in motor response to L-dopa, the occurrence of involuntary movements, shortened response to L-dopa or any other change in response to L-dopa suggestive of wearing off or other motor fluctuations. From the original database of 325 patients, we selected 116 patients (89 males / 27 females) who fulfilled the following criteria: (a) duration of disease more than 7 years; (b) uninterrupted L-dopa therapy for at least 5 years; (c) no use of dopamine agonists therapy (bromocriptine, pergolide) before the onset of motor complications. Chorea, athetosis, dystonia and mixed patterns of hyperkinetic involuntary movements were classified as ‘dyskinesias’ and the time of onset recorded. Similarly, ‘motor fluctuations’ were defined as any shortening of response to L-dopa or unpredictable recurring parkinsonism not related to the timing of L-dopa, and the time of first onset was recorded. The onset of dyskinesias was considered the time of the visit when involuntary movements were first noted. The onset of motor fluctuations was considered the time of the visit during which the frequency or L-Dopa dosing was increased to compensate for the lack of sustained L-dopa effect. For the purpose of this study, freezing of gait and early morning dystonia were not considered among the motor complications. Exclusion criteria were: (a) age less than 30; (b) history of strokes, traumatic injuries, and encephalitis; (c) prior the use of neuroleptics or dopamine receptor antagonists. L-dopa dosage was recorded at each visit. For patients who first started L-dopa before 1974 (when the dopa decarboxylase inhibitor, Carbidopa, was introduced), the conversion factor used was 5:1 equivalence [13–15]. For each patient we recorded the following data: age of onset of PD, duration of illness, interval from onset of disease to start of L-dopa treatment, duration of L-dopa treatment, maximum standardized L-dopa daily dose, interval from the time L-dopa was started and the onset of motor fluctuations or dyskinesias. 2.2. Statistical analysis The time interval between the initiation of L-dopa treatment and the appearance of either dyskinesias or motor fluctuations was calculated separately for each individual and expressed in months. Patients who did not develop dyskinesias after initiation of L-dopa treatment were censored at their time of death. Likewise, patients who did not develop motor fluctuations after initiation of L-dopa were censored. Kaplan–Meier estimator via SAS’s Proc Phreg (SAS Institute Inc., Cary, NC) was used to estimate the probability that patient was free of dyskinesias or motor fluctuations at
a given time during follow up. A c2 test for equal proportions was calculated for dyskinesias and motor fluctuations. The contribution of risk factors on the development of dyskinesias and separately on the development of motor fluctuations was assessed via SAS’s Proc Phreg using the Stepwise Cox regression model. These included age of onset of PD, duration of PD, L-dopa dosage, duration of L-dopa treatment. The main independent variable was considered duration of L-dopa treatment. Hazard ratios were estimated for those risk factors that were revealed to be statistically significant in the stepwise procedure. We also separately analyzed the effect of age at initiation of L-dopa therapy using a Pearson coefficient correlation with natural log transformation to correct for skewed age distribution.
3. Results The demographic characteristics (means and SDs) of the patient are summarized in Table 1. The mean age of onset of PD was 58.7 years (G9.0 SD), the mean of duration of disease was 16.1 years (G5.9 SD) and duration of L-dopa treatment was 9.9 years (G3.8 SD) with an average dose of 992.4G333.7 mg/die. The mean of the average daily dose of LD at the onset of dyskinesias is 896.0G268.5 mg/die. The mean cumulative dose of LD, calculated between its initiation and the onset of dyskinesias was 173.8G263.2 g. Because the distribution of the cumulative dose of LD was skewed we will also present the median and the range. The median of the cumulative dose of LD between its initiation and the onset of dyskinesias is 64.4 g. Since the LD dose at initiation of therapy was not available for most patients, we estimated a 400 mg initial LD dose for all patients, approximating a linear increase of LD dose across years. Table 1 Demographics Total number of patients Male: female Age of onset (ys) Duration of PD (ys) Duration of disease prior L-dopa treatment Mean duration of L-dopa treatment Mean L-dopa dose Time of onset of dyskinesias after L-dopa Time of onset of motor fluctuations after L-dopa Time of onset of dyskinesias after PD onset Time of onset of motor fluctuations after PD onset Difference of time interval between dyskinesias and MF Average daily L-dopa dose at onset of dyskinesia
116 89:27 58.7G9.0 ys 16.1G5.9 ys 81.3G58.4 months 9.9G3.8 ys 992.4G333.7 mg/die 16.5G27.6 months (1.4G2.3 ys) 34.3G24.3 months (2.9G2.0 ys) 99.6G64.8 months (8.3G5.4 ys) 120.1G66,2 months (10.0G5.5 ys) 36.4G20.8 months (2.5G1.7 ys) 648.5G136.7 mg/die
L. Mazzella et al. / Parkinsonism and Related Disorders 11 (2005) 151–155
For patients who first initiated LD before 1974, the conversion factor of 5:1 was used. The mean age of patients at time of onset of MF was 64.5 years (G7.6 SD) and for dyskinesias 62.5 years (G7.0 SD). Dyskinesias occurred in 102 patients (87.9%) with mean interval from the time L-dopa was started of 1.4 years (G2.3 SD) and 8.3 years (G5.4 SD) from the time of PD onset. Of these, 48 (41.4%) developed dyskinesias without associated motor fluctuations while 54 (46.6%) had both dyskinesias and motor fluctuations. Among patients with both complications, 49 (90.7%) developed dyskinesias before fluctuations, and only 5 (9.3%) had dyskinesias after the onset of fluctuations. Only 1 patient had motor fluctuations without dyskinesias. In the 55 subjects (47.4%) with motor fluctuations, the mean interval from the time L-dopa was started was 2.9 years (G2.0 SD) and the mean interval from the time of PD onset was 10.0 years (G5.5 SD). No complication occurred in 13 patients (11.2%). The mean interval from the time patients developed dyskinesias to time of onset of motor fluctuations was 30.4 months (G20.8 SD). As shown in Fig. 1, the probability for patients to remain without dyskinesia and MF free after starting L-dopa therapy decreased mostly during the first 50 months, with dyskinesia appearing earlier than MF. We considered age at onset, L-dopa dosage and years of L-dopa treatment as possible risk factors. None of the possible risk factors assessed in the Cox regression analysis were significantly associated with the development of dyskinesias.
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Younger age at onset of PD was associated with higher risk of developing dyskinesias (Hazard ratioZ0.979) though the correlation did not reach significance (pZ 0.0644). This translates into lowering the yearly probability of developing dyskinesias of approximately 2% with aging. As per motor fluctuations, L -dopa dosage was the only risk factor that was associated with a higher risk of developing motor fluctuations (Hazard ratioZ1.001; pZ0.0429). There was also no significant correlation between the age L-dopa was initiated and the development of dyskinesias (RZ0.13, pZ0.40) or the development of MF (RZ0.20, pZ0.15), although the trend observed for MF suggests that L-dopa initiation at a younger age may predispose to earlier development of MF. None of the other factors had any significant association with developing motor fluctuations. We compared the risk of developing dyskinesias in patients who developed the complication before or after 12 months of L-dopa initiation. A multiple regression between the time interval between L-dopa initiation and PD onset age, years of L-dopa therapy and standardized maximum L-dopa dose, showed no significant correlations.
4. Discussion Our study suggests that dyskinesias are more common complications and are a strong predictor of the development
Fig. 1. Cumulative probability of developing dyskinesias and motor fluctuations. For any given time after the initiation of L-dopa monotherapy the probability of developing dyskinesias is greater than that of developing motor fluctuations.
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Table 2 Incidence of motor complications
Dyskinesias Motor fluctuations None Dyskinesias only Motor fluctuations only Both motor complications † Dyskinesias developed before motor fluctuations † Motor fluctuations developed before dyskinesias
Number of patients
%
c2 test
102 55 13 48 1 54 49
87.9 47.4 11.2 41.4 0.9 46.6 90.7
p! 0.001
5
9.3
p! 0.0001
p! 0.0001
of motor fluctuations in PD patients on L-dopa monotherapy. Dyskinesias preceded motor fluctuations in 49 out 54 patients (90.7%) who developed both complications, while only 5 subjects (9.3%) had a reverse pattern, with fluctuations developing before the onset of dyskinesias. Further, motor fluctuations occurred in isolation only in one single case (0.9%), highlighting the predictive role of dyskinesias. (Table 2) Our finding that dyskinesias develop at an earlier time compared with motor fluctuations is consistent with other reports [5,11,12,16,17]. Particularly in a recent study, Rajput et al. [12] showed that dyskinesias is the earliest adverse effect as 25% of dyskinesias evolved after 2.6 years on L-dopa compared with 4.9 years and 12.5 years of the same proportion of wearing off and on–off phenomena, respectively. The number of patients evaluated in that study was, however, comparatively lower and the duration of follow up limited. Further, that study included patients on other dopaminergic agents. Our results are particularly significant in that they refer to a population treated and maintained on L-dopa monotherapy. Thus the phenomena described can be conceivably interpreted as due to a direct effect of L-dopa without other interference of other anti-parkinsonian treatment. Moreover, this is one of the few reports focused on L-dopainduced motor complications to be characterized by such a long follow up. In addition to the duration of L-dopa treatment, other factors have been associated with the development of L-dopa induced motor complications. Age at onset of PD has been associated with the risk of developing dyskinesias but not motor fluctuations [5,18,19]. In our study, we observed a non-significant trend of younger age at onset of PD to be a risk factor for developing dyskinesias, consistently with previous reports [8–10,20, 21]. In this study there was also suggestion that L-dopa therapy started at a younger age could predispose to early development of MF, although the correlation did not reach significance. Higher L-dopa dosage has also been correlated with the risk of motor fluctuations [1,6,22].Our study also demonstrates a strong correlation between
higher dose of L-dopa and the onset of MF, but there was no clear association with onset of dyskinesias. We also find a correlation between duration of therapy and risk of developing dyskinesias, as previously noted in other studies [6,8,21]. These data should be interpreted however, in the proper historical perspective. Included in the study are patients who were treated in the early years of L-dopa use, when high dosages were normally employed, and patients were first treated years after they develop the disease. This is reflected in the unusually long mean interval from the time of PD diagnosis to the time L-dopa was started. The majority of patients, however, were first treated in the 1970s and 1980s, when L-dopa was started at the time of early disability. This heterogeneous population and evolving management philosophy also limited the analysis of risk factors predicting the onset of these complications. Nevertheless all patients were denovo treated with L-dopa and maintained until they developed motor complications. Our findings suggesting that dyskinesias predict the onset of motor fluctuations lends support to the hypothesis that the two L-dopainduced motor complications share a common pathophysiological mechanism. However, most of the studies have considered L-dopa-induced motor complications as distinctive processes and, to our knowledge, this is the first report analyzing the relationship and the predictive factor between dyskinesias and motor fluctuations. In a recent review, Blanchet [23] hypothesized that the mechanisms underlying dyskinesias and motor fluctuations may overlap. Chase et al. [24] also suggested that both on– off fluctuations and peak-dose dyskinesias might reflect alterations in post-synaptic mechanisms due to pulsatile dopamine receptor stimulation together with the loss of nigrostriatal neurons and their buffering ability. This observation may have important practical implications in that many trials with dopamine agonists or other agents use the onset of dyskinesias as end point to determine possible neuroprotection. Our study supports the use of dyskinesias as the first motor response complication occurring in long term L-dopa treatment and as a reasonable individual end point to assess the onset of long term motor complication of dopaminergic therapy. Many of the results of prospective studies, including the DATATOP and CALM-PD study have demonstrated a strong overlap between the two type of complications [25,26]. However, other small prospective studies have shown an association, but not a total overlap between the two complications [27]. However, symptomatic treatment of dyskinesias with NMDA glutamate antagonists or adenosine A2A antagonists have no effect on motor fluctuations, suggesting that the pathophysiology of the two type of motor complications may not completely overlap, and animal models of dyskinesias often do not cause motor fluctuations [28].
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References [1] Jankovic J. L-dopa strengths and weaknesses. Neurology 2002;58: S19–S32. [2] Nutt JG. Motor fluctuations and dyskinesias in Parkinson’s disease. Parkinsonism Relat Disord 2001;8:101–8. [3] Ahlskog JE, Muenter MD. Frequency of L-dopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16:448–58. [4] Marras C, Lang AE. Measuring motor complications in clinical trial for early Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003;74: 143–6. [5] Kostic VS, Marinkovic J, Svetel M, Stefanova E, Przedborski S. The effect of stage of Parkinson’s disease at the onset of levodopa therapy on development of motor complications. Eur J Neurol 2002;9:9–14. [6] Peppe A, Dambrosia JM, Chase TN. Risk factors for motor response complications in L-dopa treated parkinsonian patients. Adv Neurol 1993;60:698–702. [7] Denny AP, Behari M. Motor fluctuations in Parkinson’s disease. J Neurol Sci 1999;165:18–23. [8] Grandas F, Galiano ML, Tabernero C. Risk factors for L-dopa-induced dyskinesias in Parkinson’s disease. J Neurol 1999;246:1127–33. [9] Baas H. Dyskinesias in Parkinson’s disease. Pathophysiology and clinical risk factors. J Neurol 2000;247(S4):12–16. [10] Rascol O, Brooks DJ, Korczyn AD, DeDeyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or L-dopa. N Engl J Med 2000;342:1484–91. [11] Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease; a community-based study. Brain 2000;123:2297–305. [12] Rajput AH, Fenton ME, Birdi S, Macaulay R, George D, Rozdilsky B, Ang LC, Senthilselvan A, Hornykiewicz O. Clinical-pathological study of L-dopa complications. Mov Disord 2002;17:289–96. [13] Barbeau A. Treatment of Parkinson’s disease with L-dopa and Ro 44602: review and present status. Adv Neurol 1973;2:173–98. [14] Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. New Engl J Med 1967;276:374–9.
155
[15] Yahr MD, Duvoisin RC, Schear MJ, Barrett RE, Hoehn MM. Treatment of parkinsonism with L-dopa. Arch Neurol 1969;21: 343–54. [16] Barbeau A, Mars H, Gillo-Joffroy L. Adverse clinical side effects of Ldopa therapy. In: Mc Dowell FH, Markham CH, editors. Recent advances in Parkinson’s disease. Philadelphia: FA Davis Co; 1971. [17] Markham CH, Treciokas LJ, Diamond SG. Parkinson’s disease and Ldopa. A five-year follow-up and review. West J Med 1974;121: 188–206. [18] Quinn N, Critchley P, Marsden CD. Young- onset Parkinson’s disease. Mov Disord 1987;2:73–91. [19] Gomez Arevalo G, Jorge R, Garcia S, Scipioni O, Gershanik O. Clinical and pharmacological differences in early-versus late-onset Parkinson’s disease. Mov Disord 1997;12:277–84. [20] Reardon KA, Shiff M, Kempster PA. Evolution of motor fluctuations in Parkinson’s disease: a longitudinal study over 6 years. Mov Disord 1999;14:605–11. [21] Hoehn MM. Parkinsonism treated with L-dopa: progression and mortality. J Neural Trans Suppl 1983;19:253–64. [22] Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y. Ten-year followup of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001;57:1687–94. [23] Blanchet PJ. The fluctuating parkinsonian patient: clinical and pathophysiological aspects. Can J Neurol Sci 2003;30:S19–S26. [24] Chase TN, Mouradian MM, Engber TM. Motor response complications and the function of striatal efferent systems. Neurology 1993; 43(6):S23–S7. [25] Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol 1996;39:37–45. [26] Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47(suppl1):S2–S11. [27] Garcia Ruiz PJ, Meseguer E, del Val J, Vazquez A, Sanchez Bernardos V, Vazquez A. Motor complications in Parkinson disease: a prospective follow-up study. Clin Neuropharmacol 2004;27:49–52. [28] Calon F, Dridi M, Hornykiewicz O, Bedard PJ, Rajput AH. Di Paolo T. Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain 2004;127:1075–84.
Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson’s disease on L-dopa monotherapy L. Mazzellaa,b, M.D. Yahrd,1, L. Marinellia,b, N. Huangc, E. Moshierd, A. Di Roccoa,* a
Department of Neurology, Beth Israel Medical Center—Albert Einstein College of Medicine, PACC-10 Union Square East #5K, New York, NY 10003, USA b Dipartimento di Neuroscienze, Oftalmologia e Genetica, Universita` di Genova, Genova, Italy c The Parkinson’s Institute, Sunnyvale, CA, USA d Mount Sinai School of Medicine, New York, NY, USA Received 14 October 2003; revised 6 October 2004; accepted 13 October 2004
Abstract The aim of the study was to investigate the relationship between dyskinesias and motor fluctuations in patients with Parkinson’s disease on monotherapy. We identified 116 patients on L-dopa monotherapy treated between 1965 and 1992 and followed until death. Dyskinesias occurred in 102 patients. Of these, 48 only developed dyskinesias while 54 had both dyskinesias and motor fluctuations. Among patients with both complications, 49 developed dyskinesias before fluctuations, and only five had dyskinesias after the onset of fluctuations. Our findings suggest that dyskinesias predict the onset of motor fluctuations, and may share a common pathophysiological mechanism. q 2004 Published by Elsevier Ltd. L-dopa
Keywords: Parkinson’s disease; Dyskinesias; Motor fluctuations; L-dopa; Risk factors
1. Introduction Dyskinesias and motor response fluctuations are very common and potentially disabling complications of chronic L-dopa treatment for Parkinson’s disease (PD) [1]. After 5–6 years of L-dopa therapy, the combined frequency of motor complication has been estimated to range between 20% to more than 90% [2,3]. Such different rates in prevalence probably reflect the lack of uniform definition criteria and the wide heterogeneity of L-dopa dosage, severity of disease and concomitant use of other antiparkinsonian drugs [4]. There have been a number of longitudinal studies reporting the cumulative incidence of dyskinesias and motor fluctuations and the risk factors of each motor complication [2,3,5–12]. There is however, very little data on whether in individual patients the onset of one motor complication predicts the development of the other. * Corresponding author. Tel.: C1 212 844 8362; fax: C1 212 844 8707. E-mail address: [email protected] (A. Di Rocco). 1 Deceased. 1353-8020/$ - see front matter q 2004 Published by Elsevier Ltd. doi:10.1016/j.parkreldis.2004.10.002
It is also unknown whether dyskinesias and motor fluctuations are due to a common mechanism or are related to different pathogenic events. A better clinical and pathophysiological understanding of the relationship between these motor complications may thus have important clinical implication and may influence therapeutic strategies. We reviewed the clinical records of a large PD population treated with L-dopa monotherapy to determine whether either motor complication would predict the onset of the other and to assess relative risk factors for each of the complications.
2. Patients and methods 2.1. Study population We examined the records of 325 patients treated by one of the investigators (MDY) between 1965 and 1992 at the Department of Neurology, Mount Sinai School of Medicine and followed till death. The diagnosis of PD was established
152
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when two of the three following signs: bradykinesia, resting tremor, and rigidity, were present for more then 6 months. The patients were seen at regular intervals (1–3 months) and followed for at least 7 years. At every follow-up visit, the treating neurologist routinely assessed for the presence of any change in motor response to L-dopa, the occurrence of involuntary movements, shortened response to L-dopa or any other change in response to L-dopa suggestive of wearing off or other motor fluctuations. From the original database of 325 patients, we selected 116 patients (89 males / 27 females) who fulfilled the following criteria: (a) duration of disease more than 7 years; (b) uninterrupted L-dopa therapy for at least 5 years; (c) no use of dopamine agonists therapy (bromocriptine, pergolide) before the onset of motor complications. Chorea, athetosis, dystonia and mixed patterns of hyperkinetic involuntary movements were classified as ‘dyskinesias’ and the time of onset recorded. Similarly, ‘motor fluctuations’ were defined as any shortening of response to L-dopa or unpredictable recurring parkinsonism not related to the timing of L-dopa, and the time of first onset was recorded. The onset of dyskinesias was considered the time of the visit when involuntary movements were first noted. The onset of motor fluctuations was considered the time of the visit during which the frequency or L-Dopa dosing was increased to compensate for the lack of sustained L-dopa effect. For the purpose of this study, freezing of gait and early morning dystonia were not considered among the motor complications. Exclusion criteria were: (a) age less than 30; (b) history of strokes, traumatic injuries, and encephalitis; (c) prior the use of neuroleptics or dopamine receptor antagonists. L-dopa dosage was recorded at each visit. For patients who first started L-dopa before 1974 (when the dopa decarboxylase inhibitor, Carbidopa, was introduced), the conversion factor used was 5:1 equivalence [13–15]. For each patient we recorded the following data: age of onset of PD, duration of illness, interval from onset of disease to start of L-dopa treatment, duration of L-dopa treatment, maximum standardized L-dopa daily dose, interval from the time L-dopa was started and the onset of motor fluctuations or dyskinesias. 2.2. Statistical analysis The time interval between the initiation of L-dopa treatment and the appearance of either dyskinesias or motor fluctuations was calculated separately for each individual and expressed in months. Patients who did not develop dyskinesias after initiation of L-dopa treatment were censored at their time of death. Likewise, patients who did not develop motor fluctuations after initiation of L-dopa were censored. Kaplan–Meier estimator via SAS’s Proc Phreg (SAS Institute Inc., Cary, NC) was used to estimate the probability that patient was free of dyskinesias or motor fluctuations at
a given time during follow up. A c2 test for equal proportions was calculated for dyskinesias and motor fluctuations. The contribution of risk factors on the development of dyskinesias and separately on the development of motor fluctuations was assessed via SAS’s Proc Phreg using the Stepwise Cox regression model. These included age of onset of PD, duration of PD, L-dopa dosage, duration of L-dopa treatment. The main independent variable was considered duration of L-dopa treatment. Hazard ratios were estimated for those risk factors that were revealed to be statistically significant in the stepwise procedure. We also separately analyzed the effect of age at initiation of L-dopa therapy using a Pearson coefficient correlation with natural log transformation to correct for skewed age distribution.
3. Results The demographic characteristics (means and SDs) of the patient are summarized in Table 1. The mean age of onset of PD was 58.7 years (G9.0 SD), the mean of duration of disease was 16.1 years (G5.9 SD) and duration of L-dopa treatment was 9.9 years (G3.8 SD) with an average dose of 992.4G333.7 mg/die. The mean of the average daily dose of LD at the onset of dyskinesias is 896.0G268.5 mg/die. The mean cumulative dose of LD, calculated between its initiation and the onset of dyskinesias was 173.8G263.2 g. Because the distribution of the cumulative dose of LD was skewed we will also present the median and the range. The median of the cumulative dose of LD between its initiation and the onset of dyskinesias is 64.4 g. Since the LD dose at initiation of therapy was not available for most patients, we estimated a 400 mg initial LD dose for all patients, approximating a linear increase of LD dose across years. Table 1 Demographics Total number of patients Male: female Age of onset (ys) Duration of PD (ys) Duration of disease prior L-dopa treatment Mean duration of L-dopa treatment Mean L-dopa dose Time of onset of dyskinesias after L-dopa Time of onset of motor fluctuations after L-dopa Time of onset of dyskinesias after PD onset Time of onset of motor fluctuations after PD onset Difference of time interval between dyskinesias and MF Average daily L-dopa dose at onset of dyskinesia
116 89:27 58.7G9.0 ys 16.1G5.9 ys 81.3G58.4 months 9.9G3.8 ys 992.4G333.7 mg/die 16.5G27.6 months (1.4G2.3 ys) 34.3G24.3 months (2.9G2.0 ys) 99.6G64.8 months (8.3G5.4 ys) 120.1G66,2 months (10.0G5.5 ys) 36.4G20.8 months (2.5G1.7 ys) 648.5G136.7 mg/die
L. Mazzella et al. / Parkinsonism and Related Disorders 11 (2005) 151–155
For patients who first initiated LD before 1974, the conversion factor of 5:1 was used. The mean age of patients at time of onset of MF was 64.5 years (G7.6 SD) and for dyskinesias 62.5 years (G7.0 SD). Dyskinesias occurred in 102 patients (87.9%) with mean interval from the time L-dopa was started of 1.4 years (G2.3 SD) and 8.3 years (G5.4 SD) from the time of PD onset. Of these, 48 (41.4%) developed dyskinesias without associated motor fluctuations while 54 (46.6%) had both dyskinesias and motor fluctuations. Among patients with both complications, 49 (90.7%) developed dyskinesias before fluctuations, and only 5 (9.3%) had dyskinesias after the onset of fluctuations. Only 1 patient had motor fluctuations without dyskinesias. In the 55 subjects (47.4%) with motor fluctuations, the mean interval from the time L-dopa was started was 2.9 years (G2.0 SD) and the mean interval from the time of PD onset was 10.0 years (G5.5 SD). No complication occurred in 13 patients (11.2%). The mean interval from the time patients developed dyskinesias to time of onset of motor fluctuations was 30.4 months (G20.8 SD). As shown in Fig. 1, the probability for patients to remain without dyskinesia and MF free after starting L-dopa therapy decreased mostly during the first 50 months, with dyskinesia appearing earlier than MF. We considered age at onset, L-dopa dosage and years of L-dopa treatment as possible risk factors. None of the possible risk factors assessed in the Cox regression analysis were significantly associated with the development of dyskinesias.
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Younger age at onset of PD was associated with higher risk of developing dyskinesias (Hazard ratioZ0.979) though the correlation did not reach significance (pZ 0.0644). This translates into lowering the yearly probability of developing dyskinesias of approximately 2% with aging. As per motor fluctuations, L -dopa dosage was the only risk factor that was associated with a higher risk of developing motor fluctuations (Hazard ratioZ1.001; pZ0.0429). There was also no significant correlation between the age L-dopa was initiated and the development of dyskinesias (RZ0.13, pZ0.40) or the development of MF (RZ0.20, pZ0.15), although the trend observed for MF suggests that L-dopa initiation at a younger age may predispose to earlier development of MF. None of the other factors had any significant association with developing motor fluctuations. We compared the risk of developing dyskinesias in patients who developed the complication before or after 12 months of L-dopa initiation. A multiple regression between the time interval between L-dopa initiation and PD onset age, years of L-dopa therapy and standardized maximum L-dopa dose, showed no significant correlations.
4. Discussion Our study suggests that dyskinesias are more common complications and are a strong predictor of the development
Fig. 1. Cumulative probability of developing dyskinesias and motor fluctuations. For any given time after the initiation of L-dopa monotherapy the probability of developing dyskinesias is greater than that of developing motor fluctuations.
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Table 2 Incidence of motor complications
Dyskinesias Motor fluctuations None Dyskinesias only Motor fluctuations only Both motor complications † Dyskinesias developed before motor fluctuations † Motor fluctuations developed before dyskinesias
Number of patients
%
c2 test
102 55 13 48 1 54 49
87.9 47.4 11.2 41.4 0.9 46.6 90.7
p! 0.001
5
9.3
p! 0.0001
p! 0.0001
of motor fluctuations in PD patients on L-dopa monotherapy. Dyskinesias preceded motor fluctuations in 49 out 54 patients (90.7%) who developed both complications, while only 5 subjects (9.3%) had a reverse pattern, with fluctuations developing before the onset of dyskinesias. Further, motor fluctuations occurred in isolation only in one single case (0.9%), highlighting the predictive role of dyskinesias. (Table 2) Our finding that dyskinesias develop at an earlier time compared with motor fluctuations is consistent with other reports [5,11,12,16,17]. Particularly in a recent study, Rajput et al. [12] showed that dyskinesias is the earliest adverse effect as 25% of dyskinesias evolved after 2.6 years on L-dopa compared with 4.9 years and 12.5 years of the same proportion of wearing off and on–off phenomena, respectively. The number of patients evaluated in that study was, however, comparatively lower and the duration of follow up limited. Further, that study included patients on other dopaminergic agents. Our results are particularly significant in that they refer to a population treated and maintained on L-dopa monotherapy. Thus the phenomena described can be conceivably interpreted as due to a direct effect of L-dopa without other interference of other anti-parkinsonian treatment. Moreover, this is one of the few reports focused on L-dopainduced motor complications to be characterized by such a long follow up. In addition to the duration of L-dopa treatment, other factors have been associated with the development of L-dopa induced motor complications. Age at onset of PD has been associated with the risk of developing dyskinesias but not motor fluctuations [5,18,19]. In our study, we observed a non-significant trend of younger age at onset of PD to be a risk factor for developing dyskinesias, consistently with previous reports [8–10,20, 21]. In this study there was also suggestion that L-dopa therapy started at a younger age could predispose to early development of MF, although the correlation did not reach significance. Higher L-dopa dosage has also been correlated with the risk of motor fluctuations [1,6,22].Our study also demonstrates a strong correlation between
higher dose of L-dopa and the onset of MF, but there was no clear association with onset of dyskinesias. We also find a correlation between duration of therapy and risk of developing dyskinesias, as previously noted in other studies [6,8,21]. These data should be interpreted however, in the proper historical perspective. Included in the study are patients who were treated in the early years of L-dopa use, when high dosages were normally employed, and patients were first treated years after they develop the disease. This is reflected in the unusually long mean interval from the time of PD diagnosis to the time L-dopa was started. The majority of patients, however, were first treated in the 1970s and 1980s, when L-dopa was started at the time of early disability. This heterogeneous population and evolving management philosophy also limited the analysis of risk factors predicting the onset of these complications. Nevertheless all patients were denovo treated with L-dopa and maintained until they developed motor complications. Our findings suggesting that dyskinesias predict the onset of motor fluctuations lends support to the hypothesis that the two L-dopainduced motor complications share a common pathophysiological mechanism. However, most of the studies have considered L-dopa-induced motor complications as distinctive processes and, to our knowledge, this is the first report analyzing the relationship and the predictive factor between dyskinesias and motor fluctuations. In a recent review, Blanchet [23] hypothesized that the mechanisms underlying dyskinesias and motor fluctuations may overlap. Chase et al. [24] also suggested that both on– off fluctuations and peak-dose dyskinesias might reflect alterations in post-synaptic mechanisms due to pulsatile dopamine receptor stimulation together with the loss of nigrostriatal neurons and their buffering ability. This observation may have important practical implications in that many trials with dopamine agonists or other agents use the onset of dyskinesias as end point to determine possible neuroprotection. Our study supports the use of dyskinesias as the first motor response complication occurring in long term L-dopa treatment and as a reasonable individual end point to assess the onset of long term motor complication of dopaminergic therapy. Many of the results of prospective studies, including the DATATOP and CALM-PD study have demonstrated a strong overlap between the two type of complications [25,26]. However, other small prospective studies have shown an association, but not a total overlap between the two complications [27]. However, symptomatic treatment of dyskinesias with NMDA glutamate antagonists or adenosine A2A antagonists have no effect on motor fluctuations, suggesting that the pathophysiology of the two type of motor complications may not completely overlap, and animal models of dyskinesias often do not cause motor fluctuations [28].
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References [1] Jankovic J. L-dopa strengths and weaknesses. Neurology 2002;58: S19–S32. [2] Nutt JG. Motor fluctuations and dyskinesias in Parkinson’s disease. Parkinsonism Relat Disord 2001;8:101–8. [3] Ahlskog JE, Muenter MD. Frequency of L-dopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16:448–58. [4] Marras C, Lang AE. Measuring motor complications in clinical trial for early Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003;74: 143–6. [5] Kostic VS, Marinkovic J, Svetel M, Stefanova E, Przedborski S. The effect of stage of Parkinson’s disease at the onset of levodopa therapy on development of motor complications. Eur J Neurol 2002;9:9–14. [6] Peppe A, Dambrosia JM, Chase TN. Risk factors for motor response complications in L-dopa treated parkinsonian patients. Adv Neurol 1993;60:698–702. [7] Denny AP, Behari M. Motor fluctuations in Parkinson’s disease. J Neurol Sci 1999;165:18–23. [8] Grandas F, Galiano ML, Tabernero C. Risk factors for L-dopa-induced dyskinesias in Parkinson’s disease. J Neurol 1999;246:1127–33. [9] Baas H. Dyskinesias in Parkinson’s disease. Pathophysiology and clinical risk factors. J Neurol 2000;247(S4):12–16. [10] Rascol O, Brooks DJ, Korczyn AD, DeDeyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or L-dopa. N Engl J Med 2000;342:1484–91. [11] Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease; a community-based study. Brain 2000;123:2297–305. [12] Rajput AH, Fenton ME, Birdi S, Macaulay R, George D, Rozdilsky B, Ang LC, Senthilselvan A, Hornykiewicz O. Clinical-pathological study of L-dopa complications. Mov Disord 2002;17:289–96. [13] Barbeau A. Treatment of Parkinson’s disease with L-dopa and Ro 44602: review and present status. Adv Neurol 1973;2:173–98. [14] Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. New Engl J Med 1967;276:374–9.
155
[15] Yahr MD, Duvoisin RC, Schear MJ, Barrett RE, Hoehn MM. Treatment of parkinsonism with L-dopa. Arch Neurol 1969;21: 343–54. [16] Barbeau A, Mars H, Gillo-Joffroy L. Adverse clinical side effects of Ldopa therapy. In: Mc Dowell FH, Markham CH, editors. Recent advances in Parkinson’s disease. Philadelphia: FA Davis Co; 1971. [17] Markham CH, Treciokas LJ, Diamond SG. Parkinson’s disease and Ldopa. A five-year follow-up and review. West J Med 1974;121: 188–206. [18] Quinn N, Critchley P, Marsden CD. Young- onset Parkinson’s disease. Mov Disord 1987;2:73–91. [19] Gomez Arevalo G, Jorge R, Garcia S, Scipioni O, Gershanik O. Clinical and pharmacological differences in early-versus late-onset Parkinson’s disease. Mov Disord 1997;12:277–84. [20] Reardon KA, Shiff M, Kempster PA. Evolution of motor fluctuations in Parkinson’s disease: a longitudinal study over 6 years. Mov Disord 1999;14:605–11. [21] Hoehn MM. Parkinsonism treated with L-dopa: progression and mortality. J Neural Trans Suppl 1983;19:253–64. [22] Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y. Ten-year followup of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001;57:1687–94. [23] Blanchet PJ. The fluctuating parkinsonian patient: clinical and pathophysiological aspects. Can J Neurol Sci 2003;30:S19–S26. [24] Chase TN, Mouradian MM, Engber TM. Motor response complications and the function of striatal efferent systems. Neurology 1993; 43(6):S23–S7. [25] Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol 1996;39:37–45. [26] Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47(suppl1):S2–S11. [27] Garcia Ruiz PJ, Meseguer E, del Val J, Vazquez A, Sanchez Bernardos V, Vazquez A. Motor complications in Parkinson disease: a prospective follow-up study. Clin Neuropharmacol 2004;27:49–52. [28] Calon F, Dridi M, Hornykiewicz O, Bedard PJ, Rajput AH. Di Paolo T. Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain 2004;127:1075–84.