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Diphasic dyskinesias during levodopa-carbidopa intestinal gel (LCIG) infusion in Parkinson's disease
Accepted Manuscript Diphasic dyskinesias during levodopa-carbidopa intestinal gel (LCIG) infusion in Parkinson's disease Meloni Mario, Solla Paolo, Mascia Mario Marcello, Marrosu Francesco, Cannas Antonino PII:
S1353-8020(16)30523-5
DOI:
10.1016/j.parkreldis.2016.12.030
Reference:
PRD 3209
To appear in:
Parkinsonism and Related Disorders
Received Date: 28 July 2016 Revised Date:
19 December 2016
Accepted Date: 31 December 2016
Please cite this article as: Mario M, Paolo S, Marcello MM, Francesco M, Antonino C, Diphasic dyskinesias during levodopa-carbidopa intestinal gel (LCIG) infusion in Parkinson's disease, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2016.12.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Diphasic dyskinesias during levodopa-carbidopa intestinal gel (LCIG) infusion in Parkinson’s disease. Meloni Mario MD; Solla Paolo MD, PhD; Mascia Mario Marcello MD; Marrosu Francesco MD; Cannas
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Antonino MD. Movement Disorders Center, Department of Neurology, Institute of Neurology, University of Cagliari, Cagliari, Italy. Keywords: Parkinson's disease; Diphasic dyskinesias; Levodopa-Carbidopa Intestinal Gel (LCIG)
Corresponding Author:
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Dr. Mario Meloni, MD Department of Neurology Movement Disorders Center,
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University of Cagliari SS 554 Bivio per Sestu 09042 Monserrato, Cagliari, Italy. E-mail: [email protected] Telephone number: +393466260026
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Objectives: Levodopa-carbidopa intestinal gel infusion (LCIG) is indicated in patients with advanced levodopa-responsive Parkinson's disease (PD) for the treatment of motor fluctuations and dyskinesias. Here we describe 4 PD patients who developed disabling diphasic dyskinesias after LCIG initiation.
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Methods: The clinical data of 33 PD patients consecutively treated with LCIG therapy were obtained through direct clinical observation and detailed review of medical records.
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Results: Within 10 days, after LCIG introduction, we identified 4 subjects (12.1%) with persistent and disabling diphasic dyskinesia (DD). We tried to manage these symptoms by increasing morning LCIG flow and adding "extended-release" formulations of dopamine-agonists and levodopa/carbidopa during bedtime. Within 1 month, all patients presented a gradual reduction in the duration and severity of DD. Conclusions: To our knowledge, this is the first report describing the occurrence of DD in a small cohort of advanced PD patients after LCIG initiation. We wish to draw the attention of clinicians to the risk of developing disabling DD in PD patients switched to the LCIG monotherapy.
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1.Introduction The occurrence of dyskinesias and motor fluctuations is a major problem in the long-term management of patients with Parkinson's disease (PD). Dyskinesias may be classified on the basis of their course
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and clinical phenomenology following a regular or over-threshold dose of oral levodopa. The most commonly recognized pattern of dyskinesias are the "peak-dose" dyskinesias [1, 2], which occurred around the time of the peak plasma levels of medication [3].
Muenter et al. (1977) also described a "dystonia-improvement-dystonia" response, whereby patients
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experience dyskinesia phenomena as the effects of levodopa wearing "on" and "off". The authors reported that these occurred when the concentration of levodopa in plasma passed through a critical but relatively low level, whereas it remained absent as long as the concentration remained above that level.
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This type of dyskinesia, due to its occurrence at the onset and/or end of action of levodopa, is now more commonly referred as ‘diphasic’ dyskinesia (DD). The clinical phenomenology of DD is generally different from other common forms of levodopa-induced dyskinesias (LIDs). DD usually predominates in lower limbs and tends to be dystonic or ballistic, while peak dose dyskinesias involve more the upper limbs, have a choreic phenotype and tend to be less disabling and less painful [4].
parkinsonian signs [5].
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Frequently, while the legs are moving involuntarily, the upper half of the body still exhibits
Levodopa-carbidopa intestinal gel (LCIG) is a treatment option for advanced PD patients. Compared to
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orally administered levodopa/carbidopa, pharmacokinetic studies have shown that continuous intestinal infusion provides less variability in levodopa plasma levels [6]. Previously published data in advanced PD patients demonstrated that switching from oral levodopa to LCIG significantly reduced “off” time,
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improving motor conditions with a global increase in “on” time without increasing troublesome and disabling dyskinesias [7, 8].
Nylhom and colleagues previously reported a single case of diphasic type of dyskinesias on LCIG with predominance choreo-dystonic type in the legs at very low doses and more typical generalized chorea at high doses [9]. However, to our knowledge, the presence of DD on LCIG has not been systematically described so far. Here we describe 4 PD patients who developed disabling DD after LCIG initiation.
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2. Methods and results Among the 33 PD patients treated with LCIG therapy in our Movement Disorders Center at the University of Cagliari, we identified 4 patients (12.1%) (2 men and 2 women; mean age 68.5) with
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persistent and disabling DD. The clinical data were obtained through direct clinical observation and detailed review of medical records. Table 1 reports demographic and clinical features of these four patients. They all suffered from advanced disease with motor fluctuations; three patients had been treated only with levodopa and one
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patient with a combination of levodopa and dopamine agonist (DA). 12 of the remaining 29 patients (41.4%) were taking levodopa/carbidopa (immediate and controlled release) and the other 17 (58.6%)
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were taking levodopa/carbidopa (immediate and controlled release) and dopamine agonists. Before LCIG introduction, the following information was recorded at baseline: sex, age, age at PD onset, duration of PD (years), medications (expressed as levodopa equivalent daily dose, LEDD), Unified Parkinson’s Disease Rating Scale (UPDRS) part III/IV from 1 to 4 hours after the first usual parkinsonian medication, pre-existing occurrence of cognitive impairment/dementia, psychiatric disorders or impulse control disorder (ICD). A clinical diary, divided into 30-minute sections,
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pertaining motor complications was completed both by the patients and/or caregivers in their home and by the treating neurologist during hospitalization and follow-up visits. Diary assessments of percentage of "on" time with mild, moderate and severe dyskinesias was assessed. The diary included the following categories: "off", "on" without dyskinesia, "on" with mild dyskinesia, "on" with moderate
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dyskinesia, and "on" with severe dyskinesia. Patients were instructed to discriminate mild (nonbothersome; present but causes no difficulty), moderate (troublesome; causes some difficulty with
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function) and severe (disabling; causes great difficulty with function) dyskinesias indicating their predominant status.
LCIG was administered for up to 16 hours during the day, starting from the awakening, and was turned off at night. The only treatment allowed for nocturnal “off” symptoms was the oral levodopa/carbidopa 100/25 mg extended-release (ER). The follow-up visits after 10 days, after 1 month and after 3 months were performed to optimize LCIG dose and to evaluate efficacy of the treatment through UPDRS part III/IV and home/clinic diary assessments.
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At first follow-up observation, 4 patients presented disabling and involuntary choreoathetotic and choreo-dystonic movements that lasted around 30-90 minutes. These abnormal movements appeared mainly 15-25 minutes after the morning dose and more than 1 hour after the pump disconnection (at the
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end of the daily treatment). The involuntary movements initially involved the foot and shortly after became generalized in an "ascending wave". The ‘diphasic’ pattern became apparent when the abnormal movements were noted during the wearing-off period and were followed by the re-appearance of tremor and rigidity.
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This condition was firstly considered as caused by the stress of procedures and hospitalization and afterwards misinterpreted as LCIG being overdosed. Therefore, we decided to reduce the total daily LCIG flow that caused a clear worsening of motor symptoms and mild increase in the duration of
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dyskinesias. Moreover, with the gradual increment of the parameters of continuous infusion, the patients, instead of showing the expected improvement in motor performances, started to develop abnormal movements.
More specifically, in one case (see case 1), the incontrovertible proof of the correct interpretation of DD was obtained by reducing LCIG dosage at a dose insufficient to reach the "on" condition, after
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followed by the gradual increase of the parameters of continuous infusion of 2 ml per hour. It was clear that under a certain value infusion (2.6 ml/h) the patient was not able to carry out any physical activity of any part of the body. The gradual increment of LCIG dosage showed that there was a sufficient dosage to activate general choreoathetotic movements of the big toe of one foot and then, in succession,
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of the whole foot, leg, thigh and pelvis, and finally spread to the contralateral leg, although the patient was not able to lift the trunk from the bed (3.0 ml/h). Only the final increase of LCIG continuous
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infusion parameters to the dose of 3.8 ml/h allowed the patient to stand, walk and carry out several activities of daily living, with an almost complete disappearance of disabling dyskinesias. We tried to manage these symptoms by increasing morning LCIG flow, mainly in association with a dopamine-agonist and a levodopa/carbidopa (ER formulations) during bedtime. At the second and third follow up observations (after 1 and 3 months) the UPDRS-IV scores on dyskinesia questions (#32-33) were significantly reduced in comparison to baseline. Patients daily diaries showed a substantial reduction of the DD duration and severity as well as an increase in daily "on" time without dyskinesia at 1-3 months. (see Table 1).
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3. Case presentation Case 1 Case 1 is a 71-year-old woman who developed PD at the age of 56 with right upper extremity rest
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tremor, rigidity and bradykinesia. She was initially treated with ropinirole ER 10 mg/day. Three years later, when parkinsonian symptoms became disabling, she began levodopa therapy (400 mg/day) which led to a dramatic improvement for 4 years.
Within five years she developed severe motor fluctuations, characterized both by “wearing off”
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phenomena and unpredictable “off” periods. Her scores on UPDRS part III during the “off” period was 44, H&Y stage was IV. Accordingly, rasagiline 1 mg/day was started and levodopa/carbidopa was
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gradually added to the treatment up to 1300 mg in nine times a day with significant improvement of the symptomatology, although increasing dyskinetic movements were noted in the next months (Hoehn e Yahr stage was III in “on” and IV in “off” periods). The question of continuous dopaminergic stimulation was then raised. One month before starting LCGI infusion, rasagiline and ropinirole were stopped. Monotherapy with LCIG was started when she was 70 years old in order to obtain a lower and more stable therapeutic regimen. An improvement of motor fluctuations was registered and dyskinesias
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became less disabling as well. A significant reduction of the “off” periods were obtained through a LCIG titration of the morning dose to 5 ml (100 mg of levodopa), of the continuous dose to 3.4 ml (68 mg) per hour per 16 h a day (total dose of 1088 mg) and of the extra-doses to 2 ml (40 mg). Ten days later, during outpatient follow-up visit, we observed the presence of choreoathetotic
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movements involving the limbs and the trunk, which subsequently progressed and affected the head and the neck. Patients and/or their caregivers referred that these choreiform movements occurred
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mainly 15-25 minutes after the pump was started and 60-90 minutes after the pump was turned off in the evening, lasting in time between 0.5 and 1.5 h. We satisfactorily managed DD by increasing morning and continuous LCIG flow respectively from 5 ml to 6.5 ml and from 3.4 ml to 3.8 ml. Concomitantly we added ropinirole ER 6 mg and levodopa/carbidopa ER 100/25 mg during bedtime, when the pump was turned off. DD considerably reduced when patient was assessed at follow up 1 and 3 months later.
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Case 2 Case 2 is a 63-year-old man who developed PD at the age of 43 with right lower rest tremor, rigidity and bradykinesia. Initial treatment with the dopamine agonist led to hypersexuality and frotteurism and
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was discontinued. Oral levodopa 400 mg/day and its subsequent increase up to 600 mg/day yielded excellent response but was associated, within ten years, with peak-dose dyskinesia and wearing offrelated gait freezing. His scores on UPDRS part III during the “off” period was 42, H&Y stage was III. His cognitive screening was normal (MMSE = 27/30) but developed mild depression symptoms and generalized anxiety disorder. Twenty years after disease onset, his collective "off" time of 7 hours,
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alternating with peak-dose dyskinesia, prompted his recruitment into the LCIG treatment. A significant reduction of the “off” periods was obtained through a LCIG titration of the morning dose to 6 ml (120
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mg of levodopa), of the continuous dose to 3.9 ml (78 mg) per hour per 16 h a day (total dose of 1248 mg) and of the extra-doses to 2.2 ml (44 mg).
Ten days after LCIG initiation, during outpatient follow-up visit, we observed choreo-dystonic movements involving distal lower extremities and subsequently trunk and upper limbs. Patients and/or their caregivers referred that these abnormal movements occurred mainly 15 minutes after the pump
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was started and 75 minutes after the pump was turned off in the evening, lasting about 1 hour. The belief that dyskinesias could be caused by the PEG-J-tube flushing prompted us to posticipate the mandatory operation of bedtime flushing after two hours of pump disconnection. Also in this case, the infusion interruption led to the appearance of choreo-dystonic dyskinesias with the same time frame as
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observed after bedtime tube cleaning.
We managed DD by increasing morning LCIG flow from 6 ml to 6.5 ml. Concomitantly, we added
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rotigotine 6 mg/24 h and levodopa/carbidopa ER 100/25 mg during bedtime, when the pump was turned off. DD considerably reduced when patient was assessed at follow up 1and 3 months later.
Case 3
Case 3 is a 63-year-old man who developed PD at the age of 47 with left upper extremity rest tremor, rigidity and bradykinesia. Within six years he developed severe motor fluctuations, characterized both by “wearing off” phenomena and unpredictable “off” periods. His scores on UPDRS part III during the “off” period was 45, H&Y stage was IV. Although we had tried to reduce levodopa doses, he continued 6
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to complain an unsatisfactory control of motor fluctuations. Accordingly, treatment with LCIG was proposed and accepted by the patient. Monotherapy with LCIG was started when he was 63 years old in order to obtain a lower and more stable therapeutic regimen. A significant reduction of the “off” periods was obtained through a LCIG titration of the morning dose to 5.8 ml (116 mg of levodopa), of
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the continuous dose to 1.8 ml (36 mg) per hour per 16 h a day (total dose of 576 mg) and of the extradoses to 1.8 ml (36 mg).
Ten days later, during outpatient follow-up visit, we observed the presence of choreoathetotic movements involving the lower limbs and the trunk, which subsequently progressed and affected the
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head and the neck. Patients and/or their caregivers referred that these abnormal movements occurred mainly 20 minutes after the pump was started and 1.5 hours after the pump was turned off in the
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evening, lasting in time between 60 and 90 minutes.
We satisfactorily managed DD by increasing morning LCIG flow from 5.8 ml to 6.5 ml. Concomitantly, we added rotigotine 6 mg/24 h and levodopa/carbidopa ER 100/25 mg during bedtime, when the pump was turned off. DD considerably reduced when patient was assessed at follow up 1 and
Case 4
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3 months later.
Case 4 is a 77-year-old woman who developed PD at age 56. Initial motor symptoms were rigidity and
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bradykinesia at the left side, with excellent response to oral levodopa at the doses of 400 mg/day. In the following years, due to progressive worsening of parkinsonism, levodopa was gradually increased up to 1000 mg/day and associated treatment with pramipexole 3.1 mg/daily was added. However, due to
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initial presence of sporadic visual hallucinations, pramipexole was gradually reduced and, finally, suspended. At age 77, her motor condition was characterized by severe off-period with related gait freezing, sometimes alternated with peak-dose dyskinesias. Her scores on UPDRS part III during the “off” period was 45, H&Y stage was IV. At this time, initial symptoms of mild cognitive impairment were present (MMSE=26/30). The presence of severe off-periods and peak-dose dyskinesias, prompted her recruitment into the LCIG treatment. A significant reduction of the “off” periods were obtained through a LCIG titration of the morning dose to 4 ml (80 mg of levodopa), of the continuous dose to 4.2 ml (84 mg) per hour per 15 h a day (total dose of 1260 mg) and of the extra-doses to 1.5 ml (30 mg). 7
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Nine days after LCIG initiation, her caregivers reported the appearance of unusual choreo-dystonic movements involving distal lower extremities and subsequently trunk and upper limbs, which occurred mainly 20 minutes after the pump was started and at least 75 minutes after the pump was turned off in
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the evening, lasting about 1 hour. We managed DD by increasing morning LCIG flow from 4 ml to 7 ml and administrating levodopa ER (100/25 mg) at bedtime. These choreo-dystonic movements considerably reduced when she was
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evaluated 1 and 3 months later.
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4. Discussion
In this paper, we have described 4 PD patients who developed LCIG-induced DD, without any definite past history of clear and disabling DD during oral levodopa therapy.
Several published data demonstrated that switching from oral levodopa to LCIG significantly reduced “off” time and troublesome dyskinesia by reducing peak levodopa levels [8, 10].
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The "peak of dose” dyskinesia and DD have distinct pathophysiological substrates. The DD is a subtype of levodopa-induced dyskinesias that appears typically at the onset and offset of levodopa action in relationship with increment or decrement of plasma level [4]. Conversely, “peak of dose” or
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“on” period dyskinesia is correlated to high plasma levels of levodopa [3]. All of our cases were characterized by the appearance, 15-25 minutes after the pump was turned on, of
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severe involuntary choreoathetotic and choreo-dystonic movements that lasted 30-60 minutes. These abnormal movements appeared suddenly from a condition of severe "off" without any intermediate stage of good "on" and were spontaneously followed by good "on" period without any change of infusional parameters.
Besides, at the end of the daily treatment, 60-90 minutes after pump disconnection, all patients presented stereotypical choreo-dystonic hyperkinesias that lasted 40-90 minutes. The morning dose ranged from 4 to 6 ml, corresponding to 80 and 120 mg levodopa. The continuous dose infusion rate ranged from 1.8 to 4.2 ml/ h (36 and 84 mg levodopa per hour). The total LCIG dose of levodopa, excluding extra doses, ranged from 692 mg to 1424 mg. 8
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It is important to emphasize that violent dyskinesias following the PEG-J-tube bedtime flushing have been described. Therefore, through the flushing the patient received extradoses of levodopa gel that caused violent peak-dose dyskinesias [11]. In our case, DD were not temporally related to the PEG-Jtube flushing. Indeed, DD appeared more than 1 hour after the tube cleaning. Moreover, in the peak-
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dose dyskinesia, during decreasing period of plasma levodopa concentration, we would expect an intermediate stage of good "on"; conversely, we observed the direct transition from the choreo-dystonic movements to the reappearance of severe "off" state without any intermediate good "on" period. Furthermore, during follow-up visits, we observed improvements of end-of-dose dyskinesias adding
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extra bolus doses.
As DD cease, or at least is reduced, at peak plasma levodopa levels, we assume that in our patients the
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initial failure to achieve peak effect with the morning bolus (80-120 mg levodopa) may have kept plasma levodopa concentrations in the DD threshold. Indeed, the treatment based on the combination of the dopamine agonist ER, the sustained-release levodopa formulations during bedtime and the increase of the morning dose enabled us to reduce the duration and severity of DD. Interestingly, end-of-dose dyskinesias, after pump disconnection, tended to last longer than the onset-of-dose dyskinesias, suggesting a slower reduction of levodopa plasmatic levels during bedtime. The mandatory operation
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of flushing the PEG-J-tube may have presumably contributed to delay the fall of plasma levodopa concentrations. In turn, this slowdown might have increased the total time spent in a critical plasma level causing end-of-dose dyskinesia.
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A reason for a more precise identification of DD in patients under LCIG is the greater possibility to recognize its effective detection threshold. Therefore, in most of the advanced PD patients treated with oral levodopa, the therapeutic window is often very narrow. The accurate differentiation between DD
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and "peak dose” dyskinesias can be difficult due to the variable time of gastrointestinal transit and the irregular gastrointestinal drug absorption. Regarding the issue of the underlying mechanisms of DD and the reason why some of these patients developed this type of dyskinesia when others did not, a conclusive response cannot be given. However, it is important to underline that, in our sample, the age of PD onset was not advanced. Indeed, one of our patients had relatively early disease onset (see case 2). In this instance, young age of PD onset, tighter with disease severity, is often described as a major intrinsic risk factors for DD [12].
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Moreover, all patients reported a natural history of behavioral disturbances such as anxiety, depression or previous occurrences of dopaminergic induced hypersexuality and dysperceptive episodes. They all led us to start LCIG at low doses, that may have contributed in turn to trigger these DD phenomena.
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The treatment of DD requires the maintenance of plasma levodopa concentrations above the dyskinesia threshold [13]. An increase in dopaminergic stimulation at doses that are higher than the threshold, necessary to induce an "on" motor state, may improve DD in the short term [14], probably through the shortening of time necessary to reach the useful therapeutic threshold.
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In our LCIG patients, the increase of morning and continuous LCIG flow was the first therapeutic strategy and was followed in most of the cases by the use of a combination treatment with the
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dopamine agonist ER and sustained-release levodopa formulations during bedtime. To our knowledge, this is the first report describing the occurrence of disabling and lasting DD in a small cohort of PD patients during LCIG treatment. Studies on a larger population of patients, possibly
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involving multiple centers, are needed to support our findings.
Conflict of Interest/Financial Disclosure: The authors have no conflicts of interest to declare.
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P. Solla has received institutional research funding from the Fondazione di Sardegna, Dystonia Europe, Abbvie (Advisory Board) and Sanofi in the last years. A. Cannas received funding from Abbvie
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(Advisory Board) in the last years.
All authors declare that they have received no financial or other support relative to the present research. Acknowledgements: none
Author's roles: All authors have reviewed the contents of the manuscript being submitted, approved of its contents, and validated the accuracy of the data. Mario Meloni: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: 10
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A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. Paolo Solla: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A.
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Design, B. Execution, C. Review and Critique; Manuscript Preparation: B. Review and Critique. Marcello Mario Mascia: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: B. Review and Critique.
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Francesco Marrosu: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: B. Review and
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Critique.
Antonino Cannas: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: A. Writing of the
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Table 1 Demographic and clinical features of PD patients with DD before LCIG (Baseline) and at follow-up visit.
Ambulatory diary assessment (% time in "on" with mild/moderate/severe DD)
DD management
Follow-up visit after 1 month UPDRS-IV dyskinesia questions (#32-33) Home diary assessment (% time in "on" with mild/moderate/severe DD)
Case 4 77/F 21 years 9 years 26/30
1300 44 25 3-3
1150 42 27 2-3
465 45 26 2-3
1000 45 23 2-3
Detection of DD
Detection of DD
Detection of DD
Detection of DD
3.4 ml/h 2 ml 5 ml 1228 30 20 2-2
3.9 ml/h 2.2 ml 6 ml 1412 32 18 2-3
20% (moderate DD) 10% (severe DD) 25% (moderate DD) 10%(severe DD)
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Case 3 63/M 16 years 10 years 28/30
1.8 ml/h 1.8 ml 5.8 ml 728 28 18 1-3
4.2 ml/h 1.5 ml 4 ml 1370 35 19 1-3
18% (moderate DD) 18%(severe DD)
No reported
5% (moderate DD) 15% (severe DD)
12% (moderate DD) 22% (severe DD)
10% (moderate DD) 18% (severe DD)
10% (moderate DD) 13% (severe DD)
Increase of the morning bolus dose (6.5 ml) and continuous dose (3.8 ml/h). Administration of ropinirole ER (6 mg) and L-Dopa ER (100/25 mg) during bedtime.
Increase of the morning bolus dose (6.5 ml). Administration of rotigotine (6 mg) and L-Dopa ER (100/25 mg) during bedtime.
Increase of the morning bolus dose (6.5 ml). Administration of rotigotine (6 mg) L-Dopa ER (100/25 mg) during bedtime.
Increase of the morning bolus dose (7 ml). Administration of L-Dopa ER (100/25 mg) during bedtime.
1-1
1-1
1-1
1-1
8% (mild) 5% (moderate)
10% (mild)
6% (mild)
10% (moderate)
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(% time in "on" with mild/moderate/severe DD)
Case 2 63/M 20 years 10 years 27/30
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Continuous daily dose Extra doses Morning dose L-Dopa LEDD (mg/daily) UPDRS-III ("off"-period) UPDRS-III ("on"-period) UPDRS-IV dyskinesia questions (#32-33) Home diary assessment
Case 1 71/F 14 years 8 years 28/30
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Age/ Gender Disease duration Motor complications duration MMSE Baseline Total LEDD UPDRS-III ("off"-period) UPDRS-III ("on"-period) UPDRS-IV dyskinesia questions (#32-33) LCIG introduction Follow-up visit after 10 days Parameters LCIG during DD
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Table 1 Demographic and clinical features of PD patients with DD before LCIG (Baseline) and at follow-up visit.
Follow-up visit after 3 months UPDRS-IV dyskinesia questions (#32-33) Home diary assessment (% time in "on" with mild/moderate/severe DD)
Ambulatory diary assessment (% time in "on" with mild/moderate/severe DD)
10%(mild) 10%(moderate)
8% (mild) 5% (moderate)
6%(mild)
10% (moderate)
1-1
1-1
1-1
1-1
9%(mild) 5%(moderate)
9% (mild) 2% (moderate)
No reported
10% (moderate)
10%(mild) 10%(mild)
9%(mild) 5%(moderate)
8%(mild)
6%(moderate) 4%(mild)
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(% "on" with mild/moderate/severe DD)
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Ambulatory diary assessment
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Abbreviations: PD, Parkinson's disease; LCIG: levodopa/carbidopa intestinal gel infusion; MMSE: mini-mental state examination, DA: dopamine agonist, LEDD: levodopaequivalent daily dose (mg/day), UPDRS: Unified PD Rating Scale; DD: Diphasic Dyskinesia
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Highlights
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• First detailed description of Diphasic dyskinesia in PD under Duodopa pump treatment • Description of 4 cases through clinical observation and review of medical records. • We propose a easy and quick therapeutic strategy
S1353-8020(16)30523-5
DOI:
10.1016/j.parkreldis.2016.12.030
Reference:
PRD 3209
To appear in:
Parkinsonism and Related Disorders
Received Date: 28 July 2016 Revised Date:
19 December 2016
Accepted Date: 31 December 2016
Please cite this article as: Mario M, Paolo S, Marcello MM, Francesco M, Antonino C, Diphasic dyskinesias during levodopa-carbidopa intestinal gel (LCIG) infusion in Parkinson's disease, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2016.12.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Diphasic dyskinesias during levodopa-carbidopa intestinal gel (LCIG) infusion in Parkinson’s disease. Meloni Mario MD; Solla Paolo MD, PhD; Mascia Mario Marcello MD; Marrosu Francesco MD; Cannas
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Antonino MD. Movement Disorders Center, Department of Neurology, Institute of Neurology, University of Cagliari, Cagliari, Italy. Keywords: Parkinson's disease; Diphasic dyskinesias; Levodopa-Carbidopa Intestinal Gel (LCIG)
Corresponding Author:
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Dr. Mario Meloni, MD Department of Neurology Movement Disorders Center,
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University of Cagliari SS 554 Bivio per Sestu 09042 Monserrato, Cagliari, Italy. E-mail: [email protected] Telephone number: +393466260026
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Objectives: Levodopa-carbidopa intestinal gel infusion (LCIG) is indicated in patients with advanced levodopa-responsive Parkinson's disease (PD) for the treatment of motor fluctuations and dyskinesias. Here we describe 4 PD patients who developed disabling diphasic dyskinesias after LCIG initiation.
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Methods: The clinical data of 33 PD patients consecutively treated with LCIG therapy were obtained through direct clinical observation and detailed review of medical records.
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Results: Within 10 days, after LCIG introduction, we identified 4 subjects (12.1%) with persistent and disabling diphasic dyskinesia (DD). We tried to manage these symptoms by increasing morning LCIG flow and adding "extended-release" formulations of dopamine-agonists and levodopa/carbidopa during bedtime. Within 1 month, all patients presented a gradual reduction in the duration and severity of DD. Conclusions: To our knowledge, this is the first report describing the occurrence of DD in a small cohort of advanced PD patients after LCIG initiation. We wish to draw the attention of clinicians to the risk of developing disabling DD in PD patients switched to the LCIG monotherapy.
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1.Introduction The occurrence of dyskinesias and motor fluctuations is a major problem in the long-term management of patients with Parkinson's disease (PD). Dyskinesias may be classified on the basis of their course
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and clinical phenomenology following a regular or over-threshold dose of oral levodopa. The most commonly recognized pattern of dyskinesias are the "peak-dose" dyskinesias [1, 2], which occurred around the time of the peak plasma levels of medication [3].
Muenter et al. (1977) also described a "dystonia-improvement-dystonia" response, whereby patients
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experience dyskinesia phenomena as the effects of levodopa wearing "on" and "off". The authors reported that these occurred when the concentration of levodopa in plasma passed through a critical but relatively low level, whereas it remained absent as long as the concentration remained above that level.
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This type of dyskinesia, due to its occurrence at the onset and/or end of action of levodopa, is now more commonly referred as ‘diphasic’ dyskinesia (DD). The clinical phenomenology of DD is generally different from other common forms of levodopa-induced dyskinesias (LIDs). DD usually predominates in lower limbs and tends to be dystonic or ballistic, while peak dose dyskinesias involve more the upper limbs, have a choreic phenotype and tend to be less disabling and less painful [4].
parkinsonian signs [5].
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Frequently, while the legs are moving involuntarily, the upper half of the body still exhibits
Levodopa-carbidopa intestinal gel (LCIG) is a treatment option for advanced PD patients. Compared to
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orally administered levodopa/carbidopa, pharmacokinetic studies have shown that continuous intestinal infusion provides less variability in levodopa plasma levels [6]. Previously published data in advanced PD patients demonstrated that switching from oral levodopa to LCIG significantly reduced “off” time,
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improving motor conditions with a global increase in “on” time without increasing troublesome and disabling dyskinesias [7, 8].
Nylhom and colleagues previously reported a single case of diphasic type of dyskinesias on LCIG with predominance choreo-dystonic type in the legs at very low doses and more typical generalized chorea at high doses [9]. However, to our knowledge, the presence of DD on LCIG has not been systematically described so far. Here we describe 4 PD patients who developed disabling DD after LCIG initiation.
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2. Methods and results Among the 33 PD patients treated with LCIG therapy in our Movement Disorders Center at the University of Cagliari, we identified 4 patients (12.1%) (2 men and 2 women; mean age 68.5) with
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persistent and disabling DD. The clinical data were obtained through direct clinical observation and detailed review of medical records. Table 1 reports demographic and clinical features of these four patients. They all suffered from advanced disease with motor fluctuations; three patients had been treated only with levodopa and one
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patient with a combination of levodopa and dopamine agonist (DA). 12 of the remaining 29 patients (41.4%) were taking levodopa/carbidopa (immediate and controlled release) and the other 17 (58.6%)
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were taking levodopa/carbidopa (immediate and controlled release) and dopamine agonists. Before LCIG introduction, the following information was recorded at baseline: sex, age, age at PD onset, duration of PD (years), medications (expressed as levodopa equivalent daily dose, LEDD), Unified Parkinson’s Disease Rating Scale (UPDRS) part III/IV from 1 to 4 hours after the first usual parkinsonian medication, pre-existing occurrence of cognitive impairment/dementia, psychiatric disorders or impulse control disorder (ICD). A clinical diary, divided into 30-minute sections,
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pertaining motor complications was completed both by the patients and/or caregivers in their home and by the treating neurologist during hospitalization and follow-up visits. Diary assessments of percentage of "on" time with mild, moderate and severe dyskinesias was assessed. The diary included the following categories: "off", "on" without dyskinesia, "on" with mild dyskinesia, "on" with moderate
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dyskinesia, and "on" with severe dyskinesia. Patients were instructed to discriminate mild (nonbothersome; present but causes no difficulty), moderate (troublesome; causes some difficulty with
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function) and severe (disabling; causes great difficulty with function) dyskinesias indicating their predominant status.
LCIG was administered for up to 16 hours during the day, starting from the awakening, and was turned off at night. The only treatment allowed for nocturnal “off” symptoms was the oral levodopa/carbidopa 100/25 mg extended-release (ER). The follow-up visits after 10 days, after 1 month and after 3 months were performed to optimize LCIG dose and to evaluate efficacy of the treatment through UPDRS part III/IV and home/clinic diary assessments.
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At first follow-up observation, 4 patients presented disabling and involuntary choreoathetotic and choreo-dystonic movements that lasted around 30-90 minutes. These abnormal movements appeared mainly 15-25 minutes after the morning dose and more than 1 hour after the pump disconnection (at the
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end of the daily treatment). The involuntary movements initially involved the foot and shortly after became generalized in an "ascending wave". The ‘diphasic’ pattern became apparent when the abnormal movements were noted during the wearing-off period and were followed by the re-appearance of tremor and rigidity.
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This condition was firstly considered as caused by the stress of procedures and hospitalization and afterwards misinterpreted as LCIG being overdosed. Therefore, we decided to reduce the total daily LCIG flow that caused a clear worsening of motor symptoms and mild increase in the duration of
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dyskinesias. Moreover, with the gradual increment of the parameters of continuous infusion, the patients, instead of showing the expected improvement in motor performances, started to develop abnormal movements.
More specifically, in one case (see case 1), the incontrovertible proof of the correct interpretation of DD was obtained by reducing LCIG dosage at a dose insufficient to reach the "on" condition, after
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followed by the gradual increase of the parameters of continuous infusion of 2 ml per hour. It was clear that under a certain value infusion (2.6 ml/h) the patient was not able to carry out any physical activity of any part of the body. The gradual increment of LCIG dosage showed that there was a sufficient dosage to activate general choreoathetotic movements of the big toe of one foot and then, in succession,
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of the whole foot, leg, thigh and pelvis, and finally spread to the contralateral leg, although the patient was not able to lift the trunk from the bed (3.0 ml/h). Only the final increase of LCIG continuous
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infusion parameters to the dose of 3.8 ml/h allowed the patient to stand, walk and carry out several activities of daily living, with an almost complete disappearance of disabling dyskinesias. We tried to manage these symptoms by increasing morning LCIG flow, mainly in association with a dopamine-agonist and a levodopa/carbidopa (ER formulations) during bedtime. At the second and third follow up observations (after 1 and 3 months) the UPDRS-IV scores on dyskinesia questions (#32-33) were significantly reduced in comparison to baseline. Patients daily diaries showed a substantial reduction of the DD duration and severity as well as an increase in daily "on" time without dyskinesia at 1-3 months. (see Table 1).
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3. Case presentation Case 1 Case 1 is a 71-year-old woman who developed PD at the age of 56 with right upper extremity rest
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tremor, rigidity and bradykinesia. She was initially treated with ropinirole ER 10 mg/day. Three years later, when parkinsonian symptoms became disabling, she began levodopa therapy (400 mg/day) which led to a dramatic improvement for 4 years.
Within five years she developed severe motor fluctuations, characterized both by “wearing off”
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phenomena and unpredictable “off” periods. Her scores on UPDRS part III during the “off” period was 44, H&Y stage was IV. Accordingly, rasagiline 1 mg/day was started and levodopa/carbidopa was
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gradually added to the treatment up to 1300 mg in nine times a day with significant improvement of the symptomatology, although increasing dyskinetic movements were noted in the next months (Hoehn e Yahr stage was III in “on” and IV in “off” periods). The question of continuous dopaminergic stimulation was then raised. One month before starting LCGI infusion, rasagiline and ropinirole were stopped. Monotherapy with LCIG was started when she was 70 years old in order to obtain a lower and more stable therapeutic regimen. An improvement of motor fluctuations was registered and dyskinesias
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became less disabling as well. A significant reduction of the “off” periods were obtained through a LCIG titration of the morning dose to 5 ml (100 mg of levodopa), of the continuous dose to 3.4 ml (68 mg) per hour per 16 h a day (total dose of 1088 mg) and of the extra-doses to 2 ml (40 mg). Ten days later, during outpatient follow-up visit, we observed the presence of choreoathetotic
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movements involving the limbs and the trunk, which subsequently progressed and affected the head and the neck. Patients and/or their caregivers referred that these choreiform movements occurred
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mainly 15-25 minutes after the pump was started and 60-90 minutes after the pump was turned off in the evening, lasting in time between 0.5 and 1.5 h. We satisfactorily managed DD by increasing morning and continuous LCIG flow respectively from 5 ml to 6.5 ml and from 3.4 ml to 3.8 ml. Concomitantly we added ropinirole ER 6 mg and levodopa/carbidopa ER 100/25 mg during bedtime, when the pump was turned off. DD considerably reduced when patient was assessed at follow up 1 and 3 months later.
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Case 2 Case 2 is a 63-year-old man who developed PD at the age of 43 with right lower rest tremor, rigidity and bradykinesia. Initial treatment with the dopamine agonist led to hypersexuality and frotteurism and
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was discontinued. Oral levodopa 400 mg/day and its subsequent increase up to 600 mg/day yielded excellent response but was associated, within ten years, with peak-dose dyskinesia and wearing offrelated gait freezing. His scores on UPDRS part III during the “off” period was 42, H&Y stage was III. His cognitive screening was normal (MMSE = 27/30) but developed mild depression symptoms and generalized anxiety disorder. Twenty years after disease onset, his collective "off" time of 7 hours,
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alternating with peak-dose dyskinesia, prompted his recruitment into the LCIG treatment. A significant reduction of the “off” periods was obtained through a LCIG titration of the morning dose to 6 ml (120
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mg of levodopa), of the continuous dose to 3.9 ml (78 mg) per hour per 16 h a day (total dose of 1248 mg) and of the extra-doses to 2.2 ml (44 mg).
Ten days after LCIG initiation, during outpatient follow-up visit, we observed choreo-dystonic movements involving distal lower extremities and subsequently trunk and upper limbs. Patients and/or their caregivers referred that these abnormal movements occurred mainly 15 minutes after the pump
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was started and 75 minutes after the pump was turned off in the evening, lasting about 1 hour. The belief that dyskinesias could be caused by the PEG-J-tube flushing prompted us to posticipate the mandatory operation of bedtime flushing after two hours of pump disconnection. Also in this case, the infusion interruption led to the appearance of choreo-dystonic dyskinesias with the same time frame as
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observed after bedtime tube cleaning.
We managed DD by increasing morning LCIG flow from 6 ml to 6.5 ml. Concomitantly, we added
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rotigotine 6 mg/24 h and levodopa/carbidopa ER 100/25 mg during bedtime, when the pump was turned off. DD considerably reduced when patient was assessed at follow up 1and 3 months later.
Case 3
Case 3 is a 63-year-old man who developed PD at the age of 47 with left upper extremity rest tremor, rigidity and bradykinesia. Within six years he developed severe motor fluctuations, characterized both by “wearing off” phenomena and unpredictable “off” periods. His scores on UPDRS part III during the “off” period was 45, H&Y stage was IV. Although we had tried to reduce levodopa doses, he continued 6
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to complain an unsatisfactory control of motor fluctuations. Accordingly, treatment with LCIG was proposed and accepted by the patient. Monotherapy with LCIG was started when he was 63 years old in order to obtain a lower and more stable therapeutic regimen. A significant reduction of the “off” periods was obtained through a LCIG titration of the morning dose to 5.8 ml (116 mg of levodopa), of
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the continuous dose to 1.8 ml (36 mg) per hour per 16 h a day (total dose of 576 mg) and of the extradoses to 1.8 ml (36 mg).
Ten days later, during outpatient follow-up visit, we observed the presence of choreoathetotic movements involving the lower limbs and the trunk, which subsequently progressed and affected the
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head and the neck. Patients and/or their caregivers referred that these abnormal movements occurred mainly 20 minutes after the pump was started and 1.5 hours after the pump was turned off in the
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evening, lasting in time between 60 and 90 minutes.
We satisfactorily managed DD by increasing morning LCIG flow from 5.8 ml to 6.5 ml. Concomitantly, we added rotigotine 6 mg/24 h and levodopa/carbidopa ER 100/25 mg during bedtime, when the pump was turned off. DD considerably reduced when patient was assessed at follow up 1 and
Case 4
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3 months later.
Case 4 is a 77-year-old woman who developed PD at age 56. Initial motor symptoms were rigidity and
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bradykinesia at the left side, with excellent response to oral levodopa at the doses of 400 mg/day. In the following years, due to progressive worsening of parkinsonism, levodopa was gradually increased up to 1000 mg/day and associated treatment with pramipexole 3.1 mg/daily was added. However, due to
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initial presence of sporadic visual hallucinations, pramipexole was gradually reduced and, finally, suspended. At age 77, her motor condition was characterized by severe off-period with related gait freezing, sometimes alternated with peak-dose dyskinesias. Her scores on UPDRS part III during the “off” period was 45, H&Y stage was IV. At this time, initial symptoms of mild cognitive impairment were present (MMSE=26/30). The presence of severe off-periods and peak-dose dyskinesias, prompted her recruitment into the LCIG treatment. A significant reduction of the “off” periods were obtained through a LCIG titration of the morning dose to 4 ml (80 mg of levodopa), of the continuous dose to 4.2 ml (84 mg) per hour per 15 h a day (total dose of 1260 mg) and of the extra-doses to 1.5 ml (30 mg). 7
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Nine days after LCIG initiation, her caregivers reported the appearance of unusual choreo-dystonic movements involving distal lower extremities and subsequently trunk and upper limbs, which occurred mainly 20 minutes after the pump was started and at least 75 minutes after the pump was turned off in
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the evening, lasting about 1 hour. We managed DD by increasing morning LCIG flow from 4 ml to 7 ml and administrating levodopa ER (100/25 mg) at bedtime. These choreo-dystonic movements considerably reduced when she was
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evaluated 1 and 3 months later.
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4. Discussion
In this paper, we have described 4 PD patients who developed LCIG-induced DD, without any definite past history of clear and disabling DD during oral levodopa therapy.
Several published data demonstrated that switching from oral levodopa to LCIG significantly reduced “off” time and troublesome dyskinesia by reducing peak levodopa levels [8, 10].
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The "peak of dose” dyskinesia and DD have distinct pathophysiological substrates. The DD is a subtype of levodopa-induced dyskinesias that appears typically at the onset and offset of levodopa action in relationship with increment or decrement of plasma level [4]. Conversely, “peak of dose” or
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“on” period dyskinesia is correlated to high plasma levels of levodopa [3]. All of our cases were characterized by the appearance, 15-25 minutes after the pump was turned on, of
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severe involuntary choreoathetotic and choreo-dystonic movements that lasted 30-60 minutes. These abnormal movements appeared suddenly from a condition of severe "off" without any intermediate stage of good "on" and were spontaneously followed by good "on" period without any change of infusional parameters.
Besides, at the end of the daily treatment, 60-90 minutes after pump disconnection, all patients presented stereotypical choreo-dystonic hyperkinesias that lasted 40-90 minutes. The morning dose ranged from 4 to 6 ml, corresponding to 80 and 120 mg levodopa. The continuous dose infusion rate ranged from 1.8 to 4.2 ml/ h (36 and 84 mg levodopa per hour). The total LCIG dose of levodopa, excluding extra doses, ranged from 692 mg to 1424 mg. 8
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It is important to emphasize that violent dyskinesias following the PEG-J-tube bedtime flushing have been described. Therefore, through the flushing the patient received extradoses of levodopa gel that caused violent peak-dose dyskinesias [11]. In our case, DD were not temporally related to the PEG-Jtube flushing. Indeed, DD appeared more than 1 hour after the tube cleaning. Moreover, in the peak-
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dose dyskinesia, during decreasing period of plasma levodopa concentration, we would expect an intermediate stage of good "on"; conversely, we observed the direct transition from the choreo-dystonic movements to the reappearance of severe "off" state without any intermediate good "on" period. Furthermore, during follow-up visits, we observed improvements of end-of-dose dyskinesias adding
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extra bolus doses.
As DD cease, or at least is reduced, at peak plasma levodopa levels, we assume that in our patients the
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initial failure to achieve peak effect with the morning bolus (80-120 mg levodopa) may have kept plasma levodopa concentrations in the DD threshold. Indeed, the treatment based on the combination of the dopamine agonist ER, the sustained-release levodopa formulations during bedtime and the increase of the morning dose enabled us to reduce the duration and severity of DD. Interestingly, end-of-dose dyskinesias, after pump disconnection, tended to last longer than the onset-of-dose dyskinesias, suggesting a slower reduction of levodopa plasmatic levels during bedtime. The mandatory operation
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of flushing the PEG-J-tube may have presumably contributed to delay the fall of plasma levodopa concentrations. In turn, this slowdown might have increased the total time spent in a critical plasma level causing end-of-dose dyskinesia.
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A reason for a more precise identification of DD in patients under LCIG is the greater possibility to recognize its effective detection threshold. Therefore, in most of the advanced PD patients treated with oral levodopa, the therapeutic window is often very narrow. The accurate differentiation between DD
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and "peak dose” dyskinesias can be difficult due to the variable time of gastrointestinal transit and the irregular gastrointestinal drug absorption. Regarding the issue of the underlying mechanisms of DD and the reason why some of these patients developed this type of dyskinesia when others did not, a conclusive response cannot be given. However, it is important to underline that, in our sample, the age of PD onset was not advanced. Indeed, one of our patients had relatively early disease onset (see case 2). In this instance, young age of PD onset, tighter with disease severity, is often described as a major intrinsic risk factors for DD [12].
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Moreover, all patients reported a natural history of behavioral disturbances such as anxiety, depression or previous occurrences of dopaminergic induced hypersexuality and dysperceptive episodes. They all led us to start LCIG at low doses, that may have contributed in turn to trigger these DD phenomena.
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The treatment of DD requires the maintenance of plasma levodopa concentrations above the dyskinesia threshold [13]. An increase in dopaminergic stimulation at doses that are higher than the threshold, necessary to induce an "on" motor state, may improve DD in the short term [14], probably through the shortening of time necessary to reach the useful therapeutic threshold.
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In our LCIG patients, the increase of morning and continuous LCIG flow was the first therapeutic strategy and was followed in most of the cases by the use of a combination treatment with the
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dopamine agonist ER and sustained-release levodopa formulations during bedtime. To our knowledge, this is the first report describing the occurrence of disabling and lasting DD in a small cohort of PD patients during LCIG treatment. Studies on a larger population of patients, possibly
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involving multiple centers, are needed to support our findings.
Conflict of Interest/Financial Disclosure: The authors have no conflicts of interest to declare.
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P. Solla has received institutional research funding from the Fondazione di Sardegna, Dystonia Europe, Abbvie (Advisory Board) and Sanofi in the last years. A. Cannas received funding from Abbvie
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(Advisory Board) in the last years.
All authors declare that they have received no financial or other support relative to the present research. Acknowledgements: none
Author's roles: All authors have reviewed the contents of the manuscript being submitted, approved of its contents, and validated the accuracy of the data. Mario Meloni: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: 10
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A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. Paolo Solla: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A.
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Design, B. Execution, C. Review and Critique; Manuscript Preparation: B. Review and Critique. Marcello Mario Mascia: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: B. Review and Critique.
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Francesco Marrosu: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: B. Review and
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Critique.
Antonino Cannas: Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A. Design, B. Execution, C. Review and Critique; Manuscript Preparation: A. Writing of the
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[12] Merello M, Damas TI, Obeso AJ. Features and Mechanisms of Diphasic Dyskinesia in Parkinson’s Disease. Chapter: Levodopa-Induced Dyskinesia in Parkinson's Disease; Springer (Eds.), 2014, pp 135-
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Table 1 Demographic and clinical features of PD patients with DD before LCIG (Baseline) and at follow-up visit.
Ambulatory diary assessment (% time in "on" with mild/moderate/severe DD)
DD management
Follow-up visit after 1 month UPDRS-IV dyskinesia questions (#32-33) Home diary assessment (% time in "on" with mild/moderate/severe DD)
Case 4 77/F 21 years 9 years 26/30
1300 44 25 3-3
1150 42 27 2-3
465 45 26 2-3
1000 45 23 2-3
Detection of DD
Detection of DD
Detection of DD
Detection of DD
3.4 ml/h 2 ml 5 ml 1228 30 20 2-2
3.9 ml/h 2.2 ml 6 ml 1412 32 18 2-3
20% (moderate DD) 10% (severe DD) 25% (moderate DD) 10%(severe DD)
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Case 3 63/M 16 years 10 years 28/30
1.8 ml/h 1.8 ml 5.8 ml 728 28 18 1-3
4.2 ml/h 1.5 ml 4 ml 1370 35 19 1-3
18% (moderate DD) 18%(severe DD)
No reported
5% (moderate DD) 15% (severe DD)
12% (moderate DD) 22% (severe DD)
10% (moderate DD) 18% (severe DD)
10% (moderate DD) 13% (severe DD)
Increase of the morning bolus dose (6.5 ml) and continuous dose (3.8 ml/h). Administration of ropinirole ER (6 mg) and L-Dopa ER (100/25 mg) during bedtime.
Increase of the morning bolus dose (6.5 ml). Administration of rotigotine (6 mg) and L-Dopa ER (100/25 mg) during bedtime.
Increase of the morning bolus dose (6.5 ml). Administration of rotigotine (6 mg) L-Dopa ER (100/25 mg) during bedtime.
Increase of the morning bolus dose (7 ml). Administration of L-Dopa ER (100/25 mg) during bedtime.
1-1
1-1
1-1
1-1
8% (mild) 5% (moderate)
10% (mild)
6% (mild)
10% (moderate)
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(% time in "on" with mild/moderate/severe DD)
Case 2 63/M 20 years 10 years 27/30
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Continuous daily dose Extra doses Morning dose L-Dopa LEDD (mg/daily) UPDRS-III ("off"-period) UPDRS-III ("on"-period) UPDRS-IV dyskinesia questions (#32-33) Home diary assessment
Case 1 71/F 14 years 8 years 28/30
AC C
Age/ Gender Disease duration Motor complications duration MMSE Baseline Total LEDD UPDRS-III ("off"-period) UPDRS-III ("on"-period) UPDRS-IV dyskinesia questions (#32-33) LCIG introduction Follow-up visit after 10 days Parameters LCIG during DD
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Table 1 Demographic and clinical features of PD patients with DD before LCIG (Baseline) and at follow-up visit.
Follow-up visit after 3 months UPDRS-IV dyskinesia questions (#32-33) Home diary assessment (% time in "on" with mild/moderate/severe DD)
Ambulatory diary assessment (% time in "on" with mild/moderate/severe DD)
10%(mild) 10%(moderate)
8% (mild) 5% (moderate)
6%(mild)
10% (moderate)
1-1
1-1
1-1
1-1
9%(mild) 5%(moderate)
9% (mild) 2% (moderate)
No reported
10% (moderate)
10%(mild) 10%(mild)
9%(mild) 5%(moderate)
8%(mild)
6%(moderate) 4%(mild)
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(% "on" with mild/moderate/severe DD)
SC
Ambulatory diary assessment
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EP
TE D
M AN U
Abbreviations: PD, Parkinson's disease; LCIG: levodopa/carbidopa intestinal gel infusion; MMSE: mini-mental state examination, DA: dopamine agonist, LEDD: levodopaequivalent daily dose (mg/day), UPDRS: Unified PD Rating Scale; DD: Diphasic Dyskinesia
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Highlights
AC C
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TE D
M AN U
SC
RI PT
• First detailed description of Diphasic dyskinesia in PD under Duodopa pump treatment • Description of 4 cases through clinical observation and review of medical records. • We propose a easy and quick therapeutic strategy