Wednesday, November 30, 2022

What Are Motor Fluctuations In Parkinson Disease

The Professional Point Of View

Motor Fluctuations and Dyskinesia in Parkinson’s Disease

Professionals are aware that a PD patient follow-up based on a yearly, pre-scheduled visit is not adequate, especially in intermediate stages of the disease. They are well ready to accept technology support to ameliorate the patients management, facilitate decision-making, and catch signs of impairment before they occur. On the other hand, clinicians are not ready to manage large amounts of data hence, the information should be condensed in periodic reports, plus possible alarms to be received in the hospital or in the outpatient department. It must be noticed that, as also discussed in Ref. , at present we lack a proper infrastructure able to transmit and store such data. Future research must be in the direction of designing a scalable, open-source, web-based architecture, able to integrate several types of information, to manage different technology standards, to meet regulatory and security rules for medical data. The cost effectiveness, in terms of improved health and reduction of hospital admissions, needs also to be properly quantified.

Keeping A Motor Diary

You can help your doctor understand how effective your medications are by keeping diary. Typically a motor diary, or wearing off diary, will include details such as:

  • the times of day when you take your Parkinsons medication
  • the times of day when you have good symptom control
  • which symptoms re-emerge during the day and when
  • what symptoms you experience at night
  • any other complications you may experience, such as dyskinesia, and their relation to when you take your medication
  • it can also be useful to note the timing of meals, drinks and snacks. Make a note of whether eating certain foods affects your symptom control protein, for example, can interfere with the absorption of some medications.

For a sample diary and information on keeping one see Keeping a diary.

Ongoing Opicapone Trials: Supporting Evidence

Four studies are ongoing to further elucidate the best use of levodopa and opicapone in treating MF and MF-related non-motor symptoms in clinical practice. These trials are being conducted at European sites.

The ADOPTION study is a Phase IV, randomised, prospective, open-label exploratory trial with patients recruited from Germany, Italy, Portugal, Spain, and the UK.25 The aim of this study is to explore the potential of opicapone to optimise levodopa/DDCI as a first-line approach to treat wearing-off in 100 adults with signs of wearing-off for < 2 years, and treated with 34 daily oral levodopa doses up to 600 mg. The primary endpoint is change from baseline in OFF-time at 4 weeks, according to Hausers home diary.

The aim of the Phase II, open-label 203 trial26 is to assess the effect of opicapone 50 mg on levodopa pharmacokinetics in different levodopa/carbidopa treatment regimens in patients with end-of-dose MF. Twenty-four patients will receive five intakes of 500/125 mg levodopa/carbidopa dose for 2 weeks. They will then be randomised 1:1 to either four or five intakes of 400/100 mg levodopa/carbidopa plus opicapone 50 mg for 2 weeks. The primary endpoint compares the pharmacokinetics of levodopa at the end of both 2-week treatment periods.

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How Are Motor Fluctuations Treated

Motor fluctuations affect the quality of life of people with Parkinsons significantly by limiting their activities of daily living, mobility, and social interaction. The treatment aims to keep the person moving and make them carry their daily activities independently.

Doctors can use any of the following strategies to help the affected people to minimize or avoid motor fluctuations:

  • Adjusting the dose of levodopa: The doctor can either increase the dose or change the number of times the drug is taken in a day.
  • Introducing different medications: Adding different medications to the current medication can help maintain consistent levels of dopamine and thus, prevent off-times.
  • These medications include

Ongoing Clinical Trials For The Treatment Of Motor Complications In Pd

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Several novel levodopa formulations are under investigation to bypass the GI issues related to impaired absorption that contributes to motor fluctuations. Accordion pill levodopa/carbidopa is a gastroretentive slow release levodopa formulation containing a multilayer film folded in an accordion shape. Studies have been reported only in abstracts to date, and a phase III study is ongoing .

ND062L is a transcutaneous formulation available in a patch-pump device. Preliminary results are encouraging, however with limited data available . Minor adverse events reported so far are mostly local and related to subcutaneous administration. Studies at phase II and III level are ongoing .

CVT-301 is a levodopa inhalation powder that has been evaluated for sudden-OFFs. A Phase II trial showed onset of effect after 10 minutes, and significant mean OFF time change from baseline after 4 weeks . Most common side effects were dizziness, cough, and nausea. A phase III trial is currently ongoing .

Tozadenant is another adenosine A2A antagonist under development for motor fluctuations. A Phase IIb trial showed reduction of mean daily OFF time with tozadenant 120 mg and with tozadenant 180 mg group . Common adverse events were dyskinesia, nausea and dizziness. A phase III is currently active .

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Side Effects Of Protein

A modulation of levodopa dosage is the major method to control dyskinesia on a protein-restricted diet. In two studies of Pincus et al., respectively, 75 and 73% of the subjects required a reduction in levodopa dosage to avoid chorea . In addition, there were two outpatients who noticed that a reduced dosage of Sinemet helped to improve their dyskinesia without shortening their on time . Beside a smaller medication dosage, a pro re nata protein supplement was also reported to reverse dyskinesia on PRD by two patients . Compared with a low protein-high carbohydrate diet, Berry et al. indicated that a diet with a carbohydrate: protein ratio of 5:1 was less likely to cause dyskinesia as well as fluctuations in levodopa concentrations . However, the effectiveness of these approaches to relieve dyskinesia on protein-restricted diets has only been reported in small numbers of patients without any statistical analysis. Additional large-sample studies or double-blinded trails are still required.

Study : People With Pd Throughout A Complete Levodopa Medication Cycle

The third study was a non-interventional study in 26 people with mild-to-moderate PD . Participants completed two visits during which they donned the same sensors as in studies 1 and 2, and additionally shimmer sensors to record GSR and ECG. Written informed consent was obtained from all participants, all relevant ethical regulations were complied with, and the protocol was approved by the Spaulding Rehabilitation Hospital Institutional Review Board. On the morning of each visit, participants took their normal morning dose of medication and reported to the site 1h prior to their second normally scheduled medication dose for a visit that lasted approximately the duration of one levodopa medication cycle . Continuous recordings were initiated and continued for the duration of the visit.

The second visit took place in a simulated apartment-style living environment. Participants were asked to perform activities of daily living that were self-selected from a different list for each hour they stayed in the apartment . During this visit, they wore the same devices and had the option of being accompanied by a partner or caregiver. The list was provided to them at the beginning of the visit. Some of the items were repeated each hour , while others were different. In addition, each hour throughout the visit, study staff members connected to the participant through video conferencing software and administered a shortened motor assessment based on a subset of MDS-UPDRS part III tasks.

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Clinical Features Of Wearing

As soon as levodopa was introduced into clinical practice for the treatment of PD, it was recognized that the therapeutic response consists of at least two components : the short-duration response , which provides an improvement in motor disability that lasts a few hours after the administration of single doses of levodopa, and the long-duration response , which is a sustained antiparkinsonian effect derived from prolonged administration of levodopa that has been shown to last for up to 2 weeks after cessation of drug treatment . Importantly, both types of response are present from the initiation of therapy, although the SDR is largely unnoticed in the beginning as the LDR masks it .

For many years, the development of wearing-off has been mainly attributed to a shortening of the SDR over time as a result of the progressive reduction in the ability of the nigrostriatal neurons to synthesize and to store dopamine formed from exogenous levodopa . However, a number of studies have shown that the magnitude of the SDR and modifications of the LDR during the course of PD also have a critical role in the development of symptom re-emergence .

Role Of The Ldr In The Development Of Motor Fluctuations

Non-Motor Fluctuations of Parkinsonâs Disease
Fig. 1

Mean peak and baseline tapping speeds to the levodopa infusion on day 1 and day 4 and over 4 years of therapy with levodopa . The difference between peak and baseline tapping speeds is the magnitude of the SDR, which progressively increases to the levodopa infusion on day 4. Reproduced from Nutt et al. .

Similar results were reported by Zappia et al. who found that the duration of the SDR did not significantly change within the first year of therapy, but that 24% of patients lost the LDR to levodopa. These studies demonstrate the pivotal roles of the LDR and the magnitude rather than duration of the SDR in the development of motor fluctuations in the early years of levodopa therapy. They further suggest that when a sustained LDR is present, the SDR is usually masked and patients may therefore be classified clinically as stable responders to levodopa therapy even though they are experiencing fluctuations. As the LDR is progressively lost, patients lose the smooth drug effect and the magnitude of the SDR increases . Patients are then clinically observed to become fluctuators because the degree of benefit is now dependent on the magnitude of the SDR. Overall, the available evidence suggests that in the earlier stages of PD, where the difference between the ON and OFF states is less pronounced, any fluctuations in levodopa response are not noticed by the patient and therefore not reported.

Fig. 2

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Demographic And Clinical Characteristics Of The Sample

Recruitment for the first study began in July of 2016 and the last subject for the final PD study completed the last visit in April of 2018. For the first study, we recruited healthy volunteers by drawing from the local community in Andover, MA and Yorktown Heights, NY, respectively . Sixty healthy volunteers with a mean age of 44 years were enrolled, and 33 were female. Compared with PD participants, healthy volunteers were significantly younger , had a higher level of education and were more evenly balanced with regard to gender .

Table 1 Participant characteristics.

These results emphasize the significant probability of symptom severity fluctuating at a rate that cannot be captured by using diary entries every 30min. Importantly, the same consideration applies to live observations of individuals with PD experiencing motor fluctuations. In other words, these results suggest that even live assessments that are carried out at time intervals of 30min are insufficient to capture the dynamics of tremor, dyskinesia, and bradykinesia, as they evolve over the medication cycle. This observation underlines an important potential advantage of using wearable sensors to track fluctuations in motor symptoms since this approach has potential for generating continuous estimates of the severity of tremor, dyskinesia, and bradykinesia, hence overcoming the limitations of more traditional approaches.

Availability Of Data And Materials

Protocol details are available at www.clinicaltrialsregister.eu . In line with EFPIA and PhRMA guiding principles, BIAL undertakes to share, upon request, anonymised patient-level, study-level clinical trial data , and other information from clinical trials in patients for medicines and indications approved in the United States and the European Union , to qualified researchers as necessary for conducting legitimate research.

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On And Off Response Periods

On and off response periods in parkinsons disease patients take place without any warning because of fluctuations in the human brains dopamine levels. Here, you will find more or less similar symptoms with motor problems taking place because of wearing-off effect. However, doctors often face difficulty in prediction of these problems and in their treatments. Off period takes place suddenly for a few seconds or few minutes and then, parkinsons disease patients become freeze, while on periods involve uncontrollable movements.

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Levodopa remains the gold standard of symptomatic efficacy for the treatment of motor symptoms in patients with PD 1 however, as the disease progresses, patients develop motor response oscillations such as end-of-dose wearing-off and levodopa-induced dyskinesias.2,3 Wearing-off, a result of decreased therapeutic effect of levodopa/DDCI, represents a major source of disability for patients with PD, impacting on quality of life.4 Wearing-off also presents a considerable problem in the overall management of PD. Key to the timely detection and management of wearing-off is the ability to recognise that it can be present in the early stages of this disease.

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A Need To Improve Levodopa Delivery

Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinsons disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.

Types Of Motor Fluctuations

Motor fluctuations take a variety of forms:

“On-off” phenomenon. You cycle between good control and periods of symptoms. During the “on” times, your symptoms are well managed. In “off” periods, the problems come back.

Some people only get “off” periods when their levodopa starts to wear off. Others get symptoms at random times that aren’t related to their medicine. Your doctor may prescribe add-on medications which can lessen the “off” times.

Wearing off. The effect of your levodopa starts to fade before it’s time to take the next dose. You might be tempted to take your medicine earlier than usual to prevent symptoms.

Delayed “on.” You have to wait longer than usual after you take levodopa for your symptoms to improve. This delay can happen when you take your first dose in the morning. It’s also common after meals, because the protein in your food can cause the medicine to get absorbed more slowly.

Delayed “on” is more common with time-release versions of levodopa. These drugs take a while to get from your stomach into your bloodstream and then travel to your brain.

Partial “on” or dose failure. Partial “on” means that your symptoms don’t fully improve after you take a dose of levodopa. A dose failure is when you don’t feel any better after taking your medicine.

You’re more likely to have freezing during an “off” period.

Dyskinesia. This is uncontrolled twitching, jerking, or other movements. It can affect one limb, such as an arm or leg, or your whole body.

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Time To Onset Of Complications

The mean time from symptom onset to development of fluctuations, as reported by the patients, was 6.5 years, and to development of dyskinesias 6.7 years. The mean time from start of levodopa to the onset of fluctuations and dyskinesias was 4.8 and 5.7 years, respectively.

The latency from onset of symptoms to development of fluctuations and dyskinesias correlated positively with the time elapsed between onset and initiation of treatment with levodopa . This could be due to a faster development of motor complications because levodopa was given earlier, but also to more rapidly progressive disease warranting earlier introduction of levodopa in some patients. The patients with more rapidly progressive disease would then be expected to be more severely disabled after the same duration of disease. Thus, disease severity should be negatively correlated with time from onset to initiation of levodopa, when controlled for disease duration. However, we did not find such a correlation , indicating that more rapidly progressive disease is not the explanation for the earlier development of motor complications in patients treated sooner with levodopa.

Dopamine Depletion The Basal Ganglia And Motor Fluctuations

What are motor fluctuations and dyskinesias in Parkinson’s disease?

The overall determinant of the motor features in PD is the physiological state of basal ganglia output activity. Dopamine depletion can be very severe but motor features of PD can be controlled or prevented if subthalamic nucleus and globus pallidus pars interna neuronal firing stays within normal levels. Accordingly, therapeutic interventions aimed at reducing the abnormal and excessive activity of basal ganglia output neurons in PD should improve the SDR to levodopa. This is precisely what has been found in the 6-OHDA rat model where lesions of the STN ameliorated wearing-off and, more importantly, are a characteristic effect of functional neurosurgery for PD. Thus, modulation of basal ganglia output activity, without changing striatal dopamine availability, modifies the SDR. This has led to the suggestion that alterations of compensatory mechanisms involved in maintaining basal ganglia homeostasis in PD are compromised by the deleterious effects of pulsatile dopaminergic stimulation caused by the use of short-acting drug treatments .

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Management Of The Wearing Off Phenomenon

The first step when managing a patient with motor fluctuations is reviewing the levodopa schedule. Adjusting the timing of levodopa doses can be crucial in avoiding predictable end of dose wearing off. Overall, lower doses of levodopa given more frequently is typically the best option for managing motor complications. Although controlled-release carbidopa/levodopa was designed to provide a more smooth and longer duration effect of levodopa for treatment of wearing-off, it has not demonstrated significant benefits compared with regular-release levodopa/carbidopa formulation. In addition, delayed and often unpredictable responses resulting from erratic absorption have limited use, and currently is best confined to bedtime to provide more stable overnight levodopa levels.

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