Advanced Disease: Reducing Or Eliminating Established Dyskinesias
PD patients eventually need levodopa to help alleviate parkinsonian motor features. When dyskinesia emerges, one strategy is to dose levodopa so that it peaks just below the dyskinesia threshold and administer it frequently enough to avoid wearing off. This typically amounts to administering levodopa in smaller doses more often, which may be inconvenient and result in reduced compliance. At the extreme, liquid levodopa can be used to deliver very small doses of levodopa very frequently however, patients usually find this very inconvenient.
Another strategy is to use higher doses of a dopamine agonist to reduce both the total daily levodopa dose and its frequency or to gradually substitute a dopamine agonist for levodopa . Unfortunately, these strategies rarely work and typically reduce dyskinesias at the expense of less satisfactory control of parkinsonian symptoms.
How Can Parkinsons Disease Dyskinesia Be Managed
Because Parkinsons Disease Dyskinesia can become such a problem in the management of Parkinsons and is still so poorly understood, much of the effort to deal with its complication has centered on delaying, if not actually preventing the dyskinesia altogether.
One approach has been to delay the start of levodopa for as long as possible in an attempt to delay the onset of dyskinesias. However not taking, or limiting the dose of levodopa may not allow for greater movement control in early disease and throughout treatment. Another approach to forestall starting levodopa has been to use a dopamine agonist as a first line of treatment, particularly as these agents rarely cause dyskinesia on their own.
A number of large studies have shown that early agonist therapy can delay the need for levodopa by a number of years. However, this approach has gradually become less attractive for two reasons. First, dopamine agonists carry a significant burden of side-effects on their own, including excessive daytime sleepiness, impulse control disorder and pedal edema to name a few. These side-effects can be carefully monitored, and are dose dependent, so they can be dealt with when both the person with Parkinsons and physician are on the lookout for them.
This blog article was sponsored by Adamas Pharmaceuticals, Inc.
Prevalence Incidence And Risk Factors For Motor Complications
Nearly all patients develop motor fluctuations and LID by 15 to 20 years from time of diagnosis . However, prevalence and incidence figures through the course of PD vary depending on the study methodology employed and by the predominant treatment strategies of the time. Early literature suggested that approximately 10% of patients per year following initiation of treatment with levodopa develop motor fluctuations, with 40% of patients developing these complications within 46 years of treatment . A large cross-sectional study of 617 patients with PD found an overall prevalence of wearing off of 57% as assessed by neurologists and 67% as assessed by a patient-completed questionnaire . Of patients with disease duration < 2.5 years, wearing off was identified in 41.8% by the WOQ-19 and in 21.8% by neurologists, indicating that motor fluctuations can emerge as early as several months to a few years after the initiation of levodopa, as has also been observed in other studies . A retrospective analysis of an incident cohort of PD found estimated rates of dyskinesia of 30% by 5 treatment years and 59% by 10 treatment years .
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Use Of Controlledrelease Preparations Of Levodopa
The standard preparation of levodopa with a short halflife has the potential for pulsatile stimulation of the postsynaptic receptors. It was hoped that a controlledrelease formulation with a longer halflife would obviate this problem. However, a study comparing standard formulation of levodopa with a controlledrelease type in early Parkinson’s disease showed no difference in the frequency of LID after 5 years of followup.27 However, the controlled release formulation has variable absorption and it was administered in a twicedaily regimen. This could have accounted for the failure to achieve continuous dopaminergic stimulation.
Impact Of Td In Older People
The impact of TD on an individuals physical, mental, and economic health may intensify with age.3,22 The social and emotional effects of symptoms are highly debilitating for people with TD of all ages, but feelings of isolation and depression may be especially profound for older people.3,16 Older individuals are also uniquely vulnerable to the physical consequences of TD, such as impaired gait and balance, which can lead to falls.16,26 TD in older patients often presents as oro-bucco-lingual dyskinesia, and these movements can interfere with eating and swallowing incidents of choking resulting from respiratory TD have been reported.7,19,46 Further, oro-bucco-lingual TD can cause loosening of natural and artificial teeth and be augmented by edentulousness and denture use edentulousness itself can cause abnormal movements of the mouth in the absence of neurological disorders such as TD.26,46,47 Older patients may also be affected by dyskinesias of the limbs, trunk, and respiratory system, with symptoms such as grunting.7,26,48
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Ataxia / Dysmetria / Asynergia
Ataxia is an unsteady and swaying walk, often with feet planted widely apart. People have difficulty walking a straight line with their heel touching the toe of the shoe in front . Ataxia can occur in a number of neurologic conditions.
Dysmetria is misjudging the distance to a target. A person with dysmetria will have problems reaching out and accurately touching a targeted object.
Asynergia is a breakdown of movement, so that movements of the arms and legs become irregular and clumsy.
For more information, visit the National Ataxia Foundation website at www.ataxia.org.
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How Prominent Is The Problem Of Pd
The prevalence rate of PD was estimated a few years ago to be between 100 to 200/100,000 population , with an incidence rate of 10 to 20/100,000 population . However, the number of PD cases is increasing and will have grown from 10 million worldwide in the late 1980s to 40 million in 2020 due mainly to the aging population. While most patients with PD are diagnosed after the age of 55 , about 10% of patients are diagnosed before the age of forty and characterized as ‘young-onset PD’ . While most young-onset patients exhibit typical parkinsonian symptoms , they appear to display slower disease progression and show a tendency for increased prevalence and severity of motor fluctuations and dyskinesia with prolonged L-3,4-dihydroxyphenylalanine therapy . Early onset of motor complications may be especially relevant in these patients as they will live with the disease for longer periods with a diminished quality of life and impaired social and economic productivity .
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Transcranial Magnetic Field Stimulation
TMS is a safe and non-invasive method that affects the cerebral cortex but not the deep structures. TMS can be used to investigate causality in the brain-behavior relationship by utilizing neuronal depolarization or hyperpolarization .
Two primary protocols are established for TMS. In the first one, the single/paired-pulse TMS depolarizes and discharges the action potential under the region that is being stimulated. When applied to the motor cortex, s/p-pTMS can provoke motor evoked potentials, an output commonly used together with TMS . The second one, involves the repetitive TMS which has been shown to produce more durable effect after the initial stimulation . rTMS can increase or decrease the excitability of the corticospinal tract depending on the intensity of stimulation, coil orientation and frequency, and properties of the stimulation coil. The inhibitory/excitatory effects of TMS on the neurons should be distinguished from the negative/positive outcome on behavior, which can occur in any combination. For instance, an excitatory effect of TMS in one area may induce inhibition of a different area that controls the execution of cognitive tasks, resulting in a negative behavioral outcome .
Differences Between Patients With And Without Motor Fluctuations And Dyskinesias
Patients with motor fluctuations had significantly longer disease duration, treatment duration, higher doses of levodopa, and tended to have longer time since diagnosis than those without. They also had greater disability, as measured by the Schwab and England scale, and tended to have greater disease severity, as measured by the Hoehn and Yahr scale, more often had a good response to levodopa, and were receiving a levodopa dose of > 300 mg per day. They also tended more often to have a family history of parkinsonism in a first or second degree relative and to have the akinetic-rigid subtype of parkinsonism . There was no difference in the use of antiparkinsonian medication other than levodopa, but this may have been due to the small number of patients with concomitant or alternative Parkinson’s disease medication.
Patients with dyskinesias had a significantly longer treatment duration and were more severely disabled than those without. They tended to have longer disease duration, greater disease severity and to have received a higher levodopa dose, and more often reported falls than those without dyskinesias . Men and women did not differ significantly with respect to the occurrence of motor fluctuations or dyskinesias, even when only those with a treatment duration of > 5 years were considered. Age, symptom at onset, or time from onset to initiation of treatment did not differ between the groups.
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Selective Monoamine Oxidase Type B Inhibitors
Monoamine oxidase inhibitors reduce the enzymatic degradation of dopamine within the synapse, thereby increasing its concentration and extending the time over which it can activate postsynaptic dopamine receptors. Monoamine oxidase exists in two isoforms: monoamine oxidase type A and monoamine oxidase type B . MOA-A is present both centrally and peripherally. Peripherally, MAO-A deactivates circulating catecholamines as well as the dietary vasopressor tyramine. Therefore, both MAO-A selective and non-selective MAO inhibitors pose a risk of hypertensive crisis when combined with dietary ingestion of tyramine rich foods . Selective inhibition of MAO-B avoids these effects . To date, three selective MAO-B inhibitors are approved for the treatment of Parkinsons disease: selegiline, rasagiline, and safinamide.
Selegiline capsules are dosed at 5 mg twice daily. Selegiline ODT is dosed initially at 1.25 mg daily and can be increased to a maximum dosage of 2.5 mg daily as determined by clinical response .
Rasagiline, a second-generation selective and irreversible MAO-B inhibitor, is approved by the FDA as both monotherapy and as adjunctive therapy to carbidopa/levodopa in PD. Two phase III randomized, placebo-controlled, double-blind trials, LARGO and PRESTO, established the efficacy of rasagiline in treating motor fluctuations in advanced PD.
Mechanism Of Adverse Medication Reactions
The exact mechanisms of adverse medication reactions that cause TD are not well defined. However, the blockade of dopamine receptors by dopamine antagonists is the most widely accepted theory. Chronic dopamine blockade caused by dopamine D2 receptor antagonists or APDs could result in an upregulation of dopamine receptor responsiveness, resulting in a compensatory supersensitivity of the receptors, especially in the basal ganglia. However, some studies suggest that D3, D4, and D5 receptors are also involved in the pathogenesis of TD., D3 and D5 receptors have a consistent positive correlation with TD, but evaluations of D4 yield inconsistent results.,
Anticholinergic agents are also linked to TD, and taken together with the dopamine receptor supersensitivity hypothesis, an imbalance of dopamine and acetylcholine is likely involved in TD pathogenesis. Evidence also suggests an imbalance of serotonin. Selective serotonin reuptake inhibitors such as fluoxetine inhibit dopamine neurons in the nigrostriatal pathway by increasing serotonin in the raphe nucleus. SSRIs act by potentiating the inhibitory effects of serotonin on dopamine production in the basal ganglia. This decrease in dopamine production by serotonin could contribute to the pathogenesis of TD.
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Talk To Your Doctor About Changing Your Medication Dosage
Levodopa is more likely to cause side effects like dyskinesia when its taken in higher doses. “More than 600 milligrams a day in the long run is associated with a greater incidence of dyskinesia,” says Dr. Pantelyat. Thats why its important to find the lowest dose that will still control your symptoms. Your doctor will work to do this by starting you on a low dose and gradually increasing it as needed.
Medication Therapies In Late Stage Development
A number of additional medication therapies to ameliorate motor complications in PD are under investigation currently, the furthest advanced include IPX203 , ND062 , and ABBV951 . Each of these approaches aims to approximate continuous levodopa delivery in an attempt to minimize motor complications.
IPX203 is a novel oral formulation of carbidopa and levodopa capsules containing different immediate and extended release bead components. It is designed to provide an initial rapid rise in plasma LD followed by prolonged, steady concentrations that extend beyond other currently available oral LD products . In an open-label study , 28 patients with motor fluctuations were randomized to 2 weeks treatment with CD-LD IR followed by IPX203 or IPX203 followed by CD-LD IR. Mean dosing frequency at the end of each period was 4.7 for IR CD-LD and 3.1 for IPX203 . On day 1, after a single dose, LD concentrations were sustained above 50% of Cmax for 4.6 h with IPX203 versus 1.5 h with IR CD-LD . In addition, UPDRS part III scores were significantly more improved with IPX203 compared with IR CD-LD from 3 to 8 h after administration . PD diaries obtained the last 3 days of each treatment period showed that IPX203 provided a 2.3-h advantage in daily OFF time compared with CD-LD IR , and daily ON time without troublesome dyskinesia favored IPX203 by 1.9 h .
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Altered Dopaminergic Pathways And Receptors
Three signaling pathways, PKA/DARPP-32, ERK, and mTORC1, were identified, which exert significant involvement in the pathophysiology of LID. All these pathways are interrelated and are activated by a common intercellular cascade triggered in nigrostriatal SPNs expressing D1 receptors. Chronic L-DOPA administration activates all of them, which alters the striatal synaptic plasticity. DARPP-32 signaling was observed to regulate ERK and mTORC1 pathways .
Recent studies have demonstrated that D1 receptor activation leads to Shp-2 activation, which leads to activation of ERK1/2 and mTOR phosphorylation. This, in turn, induces the LID expression. This effect can easily be reversed by using a D1 receptor antagonist, which downregulates the end product of the D1R/Shp-2 pathway, p-mTOR, and p-ERK1/2 . Rapamycin was observed to be selectively affecting the mTORC1 pathway, without affecting DARPP-32 signaling, ERK pathway, and AMPA, NMDA expression .
An increased expression of D3 receptors was reported in animals with severe LID. An associated increase in the expression of GABA release was also noticed. D3 receptors can also perform the D1 receptor modulation action via affecting the ERK pathway. Upon deletion of the D3 receptor, levels of FosB, ERK, and H3 activities decreased along with the alleviation of LID symptoms, with no effect on L-DOPA treatment . A lack of D5 receptors is also associated with increased LID severity and decreased response to the L-DOPA symptoms .
Causes Of Dyskinesia In Pd Patients
Dyskinesia highly occurs in people who take Levodopa medications, which is a common medication for treating PD. Since Levodopa increases dopamine levels in the brain, and that is what PD patients need. Wherein when having Parkinsons disease, the cells ability to produce dopamine reduces, and levodopa replaces dopamine. However, the dopamine level increases when taking levodopa and decreases when its effect subsides, leading to dyskinesia.
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What Are Dyskinesias And How Can I Manage Them
Dyskinesias are abnormal, involuntary movements that occur in response to repeated dopamine-replacement therapy . Sometimes, they can be debilitating. These motor complications are typically choreiform. Chorea comes from the Greek word meaning to dance, so the dyskinesias looks similar to dance-like, constant writhing or wriggling movements of the arms, legs, trunk, and sometimes even facial muscles. However, dyskinesias can also be dystonic , or myoclonic or other movement disorders, and can become progressively more severe with increasing duration of treatment . Sometimes, with advancing disease, it becomes increasingly difficult to find a dose of levodopa that provides symptom relief while avoiding dyskinesia.
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Are There Ways To Manage Dyskinesia
Once dyskinesia has started it is difficult to treat. However, there are several ways to delay it from starting or reduce it once it has begun.
Supplemental or alternative treatment options
Things you can do on your own
- Keep a diary that logs the time and frequency of dyskinesia, which will help your doctor assess if your medications are working and help you schedule daily activities when mobility is better.
- Physical activity, including mild aerobic exercise such as walking, dancing, and swimming, will help keep the body strong and prevent muscle weakening.
- Stress can make dyskinesia symptoms worse, so find ways to reduce stress and try to keep a positive attitude.
- Poor sleep at night is associated with dyskinesia. Aim for good sleep quality and try to experiment with different positions in bed that will help you relax and sleep better.
Box 1classification Of Levodopainduced Dyskinesias
- Peak dose dyskinesia
- On state dystonia
- Peakdose dyskinesiasThese are the most common forms of LID and are related to peak plasma levels of levodopa. They involve the head, trunk, and limbs, and sometimes respiratory muscles. Dose reduction can ameliorate them, frequently at the cost of deterioration of parkinsonism. Peakdose dyskinesias are usually choreiform, though in the later stages dystonia can superimpose.
- Diphasic dyskinesiasThese develop when plasma levodopa levels are rising or falling, but not with the peak levels. They are also called DID . DID are commonly dystonic in nature, though chorea or mixed pattern may occur. They do not respond to levodopa dose reduction and may rather improve with high dose of levodopa.
- Off state dystoniasThese occur when plasma levodopa levels are low . They are usually pure dystonia occurring as painful spasms in one foot. They respond to levodopa therapy. Rare forms of LID include on state dystonias and yoyo dyskinesia .