Motor Dyskinesias Research Articles

Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease: Observations and Dilemmas after 10 Years of Real-Life Experience.

Advanced Parkinson’s disease (APD) cannot be treated efficiently using the classical medications however, in recent decades invasive therapeutical methods were implemented and confirmed as effective. One of these methods makes it possible to continue the levodopa (LD) supplementation as a gel administered directly into the upper intestine. However, there are a number of unanswered questions regarding this method. Therefore, we retrospectively analyzed a 10-year period of selected patients that were treated with levodopa/carbidopa intestinal gel (LCIG). We included all APD patients with motor fluctuations and dyskinesia at presentation. LCIG treatment was started in 150 patients: on average these patients received LD for 10.6 ± 4.4 years with a frequency of 5.2 ± 1.0/day until the introduction of LCIG. The estimated and the real LCIG dose differed significantly (mean: 1309 ± 321 mg vs. 1877 ± 769 mg). The mean duration of LCIG administration was 19.8 ± 3.6 h, but in a number of 62 patients we had to administer it for 24 h, to maximize the therapeutic benefit. A carefully and individually adjusted LCIG treatment improves the quality of life of APD patients, but questions remain unresolved even after treating a large number of patients. It is important to share the ideas and observations based on the real-life experience related to the optimal timing, the appropriate dose and duration of administration of the LCIG.

Fractal characteristics-based motor dyskinesia assessment

GoalThe purpose of the study was to evaluate the feasibility of fractal characteristics (FCs) in the motor dyskinesia assessment. MethodsThe study recruited twenty stroke patients and twenty age-matched healthy subjects. Ten upper limb surface electromyography (sEMG) signals were measured when participants performed Fugl-Meyer assessment of upper limb, reaching movement, and hand-to-mouth movement. Two fractal characteristics extracted from sEMG, fractal dimension (FD) and maximum fractal length (MFL) were compared with five time-frequency features (TFFs), root mean square, mean absolute value, variance, waveform length, and median frequency in motor dyskinesia assessment. A statistical-based feature selection method was proposed to select a feature subset. The identified features were then input into the Gaussian process regression (GPR) model to estimate the motor dyskinesia level. ResultsA small set of features was selected applying the proposed method. Two fractal characteristics showed consistency among movements, especially MFL, which could capture the disorder of the central nervous system (CNS). Comparing to the TFFs, the FCs are better for motor dyskinesia assessment. ConclusionsThe results demonstrate the feasibility of FCs to assess motor dyskinesia. Fractal-based method provides new insight into motor dyskinesia assessment.

An evaluation of the efficacy and value of CVT-301 for the treatment of Parkinson’s disease

ABSTRACT Introduction: Levodopa is the most effective drug in the treatment of Parkinson’s disease, but its chronic treatment is linked to the occurrence of motor complications with fluctuations of motor performance and dyskinesia. Unpredictable OFF episodes can be severe and disabling and current rescue medications cannot always be used safely. Rescue therapy is characterized by a rapid and predictable ON response and the safety profile of levodopa will represent a major advantage for patients affected by unresponsive OFF episodes. Areas covered: CVT-301 is a new inhaled formulation of LD recently developed as a self-administered treatment for OFF periods. Herein, the pharmacodynamic and pharmacokinetic properties, efficacy, and safety of CVT-301 are reviewed. Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism, and less plasma level variability. It should be noted that the delivery device used has been described as relatively simple to use, but the few steps required to prepare and self-administer the dose can be challenging for PD patients during their OFF state. Additionally, resolution of an OFF episode requires the administration of two capsules of CVT-301, which further complicates the use of the device.

Variable- versus constant-frequency deep-brain stimulation in patients with advanced Parkinson\u2019s disease: study protocol for a randomized controlled trial

BackgroundDeep-brain stimulation targeting the subthalamic nucleus (STN) can be used to treat motor symptoms and dyskinesia in the advanced stages of Parkinson’s disease (PD). High-frequency stimulation (HFS) of the STN can lead to consistent, long-term improvement of PD symptoms. However, the effects of HFS on the axial symptoms of PD, specifically freezing of gait, can be limited or cause further impairment. While this can be alleviated via relatively low-frequency stimulation (LFS) in selected patients, LFS does not control all motor symptoms of PD. Recently, the National Engineering Laboratory for Neuromodulation reported preliminary findings regarding an efficient way to combine the advantages of HFS and LFS to form variable-frequency stimulation (VFS). However, this novel therapeutic strategy has not been formally tested in a randomized trial.Methods/designWe propose a multicenter, double-blind clinical trial involving 11 study hospitals and an established deep-brain stimulation team. The participants will be divided into a VFS and a constant-frequency stimulation group. The primary outcome will be changes in stand–walk–sit task scores after 3 months of treatment in the “medication off” condition. Secondary outcome measures include specific item scores on the Freezing of Gait Questionnaire and quality of life. The aim of this trial is to investigate the efficacy and safety of VFS compared with constant-frequency stimulation.DiscussionThis is the first randomized controlled trial to comprehensively evaluate the effectiveness and safety of VFS of the STN in patients with advanced PD. VFS may represent a new option for clinical treatment of PD in the future.Trial registrationClinicalTrials.gov, NCT03053726. Registered on February 15, 2017.

The clinical significance of disorders of the motor function of the esophagus, stomach and duodenum

The purpose of the review is to determine the relationship between the clinical symptoms of diseases and disorders of the motor function of the esophagus, stomach and duodenal bulb, to present modern methods of their diagnosis and pathogenetic principles of treatment of diseases. Depending on the pathogenesis, it is possible to distinguish secondary motility disorders resulting from organic lesions, and primary (functional) changes. The emergence of clinical symptoms is associated with impaired motor - evacuation function of the digestive tract, which can be divided into two large groups: changes in the peristaltic activity of the organ wall and the work of the sphincter apparatus. The basis of the regulation of motility of the esophagus, stomach and duodenum is the interaction of nervous and humoral factors, the central processing of impulses is carried out in the cerebral cortex. In case of violation of the coordinated action of inhibitory and excitatory regulation systems, pathological contractile activity occurs, which manifests itself as hypo - or hyper - motor dyskinesia. X-ray, ultrasound, high resolution manometry of the esophagus, pH-meter, scintigraphy, computed tomography, antroduodenal manometry and a number of others are used to diagnose disorders of the motor function of the digestive tract, which can determine the mechanism of the development of symptoms and prescribe pathogenetic treatment to the patient. Thus, the occurrence of clinical symptoms is associated with changes in the motor - evacuation function of the digestive tract due to a violation of the coordinating action of inhibitory and excitatory factors. The use of modern diagnostic methods for the study of motor function makes it possible to determine the mechanism for the development of clinical symptoms, which allows the patient to prescribe an effective pathogenetic treatment.

Orthostatic hypotension following deep brain stimulation in parkinson’s disease: a systematic review

Background: Deep brain stimulation (DBS) is a treatment that may be suitable for patients with Parkinson’s disease (PD) with severe motor fluctuations and/or dyskinesias despite optimised medical therapy. DBS has been associated with side effects including deterioration in cognition, verbal fluency and mood. Studies assessing the effect of DBS on orthostatic hypotension (OH) have produced variable results.Objectives: The aim is to summarise peer-reviewed studies that have assessed the effect of DBS on systolic or diastolic BP in PD patients.Methods: The databases PubMed, EMBASE, Medline and Scopus were searched using the terms (Deep brain stimulation OR DBS) AND (hypotension OR hypertension OR blood pressure) on 13 April 2017.Results: Fourteen studies fulfilled the inclusion criteria. Ten studies involved subthalamic nucleus (STN) DBS, three studies globus pallidus interna (GPi) DBS and one study involved DBS of the pedunculopontine nuclei and motor thalamus. The majority of the studies found results indicating that DBS in PD does not worsen OH in PD.Conclusions: Small sample sizes and lack of blinding of outcome assessors means this result should be approached cautiously. Future research may further investigate the effect of GPi DBS on OH and should aim to address these methodological issues.

Tackling the care crisis in PD in East-Saxony, Germany – #Improve diagnosis and therapy in Parkinson's disease #Telemedicine-based care management #Intersectoral and interdisciplinary collaboration #Cost containment and quality improvement

Introduction: Four major problems in Parkinson's disease PD frame the current care crisis in Saxony and beyond in Germany: 1. Prevalence of PD in Germany is reported with 220:100.000. Data from AOK Plus in Saxony shows that the PD population with ICD code G20. idiopathic PD is at 20,000 which is far higher than what would be expected from prevalence alone. In Saxony alone, the population in need is already 2.5 times higher than expected with growing trends due to life expectancy. 2. Specialist care of PD nowadays takes place predominantly in larger cities, while in many rural regions there is an under-supply. Due to limited capacities of office-based neurologists time and specialised knowledge, motor fluctuations in advanced PD are often recognized at a late stage, leading to suboptimal treatment, unnecessary handicaps in daily life, frequent shifts to neurological clinics where patients are usually hospitalized for often unnecessary multi-modal complex treatment. This blocks capacities at expert centres, leading to long waitinglists and patients with advanced PD do not receive timely access to advancded threrapies Deep-Brain-Stimulation, Apomorphin infusion, Duodopa pumps. 3. Lack of objective measurements prevents effective and timely management of PD in clinical practice, especially in the outpatient setting. Current methods patient histories, diaries show validity and reliability problems and test and retest scores in current methods e.g. UPDRS have low intra and inter-rated reliability. 4. Uncontrolled PD e.g. dyskinesia, fluctuations is associated with significantly higher overall costs than controlled PD. Cost drivers of PD include onset of motor fluctuations & dyskinesias and increasing costs with worse motor off/on & UPDRS state. Bad mobility is a predictor of hospitalization and a high re-hospitalization rate. Method: Care Concept - Introduction of telemedicine-based care management for improved diagnosis and treatment of PD will sustainably change intersectoral and interdisciplinary collaboration, especially in East-Saxony with low supply. Through health economic evaluation based on profitability calculation, a prospective analysis of saving potentials and quality of care improvements was conducted. Results: By incorporating specialized expertise of movement disorder experts via telemedical approach, diagnostic accuracy can be improved. In particular, if improving guideline-based treatment across all care sectors inter-sectoral and interdisciplinary through a consistently structured and controlled care process. Objective measurement by means of the Parkinson-Kineto-Graph PKG, can accurate depict motor symptoms which drives the decision to start or change treatment dose; type, timing. For patients, this can improve the quality of life and increases safety, by preventing events e.g. fractures caused by fall. Cost savings based on population in East-Saxony achievable: ∼€18.9mio overall – savings that could provide economical provision of care for PD for 3 years. Savings can be achieved through case shifts from inpatient to outpatient care, non-medical and reduced drug costs. Conclusions: The new care approach is tackling the crisis at its roots. It changes the current treatment setting to address the need for specialised care. Specialists’ knowledge on the treatment of PD can be made available locally, releaving the distress of office-based neurologists by enabling them to treat their patients most accurately.

Levodopa/Carbidopa Intestinal Gel for Treatment of Advanced Parkinson’s Disease: An Update on the Effects of Cognitive Functions

Cognitive impairment is a frequent non-motorsymptom of Parkinson’s disease (PD). In early disease stage, this takes the features of dysexecutive syndrome, and is mostly dependent on derangement of frontostriatal circuitries. In advanced stages, worsening of dysexecutive symptoms is accompanied by disorientation and memory deficit leading to dementia in 30% of cases, due to multiple neurotransmitter derangement. Dysexecutive symptoms in the early stages of PD may benefit from dopamine replacement therapy (DRT). Conversely, severe cognitive symptoms in more advanced stages are frequently aggravated by DRT. In particular, pulsatile stimulation of dopaminergic receptors by orally administered levodopa (LD) plays a significant negative role on cognitive and neuropsychiatric symptoms in advanced PD. The introduction of a gel of LD-carbidopa for continuous intestinal administration (LCIG) allows marked stabilization of plasma LD concentrations and provides benefit on motor fluctuations and dyskinesia of significantly greater magnitude than conventional oral administration in advanced PD patients. The results from several preliminary studies suggest that efficacy of LCGI on motor symptoms may be accompanied by good tolerability and potential benefit on several non-motor symptoms, including cognitive impairment. Future studies with longer observation period and larger cohorts are advised to confirm these preliminary observations.

Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson's Disease Is Not Associated with Increased Body Mass Index.

Previous studies suggest that deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson's disease (PD) leads to weight gain. This study analyzes changes in body mass index (BMI) in 29 subjects from a prospective, single-blind trial of DBS in early stage PD (age 50–75, Hoehn & Yahr stage II off medication, treated with antiparkinsonian medications for ≥6 months but <4 years, and without a history of motor fluctuations, dyskinesias, or dementia). Subjects were randomized to DBS plus optimal drug therapy (DBS+ODT; n = 15) or ODT (n = 14) and followed for 24 months. Weight and height were recorded at baseline and each follow-up visit and used to calculate BMI. BMIs were compared within and between groups using nonparametric t-tests. Mean BMI at baseline was 29.7 in the ODT group and 32.3 in the DBS+ODT group (p > 0.05). BMI change over two years was not different between the groups (p = 0.62, ODT = −0.89; DBS+ODT = −0.17). This study suggests that STN-DBS is not associated with weight gain in subjects with early stage PD. This finding will be tested in an upcoming FDA-approved phase III multicenter, randomized, double-blind, placebo-controlled, pivotal clinical trial evaluating DBS in early stage PD (ClinicalTrials.gov identifier NCT00282152).

Apomorphine subcutaneous infusion, duodenal infusion of levodopa and deep brain stimulation – three advanced treatment options for the advanced Parkinson’s disease

Advanced stage of Parkinson's disease is associated with motor complications: motor fluctuations and dyskinesias. The disease can no longer be satisfactorily treated with oral therapy that is based on treatment with levodopa. Dying of dopamine neurons, a short half-life of levodopa and pulsatile stimulation of dopamine receptors are the main reasons for these complications. Currently, there are three options available to treat the advanced stage of Parkinson's disease: subcutaneous infusion of apomorphine, intrajejunal infusion of levodopa and deep brain stimulation. It is necessary to choose the optimal method of treatment that is most suitable for the individual patient.

Magnetic resonance guided focused ultrasound pallidotomy for Parkinson’s disease

Parkinson’s disease (PD) is one of the most common movement disorders in adults, often cannot be adequately controlled with medical treatment, and thereby treated with the neurosurgical procedures. Unilateral pallidotomy, making a lesion in the globus pallidus pars interna (GPi), was the predominant surgical technique until early 1900s. Thereafter, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a mainstream surgical technique for managing not only the cardinal dopaminergic features of PD, but also levodopa-induced motor fluctuations and dyskinesia. Recent review studies, however, reported that unilateral pallidotomy also has long-term effect on both cardinal symptoms (contralateral tremor and rigidity) and motor complications (contralateral dyskinesia and motor fluctuations). Currently, transcranial magnetic resonance guided focused ultrasound (MRgFUS), without necessity of opening the cranium, has been developed as a minimal invasive surgical technique, generating precise and focal thermal lesion in the brain compared to previous radiofrequency thermal lesion.

Apomorphine Therapy: The Hazard of Left Over Needles.

A 55-year-old patient with Parkinson’s disease (PD) was seen for a shoulder abscess. This abscess was related to the presence of a subcutaneous needle that was disconnected from the tubing used for continuous apomorphine therapy. The patient recovered after abscess incision and antibiotherapy. An X-ray of the shoulders confirmed that several needles remained subcutaneously in both shoulders (Fig. 1). After changing the type of catheter, no similar event occurred. After several years with levodopa treatment, PD patients develop motor fluctuations and dyskinesia, linked to iterative stimulations of dopaminergic receptors by multiple daily intakes of dopaminergic drugs. Continuous apomorphine administration may be used as an alternative therapy either as a monotherapy or in association with L-dopa. Apomorphine reduces significantly the OFF state periods, but also dyskinesia, mainly as a monotherapy. Our case report highlights that needles may occasionally be dislocated from tubing, especially when removing the injecting system. It seems that the junction between the needle and the tubing is a weak point and uncoupling may occur, especially in patients with dyskinesia. In this situation, we recommend to use a different injecting system, such as a tangential catheter, which may be more resistant because it is flexible and therefore less breakable. Education to use the injecting system should be performed before starting apomorphine therapy, and special attention should be paid to the monitoring of local side effects in patients treated with subcutaneous apomorphine.

Percutaneous Endoscopic Gastro-Jejunostomy (PEGJ): Could Drug Administation be the Only Indication for Insertion? The Levodopa/Carbidopa Infusion Treatment Experience. A Retrospective Evaluation of the Method

Enteral feeding is the preferred means of nutritional support in patients unable to eat normally. Percutaneous endoscopic gastro-jejunostomy (PEGJ) is widely used in such cases. It is also accepted that medication will be administered through the tube. In patients with severe Parkinson’s disease, a continuous delivery system of levodopa/carbidopa, formulated as a gel suspension (Duodopa®), reaches the small intestine through a jejunostomy and represents an alternative treatment method. The continuous release results in less variability in levodopa serum concentrations and fewer motor fluctuations and dyskinesias compared to oral administration. The method requires a very good collaboration between neurologists and gastroenterologists and is used in specializing centers in patients as mentioned with severe disease. A modified percutaneous endoscopic gastrostomy (PEG) kit is placed under sedation. This allows the passage of a pig tail catheter which is advanced to the jejunum and a portable pump is attached on it through a specially designed tubing system. This is the only case, known to us, where PEGJ is inserted for drug administration. We present our experience of nine cases (7 males, 2 females, mean age 72.4 years) with a follow up of up to five years. In three patients the tubing system had to be changed; the first it was accidentally pulled out, the second because of bezoar formation around the intragastric part of the tube and the third because of knot formation at the intragastric part of the jejunal tube. At the end of this five year period, all patients agreed that the neurological benefit was welcome and they had all come in terms with the undoubted difficulties the procedure causes.

Exploring Gender-Associated Socioeconomic Differences in Parkinson’s Disease

Background: Research on gender in Parkinson’s disease (PD) frequently focuses on clinical differences between men and women. Socioeconomic factors such as race, ethnicity, insurance type, and level of educational attainment, have not been extensively examined in relation to gender differences in PD. The goal of this study was to identify differences in PD presentation in men and women, and identify socioeconomic factors that may confound such differences. Methods: A movement disorder patient database containing 445 patients with idiopathic PD was analyzed for gender differences in motor symptoms and disease complications using linear or logistic regression. Socioeconomic variables were then evaluated as possible confounders. Results: A greater proportion of women were non-white (p < 0.05). Univariate analysis of gender, and multivariate analysis controlling for age at diagnosis and socioeconomic factors were concordant in demonstrating increased frequency of motor fluctuations and dyskinesia in women (p < 0.05). Controlled, multivariate analysis, when compared to univariate analysis, uniquely demonstrated that women were less likely to experience dementia and autonomic dysfunction, relative to men (p < 0.05). Conclusion: Women with PD are susceptible to motor fluctuations and dyskinesia, but may be relatively protected against dementia and autonomic dysfunction. Women and men with PD in our population had different socioeconomic profiles, which may have confounded some gender-associated differences.

Dopamine Pumps for Parkinson Disease: Has the Time Come?

Oral treatments for Parkinson disease (PD) are limited mainly by the association with motor fluctuations and dyskinesia, leading to burgeoning interest in better, more continuous delivery strategies for advanced PD. In the trial, researchers tested the safety and efficacy of an intrajejunal levodopa–carbidopa intestinal gel infusion strategy that is investigational in the U.S. The manufacturer-sponsored, randomized, double-blind, double-dummy, double-titration trial was conducted at 26 centers in Germany, New Zealand, and the U.S. All participants underwent placement of a percutaneous gastrojejunostomy tube and were …

New perspectives in non-oral drug delivery in Parkinson's disease: Highlights of a satellite symposium held at the XX world congress on Parkinson's disease and related disorders, Geneva, Switzerland, 8-11 December 2013

Oral therapies, including levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, form the mainstay of medical treatment for Parkinson's disease (PD). However, over time, chronic treatment with multiple daily doses of oral agents is often associated with the development of motor fluctuations and dyskinesias. Alternative methods of dopaminergic drug delivery, particularly if they bypass the gastrointestinal system, may be of value for PD patients who have developed motor complications despite optimised oral therapy, in particular those with gastrointestinal absorption issues, including gastroparesis. This satellite symposium, held at the XX World Congress on Parkinson's Disease and Related Disorders, Geneva, Switzerland, from 8-11 December 2013, was chaired by Professor Werner Poewe (Austria) and Professor Andrew Lees (UK) and discussed recent evidence regarding the benefits of using non-oral drug-delivery strategies with therapies such as subcutaneous apomorphine. Beginning with the history of apomorphine and its well-established use in PD both as an intermittent injection and a continuous infusion, the presenters set out the evidence for its efficacy in managing both motor and non-motor symptoms in PD. The significance of gastrointestinal involvement in PD and how this may influence responses to oral medications was also reviewed. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study of the use of subcutaneous apomorphine in PD patients with morning akinesia were also presented and the continuing main role of apomorphine in the treatment of PD was discussed, including the selection of the most appropriate patients for this effective yet underused therapy.

Risk factors and predictors of levodopa-induced dyskinesia among multiethnic Malaysians with Parkinson's disease

Chronic pulsatile levodopa therapy for Parkinson's disease (PD) leads to the development of motor fluctuations and dyskinesia. We studied the prevalence and predictors of levodopa-induced dyskinesia among multiethnic Malaysian patients with PD. Methods: This is a cross-sectional study involving 95 patients with PD on uninterrupted levodopa therapy for at least 6 months. The instrument used was the UPDRS questionnaires. The predictors of dyskinesia were determined using multivariate logistic regression analysis. Results: The mean age was 65.6 ± 8.5 years. The mean onset age was 58.5 ± 9.8 years. The median disease duration was 6 (7) years. Dyskinesia was present in 44% (n = 42) with median levodopa therapy of 3 years. There were 64.3% Chinese, 31% Malays, and 3.7% Indians and other ethnic groups. Eighty-one percent of patients with dyskinesia had clinical fluctuations. Patients with dyskinesia had lower onset age ( p < 0.001), longer duration of levodopa therapy ( p < 0.001), longer disease duration ( p < 0.001), higher total daily levodopa dose ( p < 0.001), and higher total UPDRS scores ( p = 0.005) than patients without dyskinesia. The three significant predictors of dyskinesia were duration of levodopa therapy, onset age, and total daily levodopa dose. Conclusions: The prevalence of levodopa-induced dyskinesia in our patients was 44%. The most significant predictors were duration of levodopa therapy, total daily levodopa dose, and onset age.

Central extrapontine myelinolysis appearing as acute parkinsonism

Central extrapontine myelinolysis appearing as acute parkinsonism

The effect of estrogen in a man with Parkinson's disease and a review of its therapeutic potential

Estrogen has been implicated in controlling the pathogenesis and symptoms of Parkinson's disease (PD) in women. Here, we report a 53-year-old male with PD who underwent estrogen therapy with estradiol (E2). Within a month, he exhibited increased dyskinesias. His medication was reduced by 35% from a levodopa equivalent dose (LED) of 820–535 over three months, which overall improved his motor fluctuations and dyskinesias. Therefore, E2 therapy could have therapeutic potential in males with PD.

Rasagilina en monoterapia en pacientes en fases tempranas de la enfermedad de Parkinson y en terapia combinada y coadyuvante a levodopa en fases moderada y avanzada

Rasagiline is effective in the early stages of the disease and has shown a possible effect of modifying disease progression at a dose of 1 mg. The accurate management of dopaminergic drugs in Parkinson's disease is able to delay the appearance of motor fluctuations and dyskinesias. The combination of different drugs that provide a more continuous dopaminergic stimulation (rasagiline, dopamine agonists) not only exerts a benefit through diminishing the impact of pulsatile stimulation on post-synaptic dopamine receptors, but allows to decrease total daily levodopa requirements. The combination of rasagiline with other dopaminergic drugs has demonstrated to be as efficacious as entacapone for improving both the frequency and severity of motor fluctuations. Likewise, new evidences have shown that the earlier introduction of rasagiline is associated with a delay in introducing other dopaminergic drugs, thus indicating that the symptomatic benefit of rasagiline on daily motor function is not only present in the early Parkinson's disease stages, but is maintained over time.