Cerebral Glucose Metabolism Is a Valuable Predictor of Survival in Patients with Lewy Body Diseases.

OBJECTIVE: Patients with Lewy body diseases have an increased risk of dementia, which is a significant predictor for survival. Posterior cortical hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (PET) precedes the development of dementia by years. We therefore examined the prognostic value of cerebral glucose metabolism for survival. METHODS: We enrolled patients diagnosed with Parkinson's disease (PD), Parkinson's disease with dementia, or dementia with Lewy bodies who underwent [18F]fluorodeoxyglucose PET. Regional cerebral metabolism of each patient was analyzed by determining the expression of the PD-related cognitive pattern (Z-score) and by visual PET rating. We analyzed the predictive value of PET for overall survival using Cox regression analyses (age- and sex-corrected) and calculated prognostic indices for the best model. RESULTS: Glucose metabolism was a significant predictor of survival in 259 included patients (n = 118 events; hazard ratio: 1.4 [1.2-1.6] per Z-score; hazard ratio: 1.8 [1.5-2.2] per visual PET rating score; both p < 0.0001). Risk stratification with visual PET rating scores yielded a median survival of 4.8, 6.8, and 12.9 years for patients with severe, moderate, and mild posterior cortical hypometabolism (median survival not reached for normal cortical metabolism). Stratification into 5 groups based on the prognostic index revealed 10-year survival rates of 94.1%, 78.3%, 34.7%, 0.0%, and 0.0%. INTERPRETATION: Regional cerebral glucose metabolism is a significant predictor of survival in Lewy body diseases and may allow an earlier survival prediction than the clinical milestone "dementia." Thus, [18F]fluorodeoxyglucose PET may improve the basis for therapy decisions, especially for invasive therapeutic procedures like deep brain stimulation in Parkinson's disease. ANN NEUROL 2024.

Cerebellar, Not Nigrostriatal Degeneration Impairs Dexterity in Multiple System Atrophy.

BACKGROUND: Multiple system atrophy (MSA) clinically manifests with either predominant nigrostriatal or cerebellopontine degeneration. This corresponds to two different phenotypes, one with predominant Parkinson's symptoms (MSA-P [multiple system atrophy-parkinsonian subtype]) and one with predominant cerebellar deficits (MSA-C [multiple system atrophy-cerebellar subtype]). Both nigrostriatal and cerebellar degeneration can lead to impaired dexterity, which is a frequent cause of disability in MSA. OBJECTIVE: The aim was to disentangle the contribution of nigrostriatal and cerebellar degeneration to impaired dexterity in both subtypes of MSA. METHODS: We thus investigated nigrostriatal and cerebellopontine integrity using diffusion microstructure imaging in 47 patients with MSA-P and 17 patients with MSA-C compared to 31 healthy controls (HC). Dexterity was assessed using the 9-Hole Peg Board (9HPB) performance. RESULTS: Nigrostriatal degeneration, represented by the loss of cells and neurites, leading to a larger free-fluid compartment, was present in MSA-P and MSA-C when compared to HCs. Whereas no intergroup differences were observed between the MSAs in the substantia nigra, MSA-P showed more pronounced putaminal degeneration than MSA-C. In contrast, a cerebellopontine axonal degeneration was observed in MSA-P and MSA-C, with stronger effects in MSA-C. Interestingly, the degeneration of cerebellopontine fibers is associated with impaired dexterity in both subtypes, whereas no association was observed with nigrostriatal degeneration. CONCLUSION: Cerebellar dysfunction contributes to impaired dexterity not only in MSA-C but also in MSA-P and may be a promising biomarker for disease staging. In contrast, no significant association was observed with nigrostriatal dysfunction. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Sublingual apomorphine in the treatment of Parkinson's disease.

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials.

Advanced therapies in Parkinson's disease: an individualized approach to their indication.

Device aided therapies (DAT) comprising the intrajejunal administration of levodopa/carbidopa intestinal gel (LCIG) and levodopa/carbidopa/entacapone intestinal gel (LECIG), the continuous subcutaneous application of foslevodopa/foscarbidopa or apomorphine infusion (CSAI) and deep brain stimulation (DBS) are used to treat Parkinson's disease with insufficient symptom alleviation under intensified pharmacotherapy. These DAT significantly differ in their efficacy profiles, indication, invasiveness, contraindications, and potential side effects. Usually, the evaluation of all these procedures is conducted simultaneously at the same point in time. However, as disease progression and symptom burden is extremely heterogeneous, clinical experience shows that patients reach the individual milestones for a certain therapy at different points in their disease course. Therefore, advocating for an individualized therapy evaluation for each DAT, requiring an ongoing evaluation. This necessitates that, during each consultation, the current symptomatology should be analyzed, and the potential suitability for a DAT be assessed. This work represents a critical interdisciplinary appraisal of these therapies in terms of their individual profiles and compares these DAT regarding contraindications, periprocedural considerations as well as their efficacy regarding motor- and non-motor deficits, supporting a personalized approach.

[Intrajejunal levodopa in Parkinson's disease: Optimization of PEG application]. / Intrajejunale L-Dopa-Applikation bei der Parkinson-Krankheit: Optimierung der PEG-Anlage.

The various forms of Percutaneous Endoscopic Gastrostomy (PEG) are highly relevant in neurology, as pump-administered intrajejunal levodopa application is one of the indispensable forms of therapy in advanced Parkinson's disease. Optimal PEG placement and follow-up are therefore significant for the success of the therapy. However, the standard intrajejunal administration of levodopa gel via a JET-PEG, i. e. a PEG with an internal catheter inserted into the jejunum, is not without problems for various reasons. In particular, the considerable cumulative complication rates demand a reconsideration of the situation. The very limited absorption area of the drug in the region of the flexura duodenojejunalis must also be taken into account. Causes of complications are predominantly a non-optimal application technique of PEG and internal catheter as well as the frequent lack of an adequate follow-up. In this paper, the details of a modified and optimized application technique compared to the conventional techniques are presented. These new methods have proved their usefulness in clinical applications for years, and additionally a new application form, the Hybrid-PEG, is presented. However, many of the details derived from anatomical/physiological, surgical and endoscopic aspects must be strictly observed during the application in order to reduce or avoid minor and major complications. In particular, problems are caused by local infections in the area of the insertion point of the PEG including peritonitis, leaks and buried bumper syndrome (BBS). The relatively frequent dislocations of the internal catheter also prove to be particularly troublesome. These can ultimately be avoided by clip fixation of the catheter tip down in the jejunum. In particular, the use of the newly developed Hybrid-PEG, a combination of endoscopically controlled gastropexy with three sutures and subsequent central thread-pull-through of the PEG tube, can significantly reduce the complication rate and thus achieve a decisive improvement for patients. The aspects discussed here are highly relevant for all those involved in the therapy of advanced Parkinson's disease. Trustful interdisciplinary collaboration between neurology and endoscopy/surgery/gastroenterology is a prerequisite for good clinical outcomes.

[Synergies Instead of Rivalries - Expert Opinion on the Misunderstood Roles of Continuous Intrajejunal Levodopa Therapy and Deep Brain Stimulation in the Treatment of Parkinson̓s Disease]. / Synergien statt Rivalitäten ­ die missverstandenen Rollen von kontinuierlicher intrajejunaler Levodopatherapie und Tiefer Hirnstimulation in der Behandlung des Morbus Parkinson ­ eine Expertenmeinung.

In the therapy of Parkinson̓s disease, both the intrajejunal administration of Levodopa/Carbidopa Intestinal Gel (LCIG) and, more recently, Levodopa/Carbidopa/Entacapone Intestinal Gel (LECIG), as well as deep brain stimulation (DBS), are employed. These approaches differ significantly in their efficacy and side effect profiles, as well as the timing of their use. Yet, the initiation of therapy for both methods is often simultaneously considered when patients have reached an advanced stage of the disease. From the authors' perspective, however, patients may reach the milestones for the indication of one of these respective treatments at different points in the course of the disease. Individual disease progression plays a pivotal role in this regard. The concept that all patients become candidates for a specific treatment at a predefined time appears erroneous to the authors. In the context of this review, therefore, the therapeutic modalities are presented in terms of their efficacy for different symptoms, the notion of simultaneous timing of their initiation is questioned, and an individualized therapy evaluation is derived, with a focus on quality of life and participation.

Apprends-moi l'art des petits pas: Levodopa, Carbidopa Intestinal Gel plus Entacapone.

We are always looking for the big breakthrough, ideally a cure for our advanced Parkinson's disease (aPD) patients. As long as this does not happen we must optimize the existing therapy, because many small steps may also lead to success. This also applies to the levodopa pump: Certainly, a very good therapy, but with small problems that we have to optimize. This involves, for example, the weight and volume of the previous pump. One possibility is to use the proven triple combination as intestinal gel, thereby increasing the levodopa plasma concentration. Increasing the levodopa plasma concentration enables the reduction of the given levodopa dose and hence the size of the pump. To learn more about the triple combination as intestinal gel the ELEGANCE study was started. This study is a prospective non-interventional study of the long-term effectiveness and safety of levodopa-entacapone-carbidopa intestinal gel (LECIG) in patients with aPD in routine care. This observational study is designed to collect data on the use of the drug Lecigon® in daily clinical practice. The study is intended to supplement the results of previous clinical studies with clinical data in routine medical care, collected from approximately 300 patients.

Inhaled levodopa for threatening impending OFF episodes in managing Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that leads to the degeneration of dopaminergic neurons resulting in a widespread pathology of motor and non-motor symptoms. Oral levodopa remains the most effective symptomatic treatment of PD, but motor complications such as Off episodes occur over time. The spectrum of manifestation of OFF episodes varies, e.g., early morning akinesia, end-of-dose wearing OFF, delayed ON, suboptimal ON and dose failure. The functional disability substantially impacts the quality of life for PD patients. An innovative on-demand therapy to treat Off episodes was approved for patients receiving oral levodopa/dopa deacarboxylase inhibitor: inhaled levodopa powder (Inbrija®). The pulmonary delivery of inhaled levodopa powder provides a predictable and fast treatment effect, independent of gastrointestinal dysfunctions or food intake, which could affect levodopa absorption. Levodopa is administered with a breath-actuated inhaler device and the approved dose is 84 mg per Off episode. During the pivotal SPAN-PD phase III trial, significant improvement in Unified Parkinson Disease Rating Scale III score was measured 30 min post-dose at week 12. Improvement was already seen for the first measured time point 10 min post-dose. No differences in pulmonary function was observed when using inhaled levodopa powder regularly for up to 12 months. Inhaled levodopa powder was also approved for early morning Off episodes. The aim of this review article is to give an overview of the different clinical studies of the innovative inhaled levodopa powder, a new on-demand therapy to treat Off episodes in PD.

Towards improved access to device-aided therapies in advanced PD: the importance of cooperation of different disciplines.

Managing the many issues in advanced Parkinson's disease (PD) requires education, continuous support, and specialized outpatient care involving a variety of allied healthcare professionals. It would be greatly appreciated if general neurologists and professionals from various disciplines who work with people diagnosed with Parkinson's disease (PwP) could remain knowledgeable about the existing therapies and their respective roles within the treatment continuum. The movement disorders specialist and the PD nurse are key actors in the coordination of a targeted and patient-empowering multidisciplinary approach for advanced PD. Affordable and timely access to these therapies for the PwP who may need them is presently a challenge for health systems. Education, training, and support for all the involved stakeholders in the process of PD care may improve quality of life both for PwP and caregivers, and reduce inadequate, expensive, time-consuming, and unsuccessful prolongation of standard medical therapies.

Access to device-aided therapies in advanced Parkinson's disease: navigating clinician biases, patient preference, and prognostic uncertainty.

Device-aided therapies (DAT), which include deep brain stimulation and pump-based continuous dopaminergic stimulation with either levodopa or apomorphine, are among the major advances in the clinical management of Parkinson's disease (PD). Although DAT are being increasingly offered earlier in the disease course, their classical indication remains advanced PD. Theoretically, every patient should be offered transition to DAT when faced with refractory motor and nonmotor fluctuations and functional decline. Worldwide clinical reality is far from these ideal, and, therefore, question the "real-world" equal opportunity of access to DAT for PD patients with advanced PD-even within a single health care system. Differences in access to care, referral pattern (timing and frequency), as well as physician biases (unconscious/implicit or conscious/explicit bias), and patients' preferences or health-seeking behaviour are to be considered. Compared to DBS, little information is available concerning infusion therapies, as well as neurologists' and patients' attitudes towards them. This viewpoint aims to be thought-provoking and to assist clinicians in moving through the process of DAT selection, by including in their decision algorithm their own biases, patient perspective, ethical concerns as well as the current unknowns surrounding PD prognosis and DAT-related long-term side effects for a given patient.

Clinical benefit of MAO-B and COMT inhibition in Parkinson's disease: practical considerations.

Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson's disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson's disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors.

Deep learning segmentation results in precise delineation of the putamen in multiple system atrophy.

OBJECTIVES: The precise segmentation of atrophic structures remains challenging in neurodegenerative diseases. We determined the performance of a Deep Neural Patchwork (DNP) in comparison to established segmentation algorithms regarding the ability to delineate the putamen in multiple system atrophy (MSA), Parkinson's disease (PD), and healthy controls. METHODS: We retrospectively included patients with MSA and PD as well as healthy controls. A DNP was trained on manual segmentations of the putamen as ground truth. For this, the cohort was randomly split into a training (N = 131) and test set (N = 120). The DNP's performance was compared with putaminal segmentations as derived by Automatic Anatomic Labelling, Freesurfer and Fastsurfer. For validation, we assessed the diagnostic accuracy of the resulting segmentations in the delineation of MSA vs. PD and healthy controls. RESULTS: A total of 251 subjects (61 patients with MSA, 158 patients with PD, and 32 healthy controls; mean age of 61.5 ± 8.8 years) were included. Compared to the dice-coefficient of the DNP (0.96), we noted significantly weaker performance for AAL3 (0.72; p < .001), Freesurfer (0.82; p < .001), and Fastsurfer (0.84, p < .001). This was corroborated by the superior diagnostic performance of MSA vs. PD and HC of the DNP (AUC 0.93) versus the AUC of 0.88 for AAL3 (p = 0.02), 0.86 for Freesurfer (p = 0.048), and 0.85 for Fastsurfer (p = 0.04). CONCLUSION: By utilization of a DNP, accurate segmentations of the putamen can be obtained even if substantial atrophy is present. This allows for more precise extraction of imaging parameters or shape features from the putamen in relevant patient cohorts. CLINICAL RELEVANCE STATEMENT: Deep learning-based segmentation of the putamen was superior to currently available algorithms and is beneficial for the diagnosis of multiple system atrophy. KEY POINTS: • A Deep Neural Patchwork precisely delineates the putamen and performs equal to human labeling in multiple system atrophy, even when pronounced putaminal volume loss is present. • The Deep Neural Patchwork-based segmentation was more capable to differentiate between multiple system atrophy and Parkinson's disease than the AAL3 atlas, Freesurfer, or Fastsurfer.

Diffusion microstructure imaging in progressive supranuclear palsy: reduced axonal volumes in the superior cerebellar peduncles, dentato-rubro-thalamic tracts, ventromedial thalami, and frontomesial white matter.

Differentiating between Parkinson's disease (PD) and atypical Parkinson syndromes such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration is challenging. Diffusion microstructure imaging (DMI) was analyzed in patients with clinically suspected atypical Parkinson syndromes and healthy controls. In an exploration cohort, the spatial distribution of PSP-related changes of DMI parameters were evaluated in a voxel-wise analysis and a region-of-interest (ROI)-based approach was established. The diagnostic performance was subsequently tested in an independent validation cohort. In the exploration cohort, 53 PSP patients were compared to a pooled comparison group of 19 patients with PD, 26 patients with MSA, 7 patients with corticobasal syndrome, and 25 healthy controls. PSP patients showed widespread axonal loss in the superior cerebellar peduncles, the dentato-rubro-thalamic tracts, the thalami and the frontal white matter (each P < 0.001). In the validation cohort consisting of 12 patients with PSP vs. 13 patients with other movement disorders, the accuracy of this ROI-based approach for identifying the PSP was highest in the thalamus and the frontal white matter (accuracy 0.96 each). This DMI approach can identify PSP patients on an individual level in a collective with suspected atypical Parkinson syndromes and allows further insight on microstructural alterations in vivo.

Pain in Parkinson's Disease: Pathophysiology, Classification and Treatment.

Continuous medical progress is significantly improving the quality of health care. As a result, people are living longer than during the past century, but this has also caused an increase of the prevalence of many neurological disorders. Parkinson's disease (PD) is the fastest growing neurological condition, with a doubling of cases reported between 1995 and 2015 and a further doubling projected by 2030. Parkinson's disease is generally associated with characteristic motor symptoms (resting tremor, rigidity, bradykinesia and postural instability). However, patients with PD also experience many non-motor symptoms that might be at least as debilitating as the motor symptoms and which significantly impact patients' quality of life (QoL). Pain is a frequent yet underrecognized symptom; the incidence in PD is much higher than in the general population and constitutes a silent disability that significantly contributes to a deterioration in QoL. Accurate identification of parkinsonian pain is important for its diagnosis and effective treatment. In this review, we provide an overview of the pathophysiology, classification, and management of pain in PD. We define the various modalities of chronic PD pain, suggesting possible explanations for its relationship with PD pathology, and discuss its management and currently recommended therapies.

Predictors of falls in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy: a retrospective study.

INTRODUCTION: Recurrent falling is a major clinical milestone in Parkinsonian syndromes. It has a detrimental impact on quality of life, further prognosis, and life expectancy. AIM OF THE STUDY: To improve fall management and prevention, we aimed at identifying clinical parameters predicting fall frequency. To this end, we retrospectively analysed records of fall events of patients with Parkinson's disease (PD), or progressive supranuclear palsy (PSP), or multiple system atrophy (MSA), during their two-week inpatient stay at the Parkinson-Klinik Ortenau, Wolfach, Germany. This data served as an objective proxy for patients' fall frequency and allowed us to estimate the impact of several demographic and clinical variables on the occurrence of falling. MATERIAL AND METHODS: Of 2,111 patients admitted to our hospital, 1,810 presented with PD, 191 with PSP, and 110 with MSA. We employed a multiple (quasi-) poisson regression analysis to model the fall frequency as a function of various demographic variables (age at diagnosis, gender) and clinical variables (disease duration and sub-type, motor and cognitive impairment, autonomic dysfunction). RESULTS: Statistically significant predictors for falls in PD were cognitive impairment, motor impairment, and autonomic dysfunction. In PSP, significant predictors for falls were motor and autonomic dysfunction, while in MSA only disease duration predicted falls, but with only marginal statistical significance. CONCLUSIONS: Our results stress the importance of different factors in predicting falls in the different types of Parkinsonian syndrome. Preventive interventions should address these disease-specific targets for optimal success.

A critical appraisal of MAO-B inhibitors in the treatment of Parkinson's disease.

Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly.

Time-course of decline in different cognitive domains in Parkinson's disease: a retrospective study.

Cognitive impairment and dementia are common non-motor symptoms in Parkinson's disease (PD). To elucidate the potentially typical progression of cognitive decline in PD and its variation, we retrospectively surveyed neuropsychological data obtained at the Parkinson-Klinik Ortenau, Germany in the years 1996-2015. Many of the patients in the surveyed period were repeatedly admitted to our clinic and we were thus able to compile neuropsychological re-test data for 252 patients obtained at varying time intervals. Neuropsychological testing was conducted with the NAI (Nürnberger Alters-Inventar). This battery provides sub-tests that examine cognitive processing speed, executive function, working memory, and verbal/visual memory functions. The re-test time span varied across patients from below 1 year up to about 12 years. Most patients were seen twice, but some patients were tested up to eight times. The steepest rates of cognitive decline were observed for the NAI sub-tests Trail-Making, Maze Test, and Stroop-Word Reading/Color Naming. Intermediate rates of decline were found for Digit Span, Word List-Immediate Recall, and Picture Test. Stroop Test-Interference, Word List-Delayed Recognition, and Figure Test exhibited the slowest decline rates. We did not observe a significant effect of age at diagnosis or gender on the rate of decline. In sum, this study retrospectively evaluated cognitive decline in a sample of patients with PD. Our data suggest a broad cognitive decline that particularly affects the cognitive capacities for processing speed, executive functions, and immediate memory functions.

GBA-associated PD: chances and obstacles for targeted treatment strategies.

Given the clear role of GBA in the pathogenesis of Parkinson's disease (PD) and its impact on phenotypical characteristics, this review provides an overview of the current knowledge of GBA-associated PD with a special focus on clinical trajectories and the underlying pathological mechanisms. Importantly, differences and characteristics based on mutation severity are recognized, and current as well as potential future treatment options are discussed. These findings will inform future strategies for patient stratification and cohort enrichment as well as suitable outcome measures when designing clinical trials.

Treadmill training and physiotherapy similarly improve dual task gait performance: a randomized-controlled trial in Parkinson's disease.

Motor-cognitive dual tasks are used to investigate the interplay between gait and cognition. Dual task walking in patients with Parkinson's disease (PD) results in decreased gait speed and more importantly in an increased fall risk. There is evidence that physical training may improve gait during dual task challenge. Physiotherapy and treadmill walking are known to improve single task gait. The aim of this study was to investigate the impact of individualized physiotherapy or treadmill training on gait during dual task performance. 105 PD patients were randomly assigned to an intervention group (physiotherapy or treadmill). Both groups received 10 individual interventional sessions of 25 min each and additional group therapy sessions for 14 days. Primary outcome measure was the dual task gait speed. Secondary outcomes were additional gait parameters during dual task walking, UPDRS-III, BBS and walking capacity. All gait parameters were recorded using sensor-based gait analysis. Gait speed improved significantly by 4.2% (treadmill) and 8.3% (physiotherapy). Almost all secondary gait parameters, UPDRS-III, BBS, and walking capacity improved significantly and similarly in both groups. However, interaction effects were not observed. Both interventions significantly improved gait in patients with mild to moderate PD. However, treadmill walking did not show significant benefits compared to individualized physiotherapy. Our data suggest that both interventions improve dual task walking and therefore support safe and independent walking. This result may lead to more tailored therapeutic preferences.

[Relevance of COMT inhibitors in the treatment of motor fluctuations]. / Stellenwert der COMT-Hemmer in der Therapie motorischer Fluktuationen.

Catechol O­methyltransferase (COMT) inhibitors have been established in the treatment of Parkinson's disease for more than 20 years. They are considered the medication of choice for treating motor fluctuations. The available COMT inhibitors, entacapone, opicapone and tolcapone, differ pharmacokinetically in terms of their half-lives with implications for the dose frequency, in their indication requirements and in their spectrum of side effects, including diarrhea and yellow discoloration of urine. Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of a working group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed.