Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD). OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes. METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

[Additional functional symptoms in Parkinson's disease and tremor syndromes]. / Zusätzliche funktionelle Symptome bei Parkinson und Tremorsyndromen.

Patients with Parkinson's Disease or a tremor syndrome may present with additional functional movement disorders. The differential diagnosis is particularly difficult. In some cases, functional symptoms occur either before the manifestation of the organic disease or can emerge as an additional symptom after Parkinson's disease or tremor became apparent. In patients with Parkinson's disease the prevalence for additional functional symptoms is 7 %. In the case that patients with Parkinson's diseases have one side that is more severely affected, additional functional motor symptoms such as functional rest tremor also occur on that same, predominantly affected side. Functional gait disorders occur frequently. Clinically, patients appear notably slow in automatized, daily tasks. Their speech is more whispering than hypophonic, bradykinesia during finger tapping manifest without a decrement. The Dopamintransporterszintigraphy (123) I FP-CIT SPECT; DaTSCANTM) may be helpful to differentiate between functional Parkinsonism and Parkinson's disease. Functional tremor in patients with an organic tremor syndrome is diagnosed with the same distraction techniques as in solely functional tremor. This includes cognitive, motor, and suggestive distraction maneuvers. In some cases, additional neurophysiological investigations such as accelerometry are useful for the differential diagnosis. It is most important to identify patients with additional functional symptoms in non-functional movement disorders, because the therapeutic approach differs and a multi professional team is required to initiate effective treatment strategies.

[Improvement of the treatment of patients with spastic movement disorder after stroke]. / Verbesserung der Versorgung von Patientinnen und Patienten mit spastischer Bewegungsstörung nach Schlaganfall.

BACKGROUND: Spastic movement disorder (SMD) develops in up to 43% of cases as a sequela of stroke. In the event of a functionally relevant or daily life impairing SMD or to avoid an impending complication, the medicinal treatment of a focal, multifocal and segmental increase in muscle tone with botulinum neurotoxin A (BoNT-A) is recommended; however, treatment data reveal a lack of guideline-conform treatment with BoNT­A in Germany. OBJECTIVE: The aim of the reported expert meeting was to discuss solutions to the incorrect treatment and undertreatment of patients with SMD and to formulate consensus recommendations to improve the care situation. METHODS: At a consensus meeting held in April 2022, eight experts from the fields of neurology, physical medicine and rehabilitation discussed the causes for the incorrect treatment and undertreatment and formulated consensus solution approaches. RESULTS: Possible reasons for the current incorrect treatment and undertreatment in SMD management in Germany include insufficient awareness of SMD among physicians, a lack of treatment capacities, a lack of information transfer in discharge management as well as staff shortages in the specialized inpatient and outpatient SMD treatment centers. The committee therefore recommended a patient pathway in which affected patients with SMD are provided with correctly implemented BoNT­A treatment in combination with physical measures. CONCLUSION: The recommended treatment pathway for use in stroke patients is intended to close gaps in care and thus ensure guideline-conform treatment of post-stroke SMD.

Visuomotor Adaptation Deficits in Patients with Essential Tremor.

Essential tremor (ET) is a progressive movement disorder whose pathophysiology is not fully understood. Current evidence supports the view that the cerebellum is critically involved in the genesis of the tremor in ET. However, it is still unknown whether cerebellar dysfunction affects not only the control of current movements but also the prediction of future movements through dynamic adaptation toward a changed environment. Here, we tested the capacity of 28 patients with ET to adapt in a visuomotor adaptation task known to depend on intact cerebellar function. We found specific impairments in that task compared to age-matched healthy controls. Adaptation to the visual perturbation was disrupted in ET patients, while de-adaptation, the phase after abrupt removal of the perturbation, developed similarly to control subjects. Baseline tremor-independent motor performance was as well similar to healthy controls, indicating that adaptation deficits in ET patients were not rooted in an inability to perform goal-directed movements. There was no association between clinical severity scores of ET and early visuomotor adaptation abilities. These results provide further evidence that the cerebellum is dysfunctional in ET.

[Hallucinations in Patients with Idiopathic Parkinson's Disease]. / Halluzinationen bei Patienten mit idiopathischem Parkinson-Syndrom.

Patients with idiopathic Parkinson's disease develop symptoms of the hallucination-psychosis spectrum in more than 20%. Most common are visual hallucinations. The pathogenesis of hallucinations mainly depends on disease duration, the distribution and extent of alpha-synuclein pathology, and modulating effects of the dopaminergic therapy. When managing PD hallucinations both anti-delirogenic actions and medication management are important. However, decrease in dopaminergic medication may lead to critical worsening of akinesia. If appropriate neuroleptic medication - essentially quetiapin or clozapin - can be considered. Instead, anti-dopaminergic neuroleptics should not be used owing to their pro-akinetic side-effects. Here, we provide therapy recommendations to manage PD hallucinations based on an up-to-date targeted review of the literature and expert-based empirical evidence.

Intact Organization of Tactile Space Perception in Isolated Focal Dystonia.

BACKGROUND: Systematic perceptual distortions of tactile space have been documented in healthy adults. In isolated focal dystonia impaired spatial somatosensory processing is suggested to be a central pathophysiological finding, but the structure of tactile space for different body parts has not been previously explored. OBJECTIVES: The objective of this study was to assess tactile space organization with a novel behavioral paradigm of tactile distance perception in patients with isolated focal dystonia and controls. METHODS: Three groups of isolated focal dystonia patients (cervical dystonia, blepharospasm/Meige syndrome, focal hand dystonia) and controls estimated perceived distances between 2 touches across 8 orientations on the back of both hands and the forehead. RESULTS: Stimulus size judgments differed significantly across orientations in all groups replicating distortions of tactile space known for healthy individuals. There were no differences between groups in the behavioral parameters we assessed on the hands and forehead. CONCLUSIONS: Tactile space organization is comparable between patients with isolated focal dystonia and healthy controls in dystonic and unaffected body parts. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Functional movement disorders in neurogeriatric inpatients : Underdiagnosed, often comorbid to neurodegenerative disorders and treatable.

BACKGROUND: The proportion of patients with functional movement disorders (FMD) is particularly high in neurology clinics. Treatment options have not been consistently developed, not well evaluated and not validated. This article presents the preliminary data on the prevalence and treatment response of patients with FMD who were treated within the framework of an early rehabilitative geriatric complex treatment at a university hospital for neurology. METHODS: From July 2017 to November 2018 the prevalence, demographic and clinical parameters, and response to treatment of FMD patients were documented and compared to non-FMD patients treated at the neurogeriatric ward of the University Hospital Schleswig-Holstein, in Kiel. Clinical endpoints were the Short Physical Performance Battery (SPPB) for mobility and the Barthel index for instrumented activity of daily life (iADL). RESULTS: The prevalence of FMD was 11% (19/175) and predominantly observed in women (74%). Of the FMD patients nine also had a diagnosis of either idiopathic Parkinson's disease (N = 7), dementia with Lewy bodies (N = 1) or progressive supranuclear palsy (N = 1). At admission, neither the SPPB nor the iADL differed significantly between FMD and non-FMD patients. The treatment response was comparable between the groups: SPPB change was +0.3±1.8 (mean, standard deviation) in FMD and +0.4±1.9 in non-FMD patients (p = 0.83). The iADL change was +19±15 in FMD and +18±17 in non-FMD (p = 0.83). CONCLUSION: The prevalence of FMD was unexpectedly high in the neurogeriatric ward of a German university hospital. There were comparable impairments and responses to multidisciplinary treatment in mobility and iADL between FMD and non-FMD geriatric patients, suggesting that specific and informed treatment provided by a multidisciplinary geriatric team is effective in geriatric FMD patients. Further studies of this underdiagnosed disorder in older age are warranted.

Alcohol improves cerebellar learning deficit in myoclonus-dystonia: A clinical and electrophysiological investigation.

OBJECTIVE: To characterize neurophysiological subcortical abnormalities in myoclonus-dystonia and their modulation by alcohol administration. METHODS: Cerebellar associative learning and basal ganglia-brainstem interaction were investigated in 17 myoclonus-dystonia patients with epsilon-sarcoglycan (SGCE) gene mutation and 21 age- and sex-matched healthy controls by means of classical eyeblink conditioning and blink reflex recovery cycle before and after alcohol intake resulting in a breath alcohol concentration of 0.08% (0.8g/l). The alcohol responsiveness of clinical symptoms was evaluated by 3 blinded raters with a standardized video protocol and clinical rating scales including the Unified Myoclonus Rating Scale and the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: Patients showed a significantly reduced number of conditioned eyeblink responses before alcohol administration compared to controls. Whereas the conditioning response rate decreased under alcohol intake in controls, it increased in patients (analysis of variance: alcohol state × group, p = 0.004). Blink reflex recovery cycle before and after alcohol intake did not differ between groups. Myoclonus improved significantly after alcohol intake (p = 0.016). The severity of action myoclonus at baseline correlated negatively with the conditioning response in classical eyeblink conditioning in patients. INTERPRETATION: The combination of findings of reduced baseline acquisition of conditioned eyeblink responses and normal blink reflex recovery cycle in patients who improved significantly with alcohol intake suggests a crucial role of cerebellar networks in the generation of symptoms in these patients. Ann Neurol 2017;82:543-553.

Frontal Lobe Connectivity and Network Community Characteristics are Associated with the Outcome of Subthalamic Nucleus Deep Brain Stimulation in Patients with Parkinson's Disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is nowadays an evidence-based state of the art therapy option for motor and non-motor symptoms in patients with Parkinson's disease (PD). However, the exact anatomical regions of the cerebral network that are targeted by STN-DBS have not been precisely described and no definitive pre-intervention predictors of the clinical response exist. In this study, we test the hypothesis that the clinical effectiveness of STN-DBS depends on the connectivity profile of the targeted brain networks. Therefore, we used diffusion-weighted imaging (DWI) and probabilistic tractography to reconstruct the anatomical networks and the graph theoretical framework to quantify the connectivity profile. DWI was obtained pre-operatively from 15 PD patients who underwent DBS (mean age = 67.87 ± 7.88, 11 males, H&Y score = 3.5 ± 0.8) using a 3T MRI scanner (Philips Achieva). The pre-operative connectivity properties of a network encompassing frontal, prefrontal cortex and cingulate gyrus were directly linked to the postoperative clinical outcome. Eccentricity as a topological-characteristic of the network defining how cerebral regions are embedded in relation to distant sites correlated inversely with the applied voltage at the active electrode for optimal clinical response. We found that network topology and pre-operative connectivity patterns have direct influence on the clinical response to DBS and may serve as important and independent predictors of the postoperative clinical outcome.

Genome-wide association study in essential tremor identifies three new loci.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Functional impact of different muscle localization techniques for Botulinum neurotoxin A injections in clinical routine management of post-stroke spasticity.

BACKGROUND: Treatment options for spasticity include intramuscular botulinum neurotoxin A (BoNT-A) injections. Both ultrasound (US) or electromyographic (EMG) guided BoNT-A injections are employed to isolate muscles. To date, most studies have included patients naïve to BoNT-A or following a prolonged wash out phase. OBJECTIVE: To determine the impact of US/EMG guided BoNT-A injections on function in outpatients with spasticity receiving an established re-injection regime. METHODS: Thirty patients post-stroke were investigated in a single-blinded, randomized controlled trial using a cross-over design for the EMG and US and a parallel design for the control group. The Modified Ashworth (MAS), Disability Assessment (DAS), Quality of Life (EQ-5D), self-rating scale and Barthel Index were assessed pre- and post-BoNT-A injections of upper limb muscles by a to the injection technique blinded person. RESULTS: MAS improved in arm, finger and upper limb 4 weeks after BoNT-A treatment. The improvement showed no significant differences between the three injection techniques. Barthel Index, DAS and EQ-5D remained unchanged in all groups. CONCLUSIONS: This pilot study questions the impact of the instrumental guided injection techniques on everyday functionality in a routine clinical setting with established re-injection intervals. Larger trials are warranted with patients who are under long-term treatment on a regular basis.

Dopamine DRD2 polymorphism (DRD2/ANNK1-Taq1A) is not a significant risk factor in writer's cramp.

Writers' cramp is a movement disorder with dystonic co-contraction of fingers and hand during writing and is part of the clinical spectrum of focal dystonias. Previous studies showed reduced striatal dopamine receptor D2 (DRD2) availability in dystonia. The expression of D2 receptors is modulated by a DRD2/ANKK1-Taq1A polymorphism (rs1800497). This study addresses the question of whether the DRD2/ANKK1-Taq1A polymorphism is a risk factor for writer's cramp. We determined the DRD2/ANKK1-Taq1A polymorphism 34 patients with writer's cramp compared to 67 age matched controls. 35.3% of the patients and 31.3% of our controls were assigned to the A1 genotype status (p = .7). Therefore DRD2/ANKK1-Taq1A gene is not a significant risk factor in the evolution of writer's cramp.

Early- and late-onset essential tremor patients represent clinically distinct subgroups.

OBJECTIVE: Essential tremor is a very common disease defined by sparse clinical criteria. It is unlikely that essential tremor is an etiologically homogeneous disease. Stratifying broadly defined diseases using clinical characteristics has often aided the etiopathological understanding. Most studies of essential tremor show 2 distinct age at onset peaks: early and late. This study investigates phenotypical differences between early- and late-onset essential tremor patients. METHODS: We studied a sample of 1137 tremor patients. Of these patients, 978 suffered from definite or probable essential tremor. All of the patients underwent the same standardized examination encompassing, among other items, drawing of the Archimedes spiral and assessment of the Fahn-Tolosa-Marin scale. RESULTS: Two subgroups of early-onset (≤ 24 years of age, n = 317) and late-onset (≥ 46 years of age, n = 356) patients were selected based on the visual and mathematical analysis of the age-at-onset distribution. Tremor severity in both groups was comparable. Tremor progression measured as Archimedes spiral score and the Fahn-Tolosa-Marin subscales divided by the disease duration in 10-year bins was significantly faster in late-onset patients when compared with early-onset patients. Early-onset patients more frequently reported a positive family history and alcohol sensitivity of the tremor. CONCLUSIONS: The age-at-onset distribution suggests a distinction between early- and late-onset tremor. Early-onset and late-onset essential tremor differ in the progression rates and the frequencies of a positive family history and history of a positive effect of alcohol on tremor. © 2016 International Parkinson and Movement Disorder Society.

Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 × 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

Impact of Physiotherapy in the Treatment of Pain in Cervical Dystonia.

Background: Cervical dystonia (CD) is the most common form of focal dystonia in adults. Studies show that physiotherapy (PT) in combination with BoNT has an effect on pain in cervical dystonia. We intended to test this hypothesis in a real-world setting to answer the question of whether pain is a good target symptom for prescribing PT. We also aimed to assess which form of PT is most appropriate for the treatment of pain. Methods: Study design: cross-sectional survey-based study of 91 patients with a confirmed diagnosis of cervical dystonia. The survey consisted of a questionnaire on type, frequency and content of physiotherapy, an assessment of quality of life with the Craniocervical Dystonia Questionnaire 24 (CDQ 24) and subjective pain scores. Results: 53.8% of patients received physiotherapy, mostly a mixture of exercises to either correct the abnormal posture or to reduce the muscle tone. Additional therapies included stress-reducing exercises (14.3%), psychotherapy (9.9%) and EMG biofeedback (2.2%). Patients who received PT showed a non-significant tendency towards higher pain scores. The severity of dystonia-associated pain was significantly associated with the patients' quality of life (F (1,54) = 22.9, adjusted R2 = 0.286, p < 0.001). Discussion: Pain is a frequent problem in patients with CD and severely affects quality of life. Physiotherapy could therefore be a valuable treatment option for patients with CD and pain. Highlights: Our uncontrolled study illustrates the high frequency of physiotherapy in addition to BoNT treatment in a real-life cohort of patients with cervical dystonia. We were able to show that PT reduces patients' perceived pain in a patient reported outcome measure. This highlights the importance of PT in reducing CD-related pain, which considerably impairs quality of life.

Towards a better understanding of anticipatory postural adjustments in people with Parkinson's disease.

INTRODUCTION: Previous studies have shown that anticipatory postural adjustments (APAs) are altered in people with Parkinson's disease but its meaning for locomotion is less understood. This study aims to investigate the association between APAs and gait initiation, gait and freezing of gait and how a dynamic postural control challenging training may induce changes in these features. METHODS: Gait initiation was quantified using wearable sensors and subsequent straight walking was assessed via marker-based motion capture. Additionally, turning and FOG-related outcomes were measured with wearable sensors. Assessments were conducted one week before (Pre), one week after (Post) and 4 weeks after (Follow-up) completion of a training intervention (split-belt treadmill training or regular treadmill training), under single task and dual task (DT) conditions. Statistical analysis included a linear mixed model for training effects and correlation analysis between APAs and the other outcomes for Pre and Post-Pre delta. RESULTS: 52 participants with Parkinson's disease (22 freezers) were assessed. We found that APA size in the medio-lateral direction during DT was positively associated with gait speed (p<0.001) and stride length (p<0.001) under DT conditions at Pre. The training effect was largest for first step range of motion and was similar for both training modes. For the associations between changes after the training (pooled sample) medio-lateral APA size showed a significant positive correlation with first step range of motion (p = 0.033) only in the DT condition and for the non-freezers only. CONCLUSIONS: The findings of this work revealed new insights into how APAs were not associated with first step characteristics and freezing and only baseline APAs during DT were related with DT gait characteristics. Training-induced changes in the size of APAs were related to training benefits in the first step ROM only in non-freezers. Based on the presented results increasing APA size through interventions might not be the ideal target for overall improvement of locomotion.

Individualized Physiotherapy of Upper Body Functional Movement Disorder - Two Illustrative Cases.

Background: Information on specialist physiotherapeutic treatment for functional movement disorders is scarce. Previous studies focussed on functional gait disorders and availability of descriptions of the practical application especially for other body regions is very limited. Cases: We present two illustrative cases, demonstrating the key elements of physiotherapy for the treatment of functional movement disorders beyond gait difficulties. The individual applicability of the specific core elements of physiotherapy, adapted to the individual needs of each patient, are described. We also explain, how different sensory stimuli can be used to shift attention away from symptoms and thus reduce them. Moreover, we discuss how patients' agency can be encouraged and how this results in therapy key moments, contributing to a sustained improvement of symptoms. Conclusion: Thus, our case series are intended to guide clinicians and therapists alike, to promote disease-specific physiotherapy for this common and treatable neuropsychiatric disorder.

Effect of Thalamic versus Pallidal Deep Brain Stimulation on Head Tremor in Dystonic and Essential Tremor Patients-A Retrospective Video-Blinded Study.

BACKGROUND: Head tremor is common in dystonia syndromes and difficult to treat. Deep brain stimulation (DBS) is a therapeutic option in medically-refractory cases. In most DBS-centers, the globus pallidus internus (GPi) is targeted in patients with predominant dystonia and the ventrointermediate nucleus of the thalamus (Vim) in predominant tremor. The aim of the study was to evaluate the effect of GPi- versus Vim-DBS in dystonic or essential head tremor. METHODS: All patients with dystonia or essential tremor (ET) (n = 381) who underwent DBS surgery at our institution between 1999 and 2020 were screened for head tremor in our database according to predefined selection criteria. Of the 33 patients meeting inclusion criteria tremor and dystonia severity were assessed at baseline, short- (mean 10 months) and long-term follow-up (41 months) by two blinded video-raters. RESULTS: Twenty-two patients with dystonic head tremor received either GPi- (n = 12) or Vim-stimulation (n = 10), according to the prevailing clinical phenotype. These two groups were compared with 11 patients with ET, treated with Vim-stimulation. The reduction in head tremor from baseline to short- and long-term follow-up was 60-70% and did not differ significantly between the three groups. CONCLUSIONS: GPi-DBS effectively and sustainably reduced head tremor in idiopathic dystonia. The effect was comparable to the effect of Vim-DBS on head tremor in dystonia patients with predominant limb tremor and to the effect of Vim-DBS on head tremor in ET.

Physical Exercise as a Potential Treatment for Fatigue in Parkinson's Disease? A Systematic Review and Meta-Analysis of Pharmacological and Non-Pharmacological Interventions.

BACKGROUND: Fatigue is one of the most common and debilitating non-motor symptoms among patients with Parkinson's disease (PD) and significantly impacts quality of life. Therefore, effective treatment options are needed. OBJECTIVE: To provide an update on randomized controlled trials (RCTs) including pharmacological and non-pharmacological (but non-surgical) treatments that examine the effects of fatigue on PD patients. METHODS: We searched the MEDLINE, EMBASE, PsycINFO, CENTRAL, and CINAHL databases for (cross-over) RCTs on pharmacological and non-pharmacological interventions for treating fatigue in PD patients until May 2021. Meta-analyses for random-effects models were calculated when two or more studies on the same treatment option were available using standardized mean differences (SMDs) with 95% confidence intervals (CIs). RESULTS: Fourteen pharmacological and 16 non-pharmacological intervention RCTs were identified. For pharmacological approaches, a meta-analysis could only be performed for modafinil compared to placebo (n = 2) revealing a non-significant effect on fatigue (SMD = - 0.21, 95% CI - 0.74-0.31, p = 0.43). Regarding non-pharmacological approaches, physical exercise (n = 8) following different training approaches versus passive or placebo control groups showed a small significant effect (SMD = - 0.37, 95% CI - 0.69- - 0.05, p = 0.02) which could not be demonstrated for acupuncture vs. sham-acupuncture (SMD = 0.16, 95% CI - 0.19-0.50, p = 0.37). CONCLUSION: Physical exercise may be a promising strategy to treat fatigue in PD patients. Further research is required to examine the efficacy of this treatment strategy and further interventions. Future studies should differentiate treatment effects on physical and mental fatigue as the different underlying mechanisms of these symptoms may lead to different treatment responses. More effort is required to develop, evaluate, and implement holistic fatigue management strategies for PD patients.