Levodopa Response Research Articles

Disentangling nigral and putaminal contribution to motor impairment and levodopa response in Parkinson’s disease

The extent to which the degeneration of the substantia nigra (SN) and putamen each contribute to motor impairment in Parkinson’s disease (PD) is unclear, as they are usually investigated using different imaging modalities. To examine the pathophysiological significance of the SN and putamen in both motor impairment and the levodopa response in PD using diffusion microstructure imaging (DMI). In this monocentric retrospective cross-sectional study, DMI parameters from 108 patients with PD and 35 healthy controls (HC) were analyzed using a voxel- and region-based approach. Linear models were applied to investigate the association between individual DMI parameters and Movement Disorder Society Unified Parkinson’s Disease Rating Scale-Part 3 performance in ON- and OFF-states, as well as the levodopa response, controlling for age and sex. Voxel- and region-based group comparisons of DMI parameters between PD and HC revealed significant differences in the SN and putamen. In PD, a poorer MDS-UPDRS-III performance in the ON-state was associated with increased free fluid in the SN (b-weight = 65.79, p = 0.004) and putamen (b-weight = 86.00, p = 0.006), and contrariwise with the demise of cells in both structures. The levodopa response was inversely associated with free fluid both in the SN (b-weight = −83.61, p = 0.009) and putamen (b-weight = −176.56, p < 0.001). Interestingly, when the two structures were assessed together, the integrity of the putamen, but not the SN, served as a predictor for the levodopa response (b-weight = −158.03, p < 0.001). Structural alterations in the SN and putamen can be measured by diffusion microstructure imaging in PD. They are associated with poorer motor performance in the ON-state, as well as a reduced response to levodopa. While both nigral and putaminal integrity are required for good performance in the ON-state, it is putaminal integrity alone that determines the levodopa response. Therefore, the structural integrity of the putamen is crucial for the improvement of motor symptoms to dopaminergic medication, and might therefore serve as a promising biomarker for motor staging.

Clinical factors and dopamine transporter availability for the prediction of outcomes after globus pallidus deep brain stimulation in Parkinson’s disease

We aimed to investigate the predictive value of preoperative clinical factors and dopamine transporter imaging for outcomes after globus pallidus interna (GPi) deep brain stimulation (DBS) in patients with advanced Parkinson’s disease (PD). Thirty-one patients with PD who received bilateral GPi DBS were included. The patients underwent preoperative [18F] FP-CIT positron emission tomography before DBS surgery. The Unified Parkinson’s Disease Rating Scale (UPDRS) were used to assess outcomes 12 months after DBS. Univariate and multivariate linear regression analysis were performed to investigate the association between clinical variables including sex, age at onset of PD, disease duration, cognitive status, preoperative motor severity, levodopa responsiveness, daily dose of dopaminergic medication, and dopamine transporter availability in the striatum and outcomes after GPi DBS. Younger age at onset of PD was associated with greater DBS motor responsiveness and lower postoperative UPDRS III score. Greater levodopa responsiveness, lower preoperative UPDRS III score and lower striatal dopamine transporter availability were associated with lower postoperative UPDRS III score. Younger age at onset was also associated with greater decrease in UPDRS IV score and dyskinesia score after GPi DBS. Our results provide useful information to select DBS candidates and predict therapeutic outcomes after GPi DBS in advanced PD.

Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Clinical parameters predict the effect of bilateral subthalamic stimulation on dynamic balance parameters during gait in Parkinson's disease.

We investigated the effect of deep brain stimulation on dynamic balance during gait in Parkinson's disease with motion sensor measurements and predicted their values from disease-related factors. We recruited twenty patients with Parkinson's disease treated with bilateral subthalamic stimulation for at least 12 months and 24 healthy controls. Six monitors with three-dimensional gyroscopes and accelerometers were placed on the chest, the lumbar region, the two wrists, and the shins. Patients performed the instrumented Timed Up and Go test in stimulation OFF, stimulation ON, and right- and left-sided stimulation ON conditions. Gait parameters and dynamic balance parameters such as double support, peak turn velocity, and the trunk's range of motion and velocity in three dimensions were analyzed. Age, disease duration, the time elapsed after implantation, the Hoehn-Yahr stage before and after the operation, the levodopa, and stimulation responsiveness were reported. We individually calculated the distance values of stimulation locations from the subthalamic motor center in three dimensions. Sway values of static balance were collected. We compared the gait parameters in the OFF and stimulation ON states and controls. With cluster analysis and a machine-learning-based multiple regression method, we explored the predictive clinical factors for each dynamic balance parameter (with age as a confounder). The arm movements improved the most among gait parameters due to stimulation and the horizontal and sagittal trunk movements. Double support did not change after switching on the stimulation on the group level and did not differ from control values. Individual changes in double support and horizontal range of trunk motion due to stimulation could be predicted from the most disease-related factors and the severity of the disease; the latter also from the stimulation-related changes in the static balance parameters. Physiotherapy should focus on double support and horizontal trunk movements when treating patients with subthalamic deep brain stimulation.

The effect of age and disease duration on the efficacy of subthalamic nuclei deep brain stimulation in Parkinson's disease patients.

Previous studies have reported the effects of age and disease duration on the efficacy of subthalamic nuclei deep brain stimulation (STN-DBS) of Parkinson's disease (PD) patients. However, available data involving these issues are not consistent. In particular, the effect of age and disease duration on the initial efficacy of STN-DBS has not been established. A total of 51 patients with PD treated with bilateral STN-DBS were involved in the present study. They received clinical symptom evaluation during the preoperative, initial, and chronic stages of surgery. The correlations between age when undergoing surgery/age at disease onset/disease duration and outcomes of STN-DBS were measured. The preoperative levodopa response was negatively associated with age. During the initial stage, the age when undergoing surgery and age at disease onset were negatively correlated with the effect on bradykinesia, with better symptom control of general symptoms in long-term disease patients. Similarly, patients with an early time of surgery and disease onset and long-term disease duration showed better control of bradykinesia and axial symptoms at the chronic stage. Furthermore, a long-term disease duration and early disease onset benefited from an increase of therapeutic efficacy in general, rigid, and axial symptoms with STN-DBS after a long period. Nevertheless, patients with late disease onset achieved a better relief of stigma. Age and disease durations played a unique role in controlling the symptoms of PD patients treated with STN-DBS. These results may contribute to patient selection and adjustments of expectations of surgery, based on the age, disease duration, and different symptoms.

Pre-operative cognitive burden as predictor of motor outcome following bilateral subthalamic nucleus deep brain stimulation in Parkinson's disease.

The interrelationship between neurocognitive impairments and motor functions was observed in patients with advanced Parkinson's disease (PD). This study was conducted to identify pre-operative neurocognitive and clinical predictors of short-term motor outcome following subthalamic nucleus deep brain stimulation (STN-DBS). All consecutive PD patients who were eligible for bilateral STN-DBS from 2009 to 2019 were evaluated before and at 1year following surgery. Standard motor evaluation and neurocognitive tests including global cognition, memory, executive functions (attention and category fluency), confrontational speech, visuospatial abilities, and mood were conducted at baseline. The post-operative STN-DBS effects were assessed at 1year following the surgery. Multiple regression analysis was applied to identify baseline independent predictors of post-operative STN-DBS effect. A total of 82 patients were analyzed. It was found that younger age at operation, higher levodopa responsiveness at baseline based on UPDRS-III total score, and better baseline verbal delayed memory and category fluency predicted post-operative motor outcome at 1year following STN-DBS (F = 9.639, p < 0.001, R2 = .340). Our findings demonstrated the role of baseline cognitive burden, especially cognitive processes related to frontostriatal circuits, was significant clinical predictors of short-term motor outcomes following STN-DBS. Profile analysis of neurocognitive functions at baseline is recommended.

Association Between Microbial Tyrosine Decarboxylase Gene and Levodopa Responsiveness in Patients With Parkinson Disease.

Interindividual variability in levodopa efficacy is a challenge for the personalized treatment of Parkinson disease (PD). Gut microbiota might represent a new approach for personalized medicine. Recently, a novel microbial levodopa metabolism pathway was identified, which is mediated by tyrosine decarboxylase mainly encoded by tyrosine decarboxylase gene (tyrDC) in Enterococcus faecalis. In this study, we aimed to identify whether the abundance of microbial tyrDC gene and E faecalis is associated with levodopa responsiveness and could predict the drug response. This cross-sectional study enrolled patients with PD between December 2019 and January 2022 and evaluated levodopa responsiveness using a levodopa challenge test. Patients were stratified into moderate and good responders based on levodopa responsiveness. The tyrDC gene and E. faecalis abundance in fecal samples were measured using quantitative real-time PCR. Plasma levodopa concentrations were measured using liquid chromatography-tandem mass spectrometry analysis. The predictive models for levodopa responsiveness were constructed and verified through cross-validation and external validation. A total of 101 patients with PD were enrolled in the primary cohort and 43 were enrolled in the external validation cohort. Moderate responders had higher abundances of the tyrDC gene (3.6 [3.1-4.3] vs 2.6 [2.1-2.9], p < 0.001) and E faecalis (3.2 [2.5-4.4] vs 2.6 [2.1-3.6], p = 0.010) than good responders. The tyrDC gene abundance was independently associated with levodopa responsiveness (OR: 5.848; 95% CI: 2.664-12.838; p < 0.001). Notably, tyrDC gene abundance showed certain discriminative power for levodopa responsiveness in primary cohort (sensitivity: 80.0%; specificity: 84.3%; area under the curve [AUC]: 0.85; 95% CI: 0.77-0.93; p < 0.001) and external validation cohort (sensitivity: 85.0%; specificity: 95.7%; AUC: 0.95; 95% CI: 0.89-1.02; p < 0.001). The prediction of levodopa responsiveness based on tyrDC gene abundance had good calibration and discrimination in cross-validation (C-index in training and test sets: 0.856 and 0.851, respectively) and external validation (C-index: 0.952). The microbial tyrDC gene abundance could serve as a potential biomarker of levodopa responsiveness. Novel strategies targeting the tyrDC gene may provide new approaches for personalized levodopa treatment.

Levodopa responsiveness in Parkinson's disease: harnessing real-life experience with machine-learning analysis.

Responsiveness to levodopa varies greatly among patients with Parkinson's disease (PD). The factors that affect it are ill defined. The aim of the study was to identify factors predictive of long-term response to levodopa. The medical records of 296 patients with PD (mean age of onset, 62.2 ± 9.7years) were screened for demographics, previous treatments, and clinical phenotypes. All patients were assessed with the Unified PD Rating Scale (UPDRS)-III before and 3months after levodopa initiation. Regression and machine-learning analyses were used to determine factors that are associated with levodopa responsiveness and might identify patients who will benefit from treatment. The UPDRS-III score improved by ≥ 30% (good response) in 128 patients (43%). On regression analysis, female gender, young age at onset, and early use of dopamine agonists predicted a good response. Time to initiation of levodopa treatment had no effect on responsiveness except in patients older than 72years, who were less responsive. Machine-learning analysis validated these factors and added several others: symptoms of rigidity and bradykinesia, disease onset in the legs and on the left side, and fewer white vascular ischemic changes, comorbidities, and pre-non-motor symptoms. The main determinants of variations in levodopa responsiveness are gender, age, and clinical phenotype. Early use of dopamine agonists does not hamper levodopa responsiveness. In addition to validating the regression analysis results, machine-learning methods helped to determine the specific clinical phenotype of patients who may benefit from levodopa in terms of comorbidities and pre-motor and non-motor symptoms.

Gastrointestinal Motility and Response to Levodopa in Parkinson's Disease: A Proof-of-Concept Study.

Simultaneous measurement of gastrointestinal transit time (GITT) and plasma levodopa concentration (PLC) is crucial to understanding the effect of dysfunctional motility on levodopa response in patients with Parkinson's disease (PwPD). The aim is to determine if altered segmental GITT correlates with clinical response and PLC variability in PwPD. Ten typical and 10 erratic responders ingested the SmartPill (SP) wireless motility capsule. Serial PLC and finger tapping, obtained every 30minutes for 3 hours after SP/levodopa ingestion, evaluated the correlation between GITT, clinical response, and PLC. Glucose breath testing assessed small intestinal bacterial overgrowth (SIBO). GITT was not significantly different in "typical" and "erratic" responders. SIBO was positive in half of the erratic and negative in most typical responders. SP is a feasible technology for assessing GITT in PwPD. A larger study may be able to significantly differentiate/correlate GITT in different segments of the GI tract with response to levodopa. © 2022 International Parkinson and Movement Disorder Society.

Clinical Features, Neuroimaging, and Levodopa-Responsiveness in Holmes' Tremor: A Video-Based Case-Series with a Review of the Literature.

Holmes' tremor (HT) is a low-frequency tremor characterized by a combination of rest, posture, and action components. We are reporting the clinical features, neuroimaging findings, and levodopa responsiveness in 12 patients with HT. The majority of the patients were male (11/12). Dystonia was observed in 10 patients and the remaining two patients had head tremor, a "forme-fruste" of cervical dystonia. The underlying etiologies were vascular (n=8), head trauma (n=2), and tumor resection (n=2). Neuroimaging showed isolated involvement of the midbrain in four, thalamus in two, and basal ganglia and cerebellum in one patient each. A combination of the lesion (thalamus and cerebellum=2; cerebellopontine angle=1, and cortical/subcortical=1) was present in four patients. Levodopa responsiveness was seen in 75% of patients including one with levodopa-induced dyskinesia. Of 139 patients from 49 studies, levodopa was tried in 123 patients. Improvement with levodopa was seen in 71 patients (57.72%). No improvement with levodopa was observed in 33 patients (26.82%) and details regarding therapeutic response were unavailable in 19 patients (15.44%). Dystonia is an important clinical manifestation of HT. Levodopa responsiveness seen in the majority of the patients is consistent with the hypothesis that nigrostriatal pathway damage is crucial for the pathophysiology of HT.

Tau-PET and multimodal imaging in clinically atypical multiple system atrophy masquerading as progressive supranuclear palsy

IntroductionMultiple system atrophy (MSA) typically presents with parkinsonism, ataxia and/or autonomic dysfunction. Occasionally, clinically atypical (ca-MSA) cases masquerade as progressive supranuclear palsy (PSP). We aimed to investigate whether different neuroimaging modalities could facilitate differentiation and whether histopathologic characteristics could explain the atypical presentation. MethodsWe identified 3 neuropathologically-defined ca-MSA patients with clinically diagnosed PSP who underwent various antemortem brain imaging: MRI and PET imaging using 11C-Pittsburgh compound B, 18F-flortaucipir, and 18F-fluorodeoxyglucose. We compared clinical features, brainstem planimetry, and radiotracer standardized uptake value ratios in ca-MSA to 10 autopsy-confirmed PSP patients and 10 healthy controls (imaging only). We also compared histologic count of neuronal loss, iron deposition and α-synuclein-immunoreactive glial cytoplasmic inclusion burden to 10 autopsy-confirmed MSA-parkinsonism (MSA-P) cases. ResultsCa-MSA had better PSP Saccadic Impairment Scale scores (p = 0.003) and more frequent good levodopa response (p = 0.061) than PSP. Ca-MSA showed higher midbrain-to-pons ratio and lower Magnetic Resonance Parkinsonism Index than PSP (each, p = 0.036) and exhibited lower glucose metabolism in the putamen and globus pallidus versus PSP (p = 0.017) and controls (p = 0.007). These same regions showed higher flortaucipir uptake in ca-MSA than PSP (p = 0.007 for putamen, p = 0.049 for pallidum) and controls (p = 0.012). Lower flortaucipir retention was observed in the subthalamic nucleus versus PSP (p = 0.007). The putamen-to-subthalamic ratio distinguished ca-MSA from PSP. No histopathological differences were observed for ca-MSA versus typical MSA-P. ConclusionSeverity of saccadic impairment, levodopa responsiveness, MRI planimetric measurements, and different patterns of fluorodeoxyglucose and flortaucipir uptake can help improve antemortem differentiation of MSA masquerading as PSP from true PSP.

Emerging Microbiome Genetic Engineering Technology for Stable Levodopa Delivery in Parkinson’s Disease

Dopamine replacement in the form of a levodopa/carbidopa tablet has been the gold‐standard therapy for Parkinson’s disease (PD) for over six decades. Oral tablet dosing of L‐DOPA 3‐4 times/day is quite efficacious in controlling early‐stage PD symptoms). However, beyond its ~5‐yr clinical honeymoon period, this treatment becomes increasingly associated with L‐DOPA‐induced dyskinesia (LID) and ‘ON‐OFF’ motor complications resulting from the non‐continuous, pulsatile delivery of L‐DOPA to the brain. Addressing this challenge, we devised an innovative strategy to supplement the host’s microbiota with the human probiotic E.coliNissle 1917 (EcN) genetically engineered to continuously produce L‐DOPA (EcNLDOPA) with no significant side effects. By harnessing emerging synthetic biology and genetic engineering technologies, we successfully established four generations of EcNLDOPA(1‐4) and characterized their ability to endogenously synthesize L‐DOPA from tyrosine using the recombinant hpaB/C gene. The initially designed plasmid‐based EcNLDOPA1,2 systems were further improved by developing the chromosome‐integrated and regulatable systems EcN3‐4L‐DOPA using advanced Sce‐ROPE genetic engineering. The steady‐state levels of plasma and brain L‐DOPA, dopamine and its metabolites, as well as gut colonization of EcNLDOPA, were assessed over time. Our results show that all EcNLDOPAstrains effectively generate L‐DOPA in a dose‐ and time‐dependent manner in vitro, indicating that the biotherapeutic dosage can be personalized to each patient’s needs. Our mouse pharmacokinetic studies revealed that steady‐state levels of plasma L‐DOPA and brain dopamine can be achieved by oral administration of EcNLDOPA. Importantly, our pharmacodynamic efficacy studies of the L‐DOPA response in the progressive neurodegenerative MitoPark mouse model of PD showed improved performance in motor, cognitive and mood‐related tasks. Colonization studies show that our EcNLDOPA biotherapeutic requires only once or twice daily dosing. Our novel re‐engineered, self‐replicating EcNLDOPA microbial bio‐therapeutics offers an entirely new L‐DOPA treatment paradigm capable of ensuring long‐term efficacy while minimizing side‐effects

Teaching Video NeuroImage: Congenital Hemidystonia-Hemi-midbrain Atrophy Syndrome.

An 18-year-old man with normal birth and development and a negative family history complained of nonprogressive clumsiness and posturing of his left hand since early childhood. His left limbs were shorter than his right but showed no evidence of atrophy (eFigure 1, A-C, [links.lww.com/WNL/B902][1]). Examination revealed dystonic posturing with mirror dystonia of the left hand and subtle mirror movements in his feet (Video 1). MRI of the brain showed right hemiatrophy of the midbrain, bilateral cortical activation with unilateral finger taps on fMRI, and normal corticospinal tract decussation (Figure, A-F). Levodopa response was present, suggesting dopaminergic denervation due to a congenital hemi-midbrain insult.1 This case represents hemidystonia-hemiatrophy syndrome.2 Subtle limb shortening and mirror dystonia can aid in diagnosis. [1]: http://links.lww.com/WNL/B902

Sensor Measurements Can Characterize Fluctuations and Wearing Off in Parkinson's Disease and Guide Therapy to Improve Motor, Non-motor and Quality of Life Scores.

ObjectivesThe aim was to examine the role of sensor measurement in identifying and managing fluctuations in bradykinesia of Parkinson’s Disease.MethodClinical scales and data from wearable sensors obtained before and after optimization of treatment from 107 participants who participated in a previous study was used. Fluctuators were identified by a levodopa response or wearing off in their sensor data and were subdivided according to whether the sensor’s bradykinesia scores were in target range, representing acceptable bradykinesia for part of the dose (Controlled Fluctuator: n = 22) or above target for the whole dose period (Uncontrolled Fluctuator; n = 28). Uncontrolled Non-fluctuators (n = 24) were cases without a levodopa response or wearing-off and sensor bradykinesia scores above target throughout the day (un-controlled). Controlled Non-fluctuators (n = 33) were below target throughout the day (controlled) and used as a reference for good control (MDS-UPDRS III = 33 ± 8.6 and PDQ39 = 28 ± 18).ResultsTreating Fluctuators significantly improved motor and quality of life scores. Converting fluctuators into Controlled Non-fluctuators significantly improved motor, non-motor and quality of life scores and a similar but less significant improvement was obtained by conversion to a Controlled Fluctuator. There was a significantly greater likelihood of achieving these changes when objective measurement was used to guide management.ConclusionsThe sensor’s classification of fluctuators bore a relation to severity of clinical scores and treatment of fluctuation improved clinical scores. The sensor measurement aided in recognizing and removing fluctuations with treatment and resulted in better clinical scores, presumably by assisting therapeutic decisions.

The Profound Impact of Gastrointestinal Stasis on Levodopa Response in Parkinson's Disease.

Movement Disorders Clinical PracticeVolume 9, Issue 3 p. 394-396 CLINICAL VIGNETTE The Profound Impact of Gastrointestinal Stasis on Levodopa Response in Parkinson's Disease Laura J. Williams MD, Corresponding Author Laura J. Williams MD laurajane.williams@health.nsw.gov.au orcid.org/0000-0003-3077-2960 Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia Correspondence to: Dr. Laura J. Williams, Department of Neurology, Westmead Hospital, Westmead, NSW 2145, Australia; E-mail: laurajane.williams@health.nsw.gov.auSearch for more papers by this authorJane Griffith BNS, Jane Griffith BNS Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, AustraliaSearch for more papers by this authorSophie E. Waller BMed, Sophie E. Waller BMed Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, AustraliaSearch for more papers by this authorVu P. Kwan MD, Vu P. Kwan MD Department of Gastroenterology, Westmead Hospital, Westmead, New South Wales, AustraliaSearch for more papers by this authorVictor S.C. Fung FRACP, PhD, Victor S.C. Fung FRACP, PhD orcid.org/0000-0003-3085-2282 Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author Laura J. Williams MD, Corresponding Author Laura J. Williams MD laurajane.williams@health.nsw.gov.au orcid.org/0000-0003-3077-2960 Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia Correspondence to: Dr. Laura J. Williams, Department of Neurology, Westmead Hospital, Westmead, NSW 2145, Australia; E-mail: laurajane.williams@health.nsw.gov.auSearch for more papers by this authorJane Griffith BNS, Jane Griffith BNS Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, AustraliaSearch for more papers by this authorSophie E. Waller BMed, Sophie E. Waller BMed Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, AustraliaSearch for more papers by this authorVu P. Kwan MD, Vu P. Kwan MD Department of Gastroenterology, Westmead Hospital, Westmead, New South Wales, AustraliaSearch for more papers by this authorVictor S.C. Fung FRACP, PhD, Victor S.C. Fung FRACP, PhD orcid.org/0000-0003-3085-2282 Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author First published: 10 February 2022 https://doi.org/10.1002/mdc3.13425Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume9, Issue3April 2022Pages 394-396 RelatedInformation

Factors affecting postural instability after more than one-year bilateral subthalamic stimulation in Parkinson's disease: A cross-sectional study.

BackgroundBalance impairment in Parkinson’s disease is multifactorial and its changes due to subthalamic stimulation vary in different studies.ObjectiveWe aimed to analyze the combination of predictive clinical factors of balance impairment in patients with Parkinson’s disease treated with bilateral subthalamic stimulation for at least one year.MethodsWe recruited 24 patients with Parkinson’s disease treated with bilateral subthalamic stimulation and 24 healthy controls. They wore an Opal monitor (APDM Inc.) consisting of three-dimensional gyroscopes and accelerometers in the lumbar region. We investigated four stimulation conditions (bilateral stimulation OFF, bilateral stimulation ON, and unilateral right- and left-sided stimulation ON) with four tests: stance on a plain ground with eyes open and closed, stance on a foam platform with eyes open and closed. Age, disease duration, the time elapsed after implantation, levodopa, and stimulation responsiveness were analyzed. The distance of stimulation location from the subthalamic motor center was calculated individually in each plane of the three dimensions. We analyzed the sway values in the four stimulation conditions in the patient group and compared them with the control values. We explored factor combinations (with age as confounder) in the patient group predictive for imbalance with cluster analysis and a machine‐learning‐based multiple regression method.ResultsSway combined from the four tasks did not differ in the patients and controls on a group level. The combination of the disease duration, the preoperative levodopa responsiveness, and the stimulation responsiveness predicted individual stimulation-induced static imbalance. The more affected patients had more severe motor symptoms; primarily, the proprioceptive followed by visual sensory feedback loss provoked imbalance in them when switching on the stimulation.ConclusionsThe duration of the disease, the severity of motor symptoms, the levodopa responsiveness, and additional sensory deficits should be carefully considered during preoperative evaluation to predict subthalamic stimulation-induced imbalance in Parkinson’s disease.

Oculogyric Crisis Phenotype of Levodopa-Induced Ocular Dyskinesia.

Ocular dyskinesia (OD) is an uncommon form of the levodopa induced dyskinesia (LIOD) characterized by short-lasting horizontal or upward conjugate gaze deviation. More sustained deviations resembling oculogyric crises (OGC) are distinctly uncommon.1-4 A 62-yr-old man with a 10-yr history of Parkinson's disease (PD) presented florid ocular dyskinesia mimicking OGC. Levodopa introduction caused increased blinking, up rolling of the eyeballs and dose-dependent restlessness lasting 48 hr with a single dose of 300 mg. Amantadine, safinamide, clonazepam, and dopamine agonists were without benefit, and he stayed off medication for 3 yr. The symptoms recurred after restarting levodopa at age 61. There was no relevant tic, dopamine blocker, encephalitis, or family history. His OFF-UPDRS-III score was 78 (Video 1). Within 10–15 min of levodopa 100 mg increased eyeblink, blepharospasm, right-sided horizontal/upward conjugate eye movements, buccolingual and peribuccal dyskinesia were noted (Video 2). Apomorphine (4 mg) resulted in similar ocular features. MRI brain was normal. Whole-exome sequencing showed variants of unknown significance in GBA p.Arg170His (also in his asymptomatic older sister) and LRRK2 p.Arg1943Trp genes. OD and OGC are two different entities with overlapping features (Table 1). Our patient fulfilled all major proposed criteria for OGC (tonic conjugate eye deviation/lasting minutes-hrs/preserved consciousness), and 2/4 supportive criteria (anxiety, discomfort preceding symptoms/ bothersome symptoms).5 Two (dystonia, low dopamine state improved by anticholinergics/dopaminergic medication) were not met.5 LIOD has been described in 17 patients (Table 2).1-4, 6 All patients presented after ≥3 yr of levodopa and in all but one and ours, the OD was preceded by other dyskinesia. While our patient did not have limb dyskinesia, there were buccolingual dyskinesias present (not present before levodopa therapy). Most patients were unaware of symptoms.1-4, 6 Ocular movements tended to worsen during speaking/performing mental tasks/voluntary limb movements and were temporarily suppressed by will/reading/visual fixation.1-4, 6 In over half (6/9), where gaze deviation details were provided, the deviation occurred towards the more affected by PD body-side (unlike in our patient).1-4, 6 LIOD may be more common than appreciated (e.g., detected in 8/10 patients examined by electrooculography and the remaining two were not assessed at peak levodopa levels).3 Not present Levodopa responsiveness is common in other causes of OGC. In contrast, in addition to our patient there are only two reports of OGC precipitated by levodopa use in patients with parkinsonism.7, 8 The sole report in another patient with presumed PD related to the addition of rasagiline to levodopa (for 10 yr, dose 1000 mg/day).9 Symptoms lasted for 6.5 hr, but in contrast to our case, the patient was also unable to respond, had retrocollis, and foot dystonia.9 The nature of the eye movements in LIOD was proposed to be similar to those generating pursuits or slow phases of nystagmus.3 A role of frontal eye fields, substantia nigra reticulata (SNr), and brainstem nuclei linked with the caudate nucleus was also suggested.1 Recent animal studies demonstrated that selective optical stimulation of caudate tail inhibits SNr neurons projecting to the intermediate superior colliculus layer and leads to prolonged visual-saccadic neuronal excitation and induction of contralateral saccades.6 One hypothesis is that the abnormalities are initially more pronounced in the posterior putamen than in the caudate (oculomotor circuit); therefore, LID spreads from the foot depending on the denervation pattern.1-4 This would explain why LIOD occurs in more advanced PD (when caudate is affected), and with pre-existing dyskinesia. However, this would not explain the symptoms seen in our patient and one other isolated LIOD case, suggesting a different pathogenesis.1-4Further, although amantadine has been recently reported to improve LIOD this was not the case in our patient and these further questions the pathogenic relationship between these rare examples of OGC and more typical examples of LIOD.6 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. D.A.O.: 1A, 1B, 1C, 3A R.S.: 1B, 3B T.S.G.: 1B, 3B V.L.R.: 1B, 3B A.E.L.: 1A, 1B, 1C, 3B L.K.P.: 1A, 1B, 1C, 3B The authors confirm that the approval of an institutional review board was not required for this work. Written informed patient consent was obtained for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors declare that there are no funding sources or conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

Evaluation of morning bradykinesia in Parkinson’s disease in a United States cohort using continuous objective monitoring

IntroductionBradykinesia in Parkinson’s disease is a marker for clinical levodopa responsiveness, with persistent bradykinesia reflecting suboptimal response. We objectively measured prevalence and severity of morning bradykinesia using the Personal KinetiGraph® (PKG®). MethodsRetrospective evaluation of a large global database of de-identified PKG assessments from individuals (N=12,840) in routine clinical care in the United States (US; n=3288). Median bradykinesia scores (mBKS) and median dyskinesia scores (mDKS) were calculated using a validated algorithm and previously established targets to evaluate percent time in bradykinesia, levodopa responsiveness, and prevalence and severity (0–5; 5=highest severity) of morning bradykinesia. ResultsmBKS was above target (≥26) in 65% of all individuals, and mDKS was above target (≥7) in 3%. Elevated percent time in bradykinesia occurred in 79%. Among individuals where levodopa responsiveness could be evaluated (n=1933), 31% had a significant response (≥1.15 postdose decrease in severity). Morning bradykinesia was identified in 85% of individuals with available morning data (1298/1524), and 64% (954/1501) experienced continued bradykinesia after the first daily levodopa dose. Morning bradykinesia was severe (4.0–4.7) in levodopa-responsive individuals regardless of percent time spent in bradykinesia. ConclusionElevated mBKS was very common in the US. Most individuals taking levodopa had morning bradykinesia that persisted even after the first daily dose, and severity was high, indicating a need for additional treatment options.

Determinants of Levodopa Responsiveness in Patients with Vascular Parkinsonism.

Vascular Parkinsonism (VaP) is characterized by symmetric, predominantly lower limb bradykinesia and rigidity and no significant improvement with levodopa. We aimed to describe the clinical and radiological features of patients with VaP and the factors that determine levodopa responsiveness. This is a retrospective chart review of patients with VaP. The study included 44 patients (36 men) with VaP. The diagnosis was based on Zijlman's criteria. Demographic and clinical details were recorded from the case files. MRI data were available for all the patients. However, the motor severity scores assessed in the OFF and ON states using the unified Parkinson's disease rating scale (UPDRS) part III were available for 17 patients only. Based on the Magnetic Resonance Imaging (MRI) finds, patients were categorized into isolated periventricular ischemic (PVI) changes, isolated basal ganglia (BG)/thalamic infarcts, and both combined. The mean age at the diagnosis was 65.2 ± 7.4 years. Further, the age at the onset of symptoms was 61.8 ± 8.1 years and the total disease duration was 3.5 ± 2.5 years. Hypertension was the most common risk factor and was observed in 88.6% of patients. Symmetrical lower body parkinsonism was observed in 88.6%. The mean UPDRS part III OFF score was 33.76 ± 12.7 and ON score was 30 ± 13.98. PVI changes were the most common MRI abnormality detected. Patients with isolated BG/thalamic infarcts had better mini-mental status examination scores and better levodopa responsiveness compared to other groups. Hypertension was the most common risk factor seen in patients with VaP. Those with isolated BG/thalamus infarcts demonstrated better levodopa responsiveness.

Deep Brain Stimulation of the Subthalamic Nucleus and the Postoperative Levodopa Response?

Deep Brain Stimulation of the Subthalamic Nucleus and the Postoperative Levodopa Response?