"On" state freezing of gait in Parkinson disease: a paradoxical levodopa-induced complication.
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ABSTRACT: Objective
To describe the phenotype of levodopa-induced "on" freezing of gait (FOG) in Parkinson disease (PD).Methods
We present a diagnostic approach to separate "on" FOG (deterioration during the "on state") from other FOG forms. Four patients with PD with suspected "on" FOG were examined in the "off state" (>12 hours after last medication intake), "on state" (peak effect of usual medication), and "supra-on" state (after intake of at least twice the usual dose).Results
Patients showed clear "on" FOG, which worsened in a dose-dependent fashion from the "on" to the "supra-on" state. Two patients also demonstrated FOG during the "off state," of lesser magnitude than during "on." In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating "off" FOG.Conclusions
True "on" FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating "off" FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least 3 medication states.
SUBMITTER: Espay AJ
PROVIDER: S-EPMC3466608 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundFreezing in the levodopa-medicated-state (ON-state) is a debilitating feature of Parkinson's disease without treatment options. Studies detailing the distinguishing features between people with freezing of gait that improves with levodopa and those whose freezing continues even on levodopa are lacking.ObjectiveTo characterize the gross motor, gait, and non-motor features of this phenotype.MethodsInstrumented continuous gait was collected in the levodopa-medicated-state in 105 patients: 43 non-freezers (no-FOG), 36 with freezing only OFF-levodopa (OFF-FOG) and 26 with freezing both ON- and OFF-levodopa (ONOFF-FOG). Evaluation of motor and non-motor disease features was undertaken using validated scales. A linear mixed model with age, sex, disease duration, and motor UPDRS scores as covariates was used to determine differences in spatiotemporal gait and non-motor disease features among the groups.ResultsCompared to OFF-FOG, the ONOFF-FOG group had greater disease severity (on the Unified Parkinson's disease Rating Scale) and worse cognition (on the Montreal Cognitive Assessment, Frontal Assessment Battery and Scales for Outcome in Parkinson's disease-Cognition scales) and quality of life (on the PDQ-39), but similar mood (on the Hamilton depression and anxiety scales) and sleep quality (on Epworth sleepiness scale and RBD questionnaire). For several gait features, differences between the ONOFF-OFF groups were at least as large and in the opposite direction as differences between OFF-no groups, controlling for disease severity. Variability in ONOFF-FOG was greater than in other groups. Using results from our study and others, a power analysis for a potential future study reveals sample sizes of at least 80 ONOFF and 80 OFF-FOG patients would be needed to detect clinically meaningful differences.ConclusionsIntra-patient variability in spatiotemporal gait features was much greater in ONOFF-FOG than in the other two groups. Our results suggest that multifactorial deficits may lead to ONOFF-FOG development.
| S-EPMC9162361 | biostudies-literature
Project description:BackgroundThe objective of this study was to evaluate ON-state resting state functional connectivity (FC) from the mesencephalic locomotor regions (MLR) to distributed sensorimotor cortical regions in patients with Freezing of Gait (FOG) and its association with gait performance.Methods54 individuals with PD were recruited for this study (50% of whom had FOG). All individuals received a resting state functional MRI in the ON state, and underwent a series of gait assessments during single and dual task conditions. FC with the MLR was calculated using a whole brain seed to voxel approach wherein the left and right MLR seeds were extracted from a published atlas. General linear regression was used to determine differences in connectivity between the individuals with ('freezers') and without ('non-freezers') FOG as well as the correlation between MLR connectivity and gait performance in the freezers.ResultsFreezers had significantly higher MLR connectivity to a network of sensorimotor regions compared to non-freezers. Additionally, among the freezers, higher FC with these regions was related to longer single-task and dual-task performance. There were no regions in which non-freezers had higher connectivity than freezers (p < 0.05, FWE corrected clusters for all analyses).ConclusionThese data support the hypothesis that freezers have significantly higher ON-state FC between the MLR and a network of cortical structures than non-freezers. Additionally, this elevated connectivity is directly related to worsening FOG severity. These data add to a theoretical foundation which suggests that cortical hyperconnectivity to the MLR is central to the underlying pathophysiology of FOG.
| S-EPMC7208449 | biostudies-literature
Project description:Study objectives included testing whether presumed levodopa-unresponsive freezing of gait (FOG) in Parkinson's disease (PD) actually persists in the presence of adequate dopaminergic dosing and to investigate whether the presence of other parkinsonian features and their responsiveness to therapy varies across patients without FOG (NO-FOG), with levodopa-responsive FOG (OFF-FOG), and with levodopa-unresponsive FOG (ONOFF-FOG). Fifty-five PD patients completed levodopa challenges after >12-h OFF with supratherapeutic doses of dopaminergic medications. Observed responses in FOG, measured with MDS-UPDRS-III during the patient reported full "ON", were used to classify them as NO-FOG, OFF-FOG, or ONOFF-FOG. Serum levodopa levels were measured. Only those with ≥20% improvement in MDS-UPDRS-III score were included in analyses. Levodopa challenge was sufficient to bring about a full "ON" state with ≥20% improvement in 45 patients. Levodopa-equivalent-dose utilized was 142 ± 56% of patients' typical morning doses. Overall, 19/45 patients exhibited FOG in the full "ON" state (ONOFF-FOG), 11 were classified as OFF-FOG, and 15 NO-FOG. Linear mixed models revealed a highly significant association between serum levodopa level and total MDS-UPDRS-III score that was similar across groups. The ONOFF-FOG group exhibited significantly higher New-FOG-questionnaire and MDS-UPDRS-II scores compared to the OFF-FOG group. Among MDS-UPDRS-III subdomains significant effects of group (highest in ONOFF-FOG) were identified for other axial parkinsonian features. We found that FOG can persist in the full "ON" state brought about by ample dopaminergic dosing in PD. Other axial measures can also be levodopa-unresponsive among those with ONOFF-FOG only. These data provide evidence that ONOFF-FOG is distinct from responsive freezing.
| S-EPMC6874572 | biostudies-literature
Project description:ObjectiveThe objective of this cross-sectional study was to test the hypothesis that patients with Parkinson disease (PD) and freezing of gait (PD+FOG) would demonstrate sleep disturbances comparable to those seen in patients with REM sleep behavior disorder (RBD) and these changes would be significantly different from those in PD patients without FOG (PD-FOG) and age-matched controls.MethodsWe conducted overnight polysomnography studies in 4 groups of subjects: RBD, PD-FOG, PD+FOG, and controls. Tonic and phasic muscle activity during REM sleep were quantified using EMG recordings from the chin, compared among study groups, and correlated with disease metrics.ResultsThere were no significant differences in measures of disease severity, duration, or dopaminergic medications between the PD+FOG and PD-FOG groups. Tonic muscle activity was increased significantly (p < 0.007) in the RBD and PD+FOG groups compared to the PD-FOG and control groups. There was no significant difference in tonic EMG between the PD+FOG and RBD group (p = 0.364), or in tonic or phasic EMG between the PD-FOG and control group (p = 0.107). Phasic muscle activity was significantly increased in the RBD group compared to all other groups (p = 0.029) and between the PD+FOG and control group (p = 0.001), but not between the PD+FOG and PD-FOG groups (p = 0.059).ConclusionsThese findings provide evidence that increased muscle activity during REM sleep is a comorbid feature of patients with PD who exhibit FOG as a motor manifestation of their disease.
| S-EPMC3795590 | biostudies-literature
Project description:Background and purposeFOG is a troublesome symptom of PD. Despite growing evidence suggesting that FOG in PD may be associated with cognitive dysfunction, the relationship between regional brain atrophy and FOG has been poorly investigated.Materials and methodsOptimized VBM was applied to 3T brain MR images of 24 patients with PD and 12 HC. Patients were classified as either FOG- or FOG+ (n = 12) based on their responses to a validated FOG Questionnaire and clinical observation. All patients with PD also underwent a detailed neuropsychological evaluation.ResultsThe VBM analysis in patients with FOG+ showed a reduced GM volume in the left cuneus, precuneus, lingual gyrus, and posterior cingulate cortex compared with both patients with FOG- and HC. We did not detect any significant change of GM volume when comparing HC versus all patients with PD (FOG- and FOG+). FOG clinical severity was significantly correlated with GM loss in posterior cortical regions. Finally, patients with FOG+ scored lower on tests of frontal lobe function.ConclusionsOur findings provide the first evidence that the development of FOG in patients with PD is associated with posterior GM atrophy, which may play a role in the complex pathophysiology of this disabling symptom.
| S-EPMC7964749 | biostudies-literature
Project description:Objective: Determine if NC001, an oral formulation of nicotine that reduces levodopa-induced dyskinesias (LIDs) in MPTP-Parkinson monkeys, could reduce falls, freezing of gait (FOG), and LIDs in Parkinson disease (PD) patients. Methods: Previously collected data from a study analyzing the effects of NC001 on LIDs in PD patients were reanalyzed. Because indirect-acting cholinergic drugs are sometimes helpful in reducing falls, we hypothesized that NC001, a direct-acting cholinergic agonist, could reduce falls in PD. The original 12-center, double-blind, randomized trial enrolled 65 PD patients. NC001 or placebo was administered 4 times per day for 10 weeks, beginning at 4 mg/day and escalating to 24 mg/day. Assessments included the Unified Dyskinesia Rating Scale (UDysRS) and Parts II-III of the original Unified Parkinson's Disease Rating Scale (UPDRS). Results: Randomization (1:1) resulted in 35 patients on NC001 and 30 on placebo at baseline. Thirty and 27 patients, respectively, had data available for an intent-to-treat analysis. NC001 was safe and well-tolerated. After 10 weeks, NC001 patients (14/30) had a significant reduction in falls vs. placebo patients (3/27) (p = 0.0041) as assessed by UPDRS Part II. NC001 patients (12/30) also had significantly reduced FOG vs. placebo patients (4/27) (p = 0.0043). NC001 patients, compared with placebo patients, had a significant improvement (p = 0.01) in UDysRS ambulation subtest (40% vs. 3%, respectively). Although NC001 patients had a greater reduction in dyskinesias on the UDysRS than placebo patients (30% vs. 19%, respectively), this was not significant (p = 0.09). Conclusions: NC001 significantly improved two refractory symptoms of PD, falls and FOG. The reduction in falls and FOG is attributed to selective stimulation of nicotinic receptors. Clinical Trial Registration: Conducted under IND 105, 268, serial number 0000. ClinicalTrials.gov identifier NCT00957918.
| S-EPMC6514133 | biostudies-literature
Project description:Introduction. It is well documented that freezing of gait (FoG) episodes occur in situations that are mentally challenging, such as dual tasks, consistent with less automatic control of gait in people with Parkinson disease (PD) and FoG. However, most physical rehabilitation does not include such challenges. The purpose was to determine (1) feasibility of a cognitively challenging Agility Boot Camp-Cognitive (ABC-C) program and (2) effects of this intervention on FoG, dual-task cost, balance, executive function, and functional connectivity. Methods. A total of 46 people with PD and FoG enrolled in this randomized crossover trial. Each participant had 6 weeks of ABC-C and Education interventions. Outcome measures were the following: FoG, perceived and objective measures; dual-task cost on gait; balance; executive function; and right supplementary motor area (SMA)-pedunculopontine nucleus (PPN) functional connectivity. Effect sizes were calculated. Results. ABC-C had high compliance (90%), with a 24% dropout rate. Improvements after exercise, revealed by moderate and large effect sizes, were observed for subject perception of FoG after exercise, dual-task cost on gait speed, balance, cognition (Scales for Outcomes in Parkinson's disease-Cognition), and SMA-PPN connectivity. Conclusions. The ABC-C for people with PD and FoG is a feasible exercise program that has potential to improve FoG, balance, dual-task cost, executive function, and brain connectivity. The study provided effect sizes to help design future studies with more participants and longer duration to fully determine the potential to improve FoG.
| S-EPMC7217755 | biostudies-literature
Project description:IntroductionExercise improves gait in Parkinson disease (PD), but whether exercise differentially affects people with PD with (freezers) and without freezing of gait (non-freezers) remains unclear. This study examines exercise's effects on gait performance, neural correlates related to these effects, and potential neural activation differences between freezers and non-freezers during motor imagery (MI) of gait.MethodsThirty-seven participants from a larger exercise intervention completed behavioral assessments and functional magnetic resonance imaging (fMRI) scans before and after a 12-week exercise intervention. Gait performance was characterized using gait velocity and stride length, and a region of interest (ROI) fMRI analysis examined task-based blood oxygen-level dependent (BOLD) signal changes of the somatomotor network (SMN) during MI of forward (IMG-FWD) and backward (IMG-BWD) gait.ResultsVelocity (F(1,34) = 55.04, p < 0.001) and stride length (F(1,34) = 77.58, p < 0.001) were significantly lower for backward versus forward walking in all participants. The ROI analysis showed freezers had lower BOLD signal compared to non-freezers in the cerebellum (F(1,32) = 7.01, p = 0.01), primary motor (left: F(1,32) = 7.09, p = 0.01; right: F(1,32) = 7.45, p = 0.01), and primary sensory (left: F(1,32) = 9.59, p = 0.004; right: F(1,32) = 8.18, p = 0.007) cortices during IMG-BWD only. The evidence suggests the exercise intervention did not affect gait or BOLD signal during MI.ConclusionWhile all participants had significantly slower and shorter backward velocity and stride length, respectively, the exercise intervention had no effect. Similarly, BOLD signal during MI did not change with exercise; however, freezers had significantly lower BOLD signal during IMG-BWD compared to non-freezers. This suggests potential decreased recruitment of the SMN during MI of gait in freezers.
| S-EPMC6120800 | biostudies-literature
Project description:The relationship between dopaminergic treatment and freezing of gait (FOG) in Parkinson's disease (PD) is complex: levodopa is the most effective symptomatic treatment for FOG, but long-term pulsatile levodopa treatment has also been linked to an increase in the occurrence of FOG. This concept, however, continues to be debated. Here, we compared the occurrence of FOG between a levodopa-naive PD cohort and a levodopa-treated cohort. Forty-nine treatment-naive patients and 150 levodopa-treated patients were included. The time since first motor symptoms was at least 5 years. Disease severity was assessed using the MDS-UPDRS part III. Occurrence of FOG was assessed subjectively (new freezing-of-gait-questionnaire) and objectively (rapid turns test and Timed Up-and-Go test). The presence of FOG was compared between the levodopa-treated and levodopa-naive groups using a chi-square test of homogeneity. We also performed a binomial Firth logistic regression with disease duration, disease severity, country of inclusion, location of measurement, and executive function as covariates. Subjective FOG was more common in the levodopa-treated cohort (n = 41, 27%) compared to the levodopa-naive cohort (n = 2, 4%, p < 0.001). The association between FOG and levodopa treatment remained after adjustment for covariates (OR = 6.04, 95%Cl [1.60, 33.44], p = 0.006). Objectively verified FOG was more common in the levodopa-treated cohort (n = 21, 14%) compared to the levodopa-naive cohort (n = 1, 2%, p = 0.02). We found an association between long-term pulsatile levodopa treatment and an increased occurrence of FOG. Future studies should further explore the role of nonphysiological stimulation of dopamine receptors in generating FOG, as a basis for possible prevention studies.
| S-EPMC10492797 | biostudies-literature
Project description:This study investigated the risk factors for freezing of gait (FOG) in the early stage of Parkinson disease in China, using a sample of 248 patients who were followed for 3 years. Part III of the Unified Parkinson Disease Rating Scale and the modified Hoehn-Yahr grading scale were used to evaluate the severity of motor symptoms. Nonmotor symptoms were assessed using the Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale (HAMD), and Non-Motor Symptoms Scale (NMSS). The end-point was the presence of FOG at the end of follow-up; patients with FOG were classified as freezers. The risk factors for FOG were analyzed at the end of the first, second, and third years after baseline. There were 40 freezers (16.13%) 1 year later, 98 (39.52%) 2 years later, and 128 (51.61%) 3 years later. FOG 3 years later was associated with the following variables: depression (P = 0.003), older age, living in the countryside, lower education, akinetic-rigid style, lower limbs as site of onset, early use of levodopa, higher daily dose of levodopa, and not using amantadine or selegiline and dopamine receptor agonists (P < 0.001). Early use of amantadine, selegiline, and dopamine receptor agonists was negatively related to FOG (P < 0.001). Binary logistic regression found that FOG was associated with lower education (odds ratio [OR] = 0.012, P < 0.001), akinetic-rigid style (OR = 4.881, P = 0.024), not using dopamine receptor agonists (OR = 4.324, P = 0.035), cognitive disturbances (OR = 0.331, P = 0.007), and sleep disorders (OR = 2.418, P = 0.036). However, the cardiovascular domain of the NMSS (OR = 2.729, P = 0.001) was the only risk factor for FOG 1 year later. Two years later, FOG was associated with mixed style (OR = 0.189, P = 0.005), lower limbs as site of onset (OR = 4.772, P = 0.008), not using dopamine receptor agonists (OR = 0.031, P < 0.001), and the anxiety/somatic domain of the HAMD (OR = 0.596, P = 0.033). Scores at baseline, patients with Parkinson disease were more likely to experience FOG if: they were older, or from the countryside; had an akinetic-rigid style, anxiety, or higher NMSS scores; they used levodopa early or did not use amantadine or selegiline; their lower limbs were the site of onset; or they had more severe motor disability or higher HAMD scores at baseline.
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