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Background: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear., Objective: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial)., Methods: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions., Results: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions., Conclusions: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: To assess, in a cross-sectional study, the feasibility and immediate efficacy of laser shoes, a new ambulatory visual cueing device with practical applicability for use in daily life, on freezing of gait (FOG) and gait measures in Parkinson disease (PD)., Methods: We tested 21 patients with PD and FOG, both "off" and "on" medication. In a controlled gait laboratory, we measured the number of FOG episodes and the percent time frozen occurring during a standardized walking protocol that included FOG provoking circumstances. Participants performed 10 trials with and 10 trials without cueing. FOG was assessed using offline video analysis by an independent rater. Gait measures were recorded in between FOG episodes with the use of accelerometry., Results: Cueing using laser shoes was associated with a significant reduction in the number of FOG episodes, both "off" (45.9%) and "on" (37.7%) medication. Moreover, laser shoes significantly reduced the percent time frozen by 56.5% (95% confidence interval [CI] 32.5-85.8; p = 0.004) when "off" medication. The reduction while "on" medication was slightly smaller (51.4%, 95% CI -41.8 to 91.5; p = 0.075). These effects were paralleled by patients' positive subjective experience on laser shoes' efficacy. There were no clinically meaningful changes in the gait measures., Conclusions: These findings demonstrate the immediate efficacy of laser shoes in a controlled gait laboratory, and offer a promising intervention with potential to deliver in-home cueing for patients with FOG., Classification of Evidence: This study provides Class III evidence that for patients with PD, laser shoes significantly reduce FOG severity (both number and duration of FOG episodes)., (Copyright © 2017 American Academy of Neurology.)

Background: Freezing of gait (FOG) is a mysterious, complex and debilitating phenomenon in Parkinson's disease. Adequate assessment is a pre-requisite for managing FOG, as well as for assigning participants in FOG research. The episodic nature of FOG, as well as its multiple clinical expressions make its assessment challenging., Objective: To highlight the available assessment tools and to provide practical, experience-based recommendations for reliable assessment of FOG., Methods: We reviewed FOG assessment from history taking, questionnaires, lab and home-based measurements and examined how these methods account for presence and severity of FOG, their limits and advantages. The practicalities for their use in clinical and research practice are highlighted., Results: According to the available assessment tools severity of FOG is marked by one or a combination of multiple clinical expressions including frequency, duration, triggering circumstances, response to levodopa, association with falls and fear of falling, or need for assistance to avoid falls., Conclusions: To date, a unique methodological tool that encompasses the entire complexity of FOG is lacking. Combining methods should give a better picture of FOG severity, in accordance with the precise clinical or research context. Further development of any future assessment tool requires understanding and thorough analysis of the specific clinical expressions of FOG.

Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H2 (15) 0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa-responsive gait disorders and FoG, and eight age-matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor-parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor-parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper-limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa-responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery., (© 2014 Wiley Periodicals, Inc.)

We examined executive functioning in patients with Parkinson's disease exhibiting, or not, levodopa-resistant freezing of gait (L-FOG). 38 advanced-stage patients with L-FOG were identified in a consecutive series of 400 patients. They were matched with 38 patients without L-FOG. All patients underwent prospective evaluations of cognitive and motor functioning before subthalamic nucleus surgery, and 1 year after. A composite frontal score, a measure of executive functioning, was compared between the two groups. We also examined correlations between the frontal score and the score on the FOG item of the Unified Parkinson Disease Rating Scale II. Results show that after surgery, patients with L-FOG, as a group, were more impaired in executive functioning than control patients. However, individual data analysis showed preserved executive functions in 11 patients with L-FOG. In addition, there was no correlation between L-FOG severity and the degree of executive impairment. Therefore, frontal dysfunction may be one mechanism underlying L-FOG in a number of patients with Parkinson's disease. However, since some patients develop L-FOG despite the preservation of executive functions, lesions or dysfunction of other neuronal structures are likely to be involved., (Copyright © 2013 S. Karger AG, Basel.)

Gait difficulties--including freezing of gait--are frequent and disabling symptoms of advanced Parkinson's disease and other parkinsonian syndromes. They respond poorly to current medical and surgical treatments, making patient management very difficult. The underlying pathophysiology remains largely unknown. The late onset of levodopa resistance of Parkinson's disease gait abnormalities has been suggested to result from the progressive extension of the degenerative process to non-dopaminergic structures involved in locomotion, such as cortico-frontal and brainstem networks. Deficiencies in other neurotransmission systems, involving acetylcholine, serotonin or norepinephrine, have also been evoked. Neuroimaging tools appear well suited to decipher the cerebral substrates of parkinsonian gait disorders and their modulation by dopaminergic medication or deep brain stimulation. Here the main functional and metabolic neuroimaging studies aimed at identifying these cerebral networks are reviewed, in both healthy subjects and parkinsonian patients. After a brief overview of the physiology and pathophysiology of gait control, the methodology, main results and limits of the studies published to date are examined. The most promising methods to examine gait difficulties and their response to currently available treatments are then discussed.

Background: Despite optimum medical management, many patients with Parkinson's disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether methylphenidate--through its combined action on dopamine and noradrenaline reuptake--would improve gait disorders and freezing of gate in patients with advanced Parkinson's disease without dementia who also received subthalamic nucleus stimulation., Methods: This multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinson's disease, severe gait disorders, and freezing of gate despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with ClinicalTrials.gov, number NCT00914095., Findings: We screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps [IQR 26-45]), the patients in the methylphenidate group made fewer steps at 90 days (31 [26-42], F((1, 62))=6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 [SD 7·2] beats per min) and decrease in weight (mean 2·2 [SD 1·8] kg) compared with the placebo group., Interpretation: Methylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinson's disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinson's disease. The long term risk-benefit balance should be further studied., Funding: French Ministry of Health and Novartis Pharma., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Gait disorders and freezing of gait (FOG) are seen in most patients with advanced Parkinson disease. Response to levodopa and deep brain stimulation is variable across patients., State of Art: Thalamic stimulation is ineffective on gait and can even worsen balance when bilaterally applied. Pallidal stimulation moderately improves gait disorders and FOG although this effect tends to wane after three to five years. Stimulation of the subthalamic nucleus (STN) improves levodopa-responsive gait disorders and FOG. However, some patients worsen after STN stimulation and others are better improved under levodopa than under STN stimulation. Synergistic effects of the two treatments have been reported. As for pallidal stimulation, there is a failure of long-term STN stimulation to improve gait, probably due to the involvement of non-dopaminergic pathways as the disease progresses. Levodopa-resistant gait disorders and FOG do not usually benefit from STN stimulation. In the rare cases of levodopa-induced FOG, STN stimulation may be indirectly effective, as it enables reduction or arrest of the levodopa treatment., Perspectives: Pedunculopontine nucleus stimulation has recently been performed in small groups of patients with disabling gait disorders and FOG. Although encouraging, the first results need to be confirmed by controlled studies involving larger series of patients., Conclusions: Overall, gait disorders remain a motor PD symptom that is little improved, or only temporarily, by current pharmacological and surgical treatments. Patient management is complex., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

Two patients with Parkinson's disease with pedunculopontine nucleus (PPN) stimulation for gait impairments reported "trembling vision" during the setting of the electrical parameters, although there was no clinically observable abnormal eye movement. Oculomotor recordings revealed frequency locked voltage dependent vertical or oblique movements of the eye ipsilateral to the active contact, suggesting current spreading to the mesencephalic oculomotor fibres. These results emphasise the difficulty of stimulating this mesencephalic region.

Objective: We studied the effects of subthalamic nucleus (STN) stimulation vs levodopa on freezing of gait (FOG) and gait impairments in a large consecutive series of patients with Parkinson disease with bilateral STN stimulation., Methods: One hundred twenty-three patients performed the Stand Walk Sit Test before and 1 year after surgery both off and on levodopa and off and on stimulation., Results: Before surgery, 25 patients displayed FOG episodes and 48 were unable to complete the Stand Walk Sit Test when off levodopa. Both symptoms were alleviated by levodopa. After surgery, STN stimulation reproduced the improvement induced by levodopa before surgery in all but two patients with FOG and five others unable to walk. In 11 patients, FOG or inability to perform the test first occurred after surgery. In all patients but those experiencing FOG during the Stand Walk Sit Test before surgery, the benefit of STN stimulation did not reach that of levodopa before surgery. In patients with FOG before surgery, the effect of STN stimulation did not differ from that of levodopa either before or after surgery., Conclusions: Overall, subthalamic nucleus stimulation improved levodopa-responsive freezing of gait in most patients, although it was not always as effective as levodopa to improve gait impairments. In addition, surgery can induce gait problems in some patients.

The majority of patients with Parkinson's disease suffer from freezing of gait (FOG), which responds more or less to levodopa. Thalamic stimulation, mainly used in the treatment of tremor dominant Parkinson's disease is ineffective in FOG. GPi stimulation moderately improves FOG, but this effect may abate in the long term. STN stimulation was reported to improve levodopa-responsive FOG. In some patients, the benefit from levodopa is greater than that from STN stimulation, and levodopa and STN stimulation can have additive effects. On the contrary, STN stimulation is ineffective on levodopa-resistant FOG. In the few cases of levodopa-induced FOG, STN stimulation can indirectly be effective, thanks to a great decrease or arrest of levodopa. Stimulation of the pedunculopontine nucleus has recently been performed in small groups of patients suffering from both off- and on-levodopa gait impairments. The first results appear encouraging, but they need to be confirmed by controlled studies in larger series of patients., ((c) 2008 Movement Disorder Society.)