Arnaud Delval

Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial

BACKGROUND Despite optimum medical management, many patients with Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinsons disease. The long term risk-benefit balance should be further studied. FUNDING French Ministry of Health and Novartis Pharma.

Prevalence, determinants, and effect on quality of life of freezing of gait in Parkinson disease.

IMPORTANCE Freezing of gait (FOG) is a common axial symptom of Parkinson disease (PD). OBJECTIVE To determine the prevalence of FOG in a large group of PD patients, assess its relationship with quality of life and clinical and pharmacological factors, and explore its changes from the off to on conditions in patients with motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional survey of 683 patients with idiopathic PD. Scores for FOG were missing in 11 patients who were not included in the analysis. Patients were recruited from referral centers and general neurology clinics in public or private institutions in France. EXPOSURE Patients with FOG were identified as those with a score of 1 or greater on item 14 of the Unified Parkinsons Disease Rating Scale (UPDRS) in the on condition. Item 14 scores for FOG in the off condition were also collected in patients with fluctuating motor symptoms. MAIN OUTCOMES AND MEASURES Quality of life (measured by the 39-item Parkinsons Disease Questionnaire and 36-Item Short Form Health Survey), anxiety and depression (Hospital Anxiety and Depression Scale), clinical features (UPDRS), and drug consumption. RESULTS Of 672 PD patients, 257 reported FOG during the onstate (38.2%), which was significantly related to lower quality of life scores (P < .01). Freezing of gait was also correlated with longer PD duration (odds ratio, 1.92 [95% CI, 1.28-2.86]), higher UPDRS parts II and III scores (4.67 [3.21-6.78]), the presence of apathy (UPDRS item 4) (1.94 [1.33-2.82]), a higher levodopa equivalent daily dose (1.63 [1.09-2.43]), and more frequent exposure to antimuscarinics (3.07 [1.35-6.97]) (logistic regression). The FOG score improved from the off to on states in 148 of 174 patients with motor fluctuations (85.1%) and showed no change in 13.8%. The FOG score improved by more than 50% in 43.7% of patients. Greater improvement in the on state was observed in younger patients (r = -0.25; P < .01) with lower UPDRS II and III scores (r = -0.50; P < .01) and no antimuscarinic use (r = -0.21; P < .01). CONCLUSIONS AND RELEVANCE Freezing of gait in PD patients correlates with poor quality of life, disease severity, apathy, and exposure to antimuscarinics. Dopaminergic therapy improved FOG in most patients with motor fluctuations, especially younger ones with less severe disease and no antimuscarinic use. This finding suggests that quality of life is impaired in PD patients with FOG and that optimizing dopaminergic therapy and avoiding antimuscarinics should be considered.

Role of hypokinesia and bradykinesia in gait disturbances in Huntington's disease : A biomechanical study

ObjectiveTo evaluate specific patterns of locomotion in Huntingtons disease (HD) and notably the respective roles of hypokinesia (i. e. a decrease in the amplitude of movement) and bradykinesia (i. e. difficulty in executing a movement, slowness) in gait disturbance.MethodsKinematic, spatial (stride length, speed), temporal (cadence, speed, and stride time) and angular gait parameters (joint ankle range) were recorded in 15 early–stage HD patients by means of a video motion analysis system and then compared with 15 controls and 15 Parkinsons disease (PD) patients. Hypokinesia was studied in terms of both spatial (decrease in stride length) and angular gait parameters (decrease in joint ankle range), whereas hyperkinesia was characterized by an increase in joint ankle range. Bradykinesia (defined by a decrease in gait velocity) was also assessed in terms of temporal parameters (cadence, stride time). We studied the influence of clinical symptoms (motor dysfunction, chorea, overall disability and cognitive impairment) and the CAG repeat number on gait abnormalities.Resultswe observed a clear decrease in gait speed, a decrease in cadence and an increase in stride time (i. e. bradykinesia) for HD, with significant intra–individual variability. Cadence remained normal in PD. In HD, there was no evidence for a clear decrease in stride length, although the latter is a characteristic feature of hypokinetic gait (such as that observed in PD). Angle analysis revealed the coexistence of hyperkinesia and hypokinesia in HD, which thus participate in gait abnormalities. Gait speed in HD was correlated to the motor part of the UHDRS.ConclusionGait in HD is mainly characterized by a timing disorder: bradykinesia was present, with severe intra–individual variability in temporal gait parameters.

Objective detection of subtle freezing of gait episodes in Parkinson's disease†‡

Freezing of gait (FOG) is a clinically defined phenomenon of Parkinsons disease (PD). Recent evidence suggests that subtle FOG episodes can be elicited in a gait laboratory using suddenly appearing obstacles during treadmill walking. We evaluated which quantitative gait parameters identify such subtle FOG episodes. We included 10 PD patients with FOG, 10 PD patients without FOG, and 10 controls. Subjects walked on a motorized treadmill while avoiding unexpectedly appearing obstacles. Treadmill walking was videotaped, and FOG episodes were identified by two independent experts. Gait was also analyzed using detailed kinematics. Knee joint signals were processed using time–frequency analysis with combinations of sliding fast Fourier transform and wavelets transform. Twenty FOG episodes occurred during treadmill walking in 5 patients (all with clinically certified FOG), predominantly in relation to obstacle avoidance. FOG was brief when it occurred just before or after obstacle crossing and was characterized by short, rapid steps. Frequency analysis showed a typical qualitative pattern: before the FOG episode an increase in dominant frequency in the 0 to 3 Hz band (festination), followed by decreased power in 0 to 3 Hz band and an increased power in the 3 to 8 Hz band during the FOG episode. This pattern led to an increased FOG index as a qualitative measure. These approaches detected even very brief FOG with acceptable sensitivity (75–83%) and specificity (>95%). We conclude that time–frequency analysis is an appropriate approach to detect brief and subtle FOG episodes. Future work will need to decide whether this approach can support or even replace expert clinical opinion.

External globus pallidus stimulation modulates brain connectivity in Huntington's disease.

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntingtons disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Role of attentional resources on gait performance in Huntington's disease.

Patients with Huntingtons disease (HD) suffer from cognitive deficits with impaired executive functions, including limited attentional resources. We sought to use a dual‐task paradigm to evaluate attentional demands and the ability of patients with HD to concentrate on two tasks simultaneously. We analyzed the interference effects of cognitive and motor tasks on walking in HD and the contribution of clinical symptoms to gait disturbances. Patients and controls were asked to perform either a motor task (carrying a tray with four glasses), a cognitive task (counting backwards), or no task at all while walking at their preferred speed. Kinematic spatial parameters, temporal parameters, and angular parameters related to gait were recorded in 15 patients and 15 controls by means of a videomotion analysis system. Gait instability was assessed using the stride‐to‐stride variability of the various gait parameters. For patients with HD, performing a concurrent cognitive task resulted in a lower gait speed (compared with free walking), with decreased cadence and stride length. However, this effect was not observed in controls. Performing a motor task did not change any kinematic gait parameters in either HD or control subjects. We found correlations between gait speed in the dual cognitive/walking task on one hand and the motor UHDRS score, cognitive status and executive function on the other. Patients with HD had greater difficulty walking while performing a concurrent cognitive task; the drain on attentional resources deteriorated walking performance.

Freezing of Gait

Freezing of gait (FOG) is a common and disabling feature of Parkinsons disease, with unexpected episodes during which patients experience an inability to start walking or to continue moving forward. We present a practical algorithm to ascertain the diagnosis. Treatment may be challenging, but several pharmacological and physiotherapeutic options exist.

Effect of external cueing on gait in Huntington's disease

In Huntingtons disease (HD) patients, gait is characterized by a timing disorder with marked intraindividual variability in temporal gait parameters (caused by the presence of both hyperkinetic and hypokinetic features). We sought to determine the influence of use of a metronome on gait parameters in patients simultaneously performing motor or cognitive tasks that required attentional resources. The objective is to evaluate the influence of rhythmic cues on gait interference during self‐regulated walking and a dual task paradigm in HD. Fifteen HD patients and 15 paired controls were asked to walk and simultaneously perform another motor task (carrying a tray with four full glasses) or a cognitive task (counting backwards). We evaluated the effect of a metronome (set at 100% and 120% of the subjects self‐determined cadence) in three different task conditions (gait alone, gait + motor task, gait + cognitive task). The use of auditory cues during free gait and dual tasks did not improve kinematic parameters in HD patients, in contrast to the situation for control subjects (improvement in gait speed and cadence but not stride length when the metronome was set at 120% in all conditions). HD patients have difficulty in synchronizing their footsteps with a metronome, mainly due to attentional deficits.

Auditory cueing of gait initiation in Parkinson's disease patients with freezing of gait

OBJECTIVE Impaired gait initiation (GI) in patients with advanced Parkinsons disease (PD) is a typical functional sign of akinesia. Failure to initiate the first step is frequently presented by patients with freezing of gait (FOG) and is often considered a sub-type of freezing. The literature on the effects of cueing of GI preparation and execution remains controversial. Our objective was to establish whether auditory cueing improves the preparation and/or execution of GI in PD patients with a history of FOG. METHODS We recorded first-step preparation and execution in 30 PD patients with confirmed FOG under two randomised conditions: self-triggered (ST) gait and gait cued by a sound beep in off- and on-dopa conditions. Anticipatory postural adjustments (APAs) were evaluated by monitoring the trajectory of the centre of pressure. RESULTS We compared the patients with 30 patients without history of FOG and 30 healthy controls (HCs). l-Dopa only slightly improved the characteristics of APAs in freezers but was effective to improve gait hypokinesia. Auditory cueing was effective in improving step preparation in freezers, who showed adequate APAs more frequently. As seen with HCs and patients without FOG, patients released their APAs more quickly when auditory cueing was applied. However, cueing did not have a significant effect on step length. Clinically, auditory cueing also improved start hesitation in freezers. CONCLUSIONS Auditory cueing improved step preparation but not step execution in PD patients. SIGNIFICANCE A failure to link step preparation and execution during GI may explain the poor first-step execution seen in PD freezers.

Association between caffeine intake and age at onset in Huntington's disease

Habitual consumption of caffeine, a non-selective adenosine receptor (AR) antagonist, has been suggested to be beneficial in Parkinsons and Alzheimers diseases. Experimental evidence support that ARs play a role in Huntingtons disease (HD) raising the hypothesis that caffeine may be a life-style modifier in HD. To determine a possible relationship between caffeine consumption and age at onset (AAO) in HD, we retrospectively assessed caffeine consumption in 80 HD patients using a dietary survey and determined relationship with AAO. Following adjustment for gender, smoking status and CAG repeat length, caffeine consumption greater than 190mg/day was significantly associated with an earlier AAO. These data support an association between habitual caffeine intake and AAO in HD patients, but further studies are warranted to understand the link between these variables.