Seizure recurrences in generalized convulsive status epilepticus under sedation: What are its predictors and its impact on outcome?

BACKGROUND: Management of status epilepticus (SE) is focused on the early seizure termination. Refractory SE is an indication for sedation in patients with SE, but up to 75% of patients may be ventilated due to a neurological or respiratory failure. In patients requiring sedation, the clinical assessment is not sufficient to assess seizure control. Identifying those at risk of recurrent seizures could be useful to adapt their management. On the other hand, patients with low risk could benefit from an early withdrawal of sedation to avoid the impact of inappropriate sedation on outcome. OBJECTIVE: To determine the prevalence and the predictors of uncontrolled SE and its impact on outcome in patients with generalized convulsive SE (GCSE) requiring mechanical ventilation (MV). METHODS: We retrospectively included patients admitted to the intensive care unit with GCSE requiring MV. Uncontrolled SE was defined as persistent or recurrent seizures during sedation or within 24hours following withdrawal. A multivariable logistic regression model was used to assess the associated factors. RESULTS: Uncontrolled SE occurred in 37 out of 220 patients (17%). Persistent seizures at admission, higher SAPS II and central nervous system infection were associated with a higher risk of uncontrolled SE. Acute toxic or metabolic etiologies were associated with a decreased risk of uncontrolled SE. In a supplementary analysis, decrease of albumin blood levels was associated with uncontrolled SE. Uncontrolled SE was associated with a poor functional outcome and mortality at 90 days. CONCLUSIONS: Seventeen percent of patients with a GCSE requiring MV suffered from uncontrolled SE. Etiology and persistent seizures at admission were the main predictors of uncontrolled SE. Patients with uncontrolled SE had a longer duration of sedation and MV, a poor functional outcome and a higher mortality. Further studies are required to determine the impact of continuous electroencephalogram monitoring on the clinical course.

L-DOPA-induced dyskinesias, motor fluctuations and health-related quality of life: the COPARK survey.

BACKGROUND AND PURPOSE: Studies assessing the correlations between L-DOPA-induced dyskinesias (LIDs) and motor fluctuations with health-related quality of life (HRQoL) in Parkinson's disease (PD) have yielded conflicting results. This study aimed to assess the relationship between LIDs and motor fluctuations with HRQoL in patients with PD, and to assess the relative contribution of their severity and duration in a large sample of patients with PD. METHODS: A total of 683 patients with PD from the COPARK survey were evaluated. HRQoL was assessed using the 39-Item Parkinson's Disease Questionnaire (PDQ-39) (primary outcome) and 36-Item Short Form Survey (SF-36). The daily duration and severity of LIDs were obtained from Unified Parkinson's Disease Rating Scale (UPDRS) IV items 32 and 33, respectively. The daily duration of motor fluctuations was obtained from UPDRS IV item 36 and severity was estimated as the difference between the UPDRS 2 (Activities of Daily Living) score in 'OFF' versus 'ON' condition. RESULTS: A total of 235 patients with PD (35%) experienced motor fluctuations and 182 (27%) experienced LIDs. The PDQ-39 total and SF-36 physical scores were significantly worse in patients with LIDs, after adjusting for the presence of motor fluctuations. The PDQ-39 total score and SF-36 physical and mental score were significantly worse in patients with motor fluctuations, after adjusting for the presence of LIDs. The severity of LIDs and the duration of motor fluctuations significantly and independently affected PDQ-39 scores. The SF-36 physical score was affected only by the severity of motor fluctuations, whereas the mental score was not affected by any of the aforementioned variables. CONCLUSION: Our findings suggest that LIDs (mainly their severity) and motor fluctuations (mainly their duration) correlate independently with HRQoL in patients with PD.

Functional connectivity disruptions correlate with cognitive phenotypes in Parkinson's disease.

Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p < 0.001, corrected using permutation test) were mainly frontotemporal alterations. A statistically significant correlation (ρ = 0.49, p < 0.001) was also obtained between a proposed network-based index and the patients' cognitive score. Global properties of network topology in patients were relatively intact. These findings indicate that functional connectivity decreases with the worsening of cognitive performance and loss of frontotemporal connectivity may be a promising neuromarker of cognitive impairment in Parkinson's disease.

Characterization and quantification of freezing of gait in Parkinson's disease: Can detection algorithms replace clinical expert opinion?

Freezing of gait is a paroxysmal phenomenon that is frequently reported by the parkinsonian patients or their entourage. The phenomenon significantly alters quality of life but is often difficult to characterize in the physician's office. In the present review, we focus on the clinical characterization and quantification of freezing of gait. Various biomechanical methods (based mainly on time-frequency analysis) can be used to determine time-domain characteristics of freezing of gait. Methods already used to study non-gait freezing of other effectors (the lower limbs, upper limbs and orofacial area) are also being developed for the analysis of freezing in functional magnetic resonance imaging protocols. Here, we review the reliability of these methods and compare them with reliability of information obtained from physical examination and detailed analysis of the patient's medical history.

Brain metabolic abnormalities during gait with freezing in Parkinson's disease.

INTRODUCTION: Freezing of gait (FoG) is a debilitating gait disorder in Parkinson's disease (PD). In advanced PD patients with FoG, the supraspinal locomotor network may be dysregulated (relative to similar patients without FoG) during gait. Here, we sought to characterize the metabolism of locomotor networks involved in FoG. METHODS: Twenty-two PD patients (11 with off-drug FoG and 11 without) each underwent two [(18)F]-fluorodeoxyglucose PET brain scans in the off-drug state: one at rest and another during radiotracer uptake while performing a standardized gait trajectory that incorporated the usual triggers for FoG. RESULTS: For the 11 freezers, FoG was present for 39% (± 23%) of the time during the gait trajectory. The FoG-associated abnormalities were characterized by (i) hypometabolism in frontal regions (the associative premotor, temporopolar and orbitofrontal areas, i.e. Brodmann areas 6 and 8), (ii) hypermetabolism in the paracentral lobule (Brodmann area 5), and (iii) deregulation of the basal ganglia output (the globus pallidus and the mesencephalic locomotor region). CONCLUSION: FoG during a real gait task was associated with impaired frontoparietal cortical activation, as characterized by abnormally low metabolic activity of the premotor area (involved in the indirect locomotor pathway) and abnormally high metabolic activity of the parietal area (reflecting the harmful effect of external cueing).

Somatosensory evoked potentials in the assessment of peripheral neuropathies: Commented results of a survey among French-speaking practitioners and recommendations for practice.

BACKGROUND: Somatosensory evoked potentials (SSEPs) are increasingly performed for the assessment of peripheral neuropathies, but no practical guidelines have yet been established in this specific application. STUDY AIM: To determine the relevant indication criteria and optimal technical parameters for SSEP recording in peripheral neuropathy investigation. METHODS: A survey was conducted among the French-speaking practitioners with experience of SSEP recording in the context of peripheral neuropathies. The results of the survey were analyzed and discussed to provide recommendations for practice. RESULTS: SSEPs appear to be a second-line test when electroneuromyographic investigation is not sufficiently conclusive, providing complementary and valuable information on central and proximal peripheral conduction in the somatosensory pathways. CONCLUSIONS: Guidelines for a standardized recording protocol, including the various parameters to be measured, are proposed. CLINICAL RELEVANCE: We hope that these proposals will help to recognize the value of this technique in peripheral neuropathy assessment in clinical practice.

Gait and attentional performance in freezers under methylphenidate.

BACKGROUND: Attentional resources appear to be involved in the occurrence of FoG. The Parkgait study recently reported that methylphenidate reduces gait hypokinesia and freezing of gait (FoG) in advanced PD patients receiving STN-DBS in the off-dopaminergic drug condition. Methylphenidate is considered to improve attention. The primary objective of the present ancillary study was to determine whether methylphenidate reduced the interference between a cognitive task and gait in patients with FoG. The study's secondary objective was to compare attentional performance in methylphenidate-treated and placebo-treated patients. METHODS: A total of 24 patients (from two centers) were included in the study. Patients were randomly assigned 1:1 to a three-month course of methylphenidate (1mg/kg/day) or placebo. Patients were assessed after an acute L-dopa challenge. The primary outcome criterion was the stride length ratio ((dual-task stride length minus free gait stride length)/free gait stride length). Trials with FoG episodes were excluded from the analysis. Secondary outcomes included changes in reaction times for computerized attention tasks and FoG severity. RESULTS: When comparing patients receiving methylphenidate with those receiving placebo, we did not observe any significant differences in the interaction between the dual task and gait or in attentional performance. CONCLUSION: As in the main Parkgait study, methylphenidate did not reduce gait hypokinesia in patients receiving dopaminergic treatment. Our present results suggest that the reduction in the number of FoG episodes previously observed in patients on methylphenidate was neither due to interaction between a dual-task and gait nor an increase in attentional performance.

Does overestimation of an object's mass during arm-raising modify postural adjustments?

By using a dummy weight during an arm-raising movement, we sought to determine whether (i) postural adjustments are modified and (ii) the required focal movement can be performed adequately. Standing on a force platform, 30 healthy young adults performed voluntary, arm-raising movements with cube-shaped boxes: a small 1 kg box, a large 4 kg box and a large 1 kg box (i.e. the dummy weight, which looked as if it weighed 4 kg). Postural adjustments were quantified in terms of the latency, intensity and duration of the positive phase of the vertical torque (Tz) and displacements of the center of pressure. Lifting the dummy and lifting the small 1 kg box were associated with similar arm velocity curves. The characteristics of the positive Tz phase for the dummy box were intermediate between those observed for the small 1 kg box and the large 4 kg box. There were no differences between the three box-lifting conditions in terms of the latency and duration of Tz. We conclude that overestimation of the dummy's mass was rapidly corrected by a feedback mechanism. Postural control was modified online as soon as the dummy's true weight was perceived, which therefore enabled the maintenance of balance and adequate execution of the voluntary (focal) movement.

Biomechanical mechanisms and centre of pressure trajectory during planned gait termination.

AIM: Although gait initiation has been extensively studied, gait termination has received less attention. In particular, the trajectory of the centre of pressure (CoP) during gait termination, as well as the trajectory's determinants, has not yet been described. The purpose of the present study was to characterize the kinetic components of planned gait termination (including the CoP trajectory) with respect to the various gait events and centre of mass speed and trajectory. METHODS: Thirty healthy subjects were asked to walk along a test track and stop on a force platform while an optoelectronic system recorded temporal and spatial parameters. A total of 90 trials were analysed. RESULTS: Subjects needed two steps to stop on the force platform. The CoP trajectory during gait termination was composed of three phases. During the first phase, the CoP moved forward under the stance foot, which was in contact with the ground. The ground reaction forces exerted a sagittal braking action. The second phase showed a lateral CoP shift and was correlated with braking; this may correspond to anticipatory postural adjustments for gait termination. The third and last phase might correspond to compensatory adjustments before the stance phase. CONCLUSIONS: CoP trajectory is more complex during gait termination than during gait initiation. Gait termination comprises several specific sequences in the gait-stance transition. A better understanding of the kinetic parameters in gait termination should enable us to identify which kinetic parameters could be considered as risk factors for falls.

Why we should study gait initiation in Parkinson's disease.

The gait initiation process is of particular interest in Parkinson's disease because it combines motor and cognitive components of movement preparation (referred to as anticipatory postural adjustments) and movement execution (the step by itself). Moreover, gait initiation in Parkinson's disease is often affected by motor blocks (a subtype of the "freezing of gait" phenomenon). Gait initiation disturbances in Parkinson's disease include delayed release of anticipatory postural adjustments, hypokinetic anticipatory postural adjustments (reduced scaling) and bradykinetic anticipatory postural adjustments (abnormal timing). The most extreme form is freezing of gait with sometimes the absence of anticipatory postural adjustments. Other phenomena can be also described in some freezing patients (such as multiple anticipatory postural adjustments, described clinically as "knee trembling"). The fact that emotion, attention, external triggers and dopaminergic drugs can all modify this motor program suggests the existence of a complex pathophysiological mechanism that involves not only locomotor networks but also cortical areas and the basal ganglia system. Abnormal coupling between standing posture and anticipatory postural adjustments and between the latter and step execution appears to be a crucial part of the pathophysiological mechanism. Although external cueing appears to be of interest, few studies have provided evidence of the efficacy of various rehabilitation methods in routine care.

Stimulus-driven attention modulates the release of anticipatory postural adjustments during step initiation.

OBJECTIVE: Step initiation can be modified by environmental stimulations, suggesting the involvement of stimulus-driven attention. Therefore, we assessed the influence of attentional status during step preparation. METHODS: Fourteen healthy, young subjects were presented with an auditory oddball paradigm in which an infrequent "target" stimulus was presented among frequent "standard" stimuli. An imperative visual "Go" signal for step initiation was presented 1.4s after the auditory stimulus. Both the P300 event-related potential (associated with the auditory attention task) and the trajectory of the centre of pressure (associated with step initiation) were recorded. RESULTS: When presented before the visual "Go" signal, the auditory stimuli prompted the early release of low-amplitude anticipatory postural adjustments, not followed by step execution. They occurred twice as frequently in the "target" condition as they did in the "standard" condition. P300 component was greater after presentation of the target stimulus than after presentation of the standard stimulus. CONCLUSION: Stimulus-driven attention can modify the release of anticipatory postural adjustments. SIGNIFICANCE: The cortical integration of an auditory stimulus (as evidenced by the P300 component) in a subject conditioned to initiate gait appears to release postural adjustments via two different attentional mechanisms: an "alerting effect" and an "orienting effect".

Split-belt locomotion in Parkinson's disease with and without freezing of gait.

BACKGROUND: Parkinson's disease (PD) patients have an increased gait asymmetry and variability, which is most pronounced in patients with freezing of gait (FOG). We examined if stride time variability and deficits in interlimb coordination between the upper and lower limbs would increase during split-belt locomotion in PD, and particularly so in patients with FOG. METHODS: Fourteen PD patients (seven with FOG, matched for disease severity with the seven non-freezers) and 10 healthy controls walked on a treadmill with split belts at different speeds (2 versus 3km/h). Gait was recorded by means of a video motion analysis system. Outcome measures were stride length asymmetry and variability, stride time asymmetry and variability, ipsilateral and contralateral interlimb coordination, and phase coordination index. RESULTS: Both PD subjects and controls were able to adapt to split-belt walking by modulating their stride length. However, freezers showed a larger increase in stride time asymmetry and stride time variability due to split-belt walking compared to non-freezers. Furthermore, contralateral interlimb coordination improved in control subjects during split-belt walking, but not in PD patients (freezers and non-freezers). Phase coordination index did not change differently across the three groups. CONCLUSIONS: The ability to walk under split-belt conditions was preserved in PD. Non-freezers and controls compensated for the experimentally increased stride length asymmetry by decreasing their stride time asymmetry. This ability was lost in freezers, who in fact increased their stride time asymmetry during split-belt walking. As a result, stride time variability also increased in freezers. These findings support the hypothesis that FOG is related to gait asymmetries and to gait timing deficits.

Anticipatory postural adjustments during step initiation: elicitation by auditory stimulation of differing intensities.

Step initiation is associated with anticipatory postural adjustments (APAs) that vary according to the speed of the first step. When step initiation is elicited by a "go" signal (i.e. in a reaction time task), the presentation of an unpredictable, intense, acoustic startling stimulus (engaging a subcortical mechanism) simultaneously with or just before the imperative "go" signal is able to trigger early-phase APAs. The aim of the present study was to better understand the mechanisms underlying APAs during step initiation. We hypothesized that the early release of APAs by low-intensity, non-startling stimuli delivered long before an imperative "go" signal indicates the involvement of several different mechanisms in triggering APAs (and not just acoustic reflexes triggering brainstem structures). Fifteen healthy subjects were asked to respond to an imperative visual "go" signal by initiating a step with their right leg. A brief, binaural 40, 80 or 115 dB auditory stimulus was given 1.4 s before the "go" signal. Participants were instructed not to respond to the auditory stimulus. The centre of pressure trajectory and the electromyographic activity of the orbicularis oculi, sternocleidomastoid and tibialis anterior muscles were recorded. All three intensities of the auditory stimulus were able to evoke low-amplitude, short APAs without subsequent step execution. The louder the stimulus, the more frequent the elicitation. Depending on the intensity of the stimulus, APAs prior to step initiation can be triggered without the evocation of a startle response or an acoustic blink. Greater reaction times for these APAs were observed for non-startling stimuli. This observation suggested the involvement of pathways that did not involve the brainstem as a "prime mover".

Effect of bilateral subthalamic nucleus deep brain stimulation on postural adjustments during arm movement.

OBJECTIVE: Although it is well known that postural adjustment (PA) is impaired in advanced Parkinson's disease (PD), the potentially compensatory effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in this respect are less clear. METHODS: While standing on a force platform and in the absence of antiparkinsonian medication, 10 patients performed voluntary, unilateral arm movements before surgery (the 'off stim' condition) and then afterwards (the 'on stim' condition). The patients' PAs were monitored by vertical torque (Tz) and compared with those recorded in control subjects. RESULTS: Patients with STN DBS and control subjects showed similar values for PA amplitude, duration and latency. CONCLUSIONS: STN stimulation may induce better postural control during the movement preparation and execution phases. Our results argue in favour of a positive effect of STN DBS on PA. SIGNIFICANCE: The PA amplitude (provided by Tz) may be a strong marker reflecting the clinical improvement seen in stimulated PD patients.

Walking patterns in Parkinson's disease with and without freezing of gait.

The pathophysiology underlying freezing of gait (FOG) in Parkinson's disease remains incompletely understood. Patients with FOG ("freezers") have a higher temporal variability and asymmetry of strides compared to patients without FOG ("non-freezers"). We aimed to extend this view, by assessing spatial variability and asymmetry of steps and interlimb coordination between the upper and lower limbs during gait. Twelve freezers, 15 non-freezers, and 15 age-matched controls were instructed to walk overground and on a treadmill. Kinematic data were recorded with a motion analysis system. Both freezers and non-freezers showed an increased spatial variability of leg movements compared to controls. In addition, both patient groups had a deficit in interlimb coordination, not only between ipsilateral arms and legs, but also between diagonally positioned limbs. The only difference between freezers and non-freezers was a decreased step length during treadmill walking. We conclude that parkinsonian gait-regardless of FOG-is irregular, not only in the legs, but also with respect to interlimb coordination between the arms and legs. FOG is reflected by abnormal treadmill walking, presumably because this provides a greater challenge to the defective supraspinal control than overground walking, hampering the ability of freezers to increase their stride length when necessary.

[Locomotion disturbances in Huntington's disease]. / Locomotion et maladie de Huntington.

In Huntington's disease (HD), perturbed locomotion occurs early in the course of the disease and presents numerous clinical features. The gait disorders in HD might best be defined as a timing disorder; however, hypokinesia (i.e. a decrease in stride length) also plays an important role in disturbed locomotion as HD progresses. Gait impairments are particularly important because they lead to an increased risk of falls. Falls risk factors and consequences depend on the stage of the disease. A satisfactory therapeutic strategy for gait impairments is a serious challenge: the use of a metronome during gait in HD patients does not effectively improve their gait. Attention deficits in HD may be a major determinant of this failure. The effect of antichoreic medications on gait is still controversial because of the absence of specific evaluation of these medications on gait disturbances.

[Gait disorders in Parkinson's disease: and pathophysiological approaches]. / Les troubles de la marche dans la maladie de Parkinson : problématique clinique et physiopathologique.

Gait disorders and axial symptoms are the main therapeutic challenges in advanced Parkinson's disease (PD). Gait disorders in PD are characterized by spatial and temporal dysfunction. Gait hypokinesia is the first to appear and is responsible for the decrease in velocity. A good sensitivity to the levodopa is well established. Morris et al. [Morris ME, Iansek R, Matyas TA, Summers JJ. Ability to modulate walking cadence remains intact in Parkinson's disease. J Neurol Neurosurg Psychiatry 1994a;57(12):1532-4; Morris ME, Iansek R, Matyas TA, Summers JJ. The pathogenesis of gait hypokinesia in Parkinson's disease. Brain 1994b;117(Pt. 5):1169-81; Morris ME, Iansek R, Matyas TA, Summers JJ. Stride length regulation in Parkinson's disease. Brain 1996;119:551-68] demonstrated that the ability to modulate walking cadence remains intact in PD, and could correspond to a compensatory mechanism. More advanced disease stages of the disease are characterized by abnormal temporal parameters (such as stride length variability, stride time variability and cadence elevation) which are unresponsive to levodopa therapy and may be correlated with the occurrence of falls and freezing of gait (FOG). Lastly, postural instability also results in falls and is poorly responsive to levodopa. A link between gait impairment and frontal disorders has recently been suggested. After a few years of evolution, paradoxical episodic phenomena are described: festination ("hastening gait" with rapid small, short steps) and FOG (involuntary and sudden cessation of gait). Both symptoms are often incapacitating for PD patients, because of their resultant loss of independence and their poor response to levodopa therapy. Kinematical studies of FOG revealed a decrease in velocity, stride length and an exponential increase in cadence, prior to a FOG episode. New approaches (functional MRI, wavelets...) should offer new perspectives concerning these disabling symptoms.