David Devos

The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson’s disease

Background: Apathy is usually defined as reduced interest and participation in various activities. It is a frequent consequence of neurological and psychiatric disorders. Although various scoring methods have been proposed, there is a lack of validated, standardised instruments for detecting apathy and assessing its severity. Objective: To develop an apathy rating scale using a structured standardised interview capable of distinguishing between the condition’s various features. Methods: The Lille Apathy Rating Scale (LARS) is based on a structured interview. It includes 33 items, divided into nine domains. Responses are scored on a dichotomous scale. The participants used to validate the scale consisted of 159 patients with probable Parkinson’s disease and 58 healthy control subjects. The Marin Apathy Scale, the Montgomery and Asberg Depression Rating Scale, and the Mattis Dementia Rating Scale were also administered. Results: Principal component analysis showed that the LARS probed a single construct which forms the root of an oblique factor structure reflecting four dimensions: intellectual curiosity, self awareness, emotion, and action initiation. The main psychometric properties of the LARS (internal consistency, inter-rater and test-retest reliability) were satisfactory. Concurrent validity was evaluated by reference to the Marin scale and to judgements provided by expert clinicians. Conclusions: Standard validity indices showed that the LARS is sensitive and capable of distinguishing between apathy and depression. As a screening tool, the scale is able to support dichotomous judgements accurately and, when greater measurement sensitivity is required, also determine the severity of apathy within a four category classification.

STN-DBS FREQUENCY EFFECTS ON FREEZING OF GAIT IN ADVANCED PARKINSON DISEASE

Background: Severe gait disturbances and freezing episodes (frequently resistant to optimal dopaminergic treatment) often appear in advanced Parkinson disease (PD). Even several years after initiation, high-frequency subthalamic nucleus deep brain stimulation (STN-DBS) is still very effective for controlling segmental symptoms. However, there are no long-term data on the management of gait disorders and freezing in STN-DBS. Objectives: To compare the effects of various STN-DBS parameters on freezing of gait and to determine whether such effects are more related to stimulation energy (usual voltages vs high voltages at 130 Hz) or frequency (130 Hz vs approximately half this frequency: 60 Hz). Methods: We blindly assessed STN-DBS parameters in 13 PD patients reporting severe gait disorders. We compared the effects on gait of two different voltages (the patient’s usual voltage [median 3 volts] and a high voltage [median 3.7 volts]) and two different frequencies (60 and 130 Hz, while maintaining the same total energy delivered) vs “off-stimulation” conditions. Results: The number of freezing episodes was significantly lower at the 60-Hz “high voltage/equivalent energy” and higher at the 130-Hz/high voltage than for “off stimulation.” The slight improvement in the Unified Parkinson’s Disease Rating Scale motor score observed (at 130 Hz) did not achieve statistical significance. Conclusions: Our results prompt consideration of a new strategy for two-stage subthalamic nucleus deep brain stimulation (STN-DBS) frequency optimization, with stimulation at 130 Hz and the usual voltage during the initial years of STN-DBS and then at 60 Hz at a high voltage in Parkinson disease patients who develop severe gait disorders.

Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: A double-blind, randomized, placebo-controlled study

Depression is one of the most common psychiatric disturbances in Parkinsons disease (PD). Recent reviews have highlighted the lack of controlled trials and the ensuing difficulty in formulating recommendations for antidepressant use in PD. We sought to establish whether antidepressants provide real benefits and whether tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants differ in their short‐term efficacy, because the time to onset of therapeutic benefit remains an important criterion in depression. The short‐term efficacy (after 14 and 30 days) of two antidepressants (desipramine, a predominantly noradrenergic reuptake inhibitor tricyclic and citalopram, a SSRI) was assessed in a double‐blind, randomized, placebo‐ controlled study of 48 nondemented PD patients suffering from major depression. After 14 days, desipramine prompted an improvement in the Montgomery Asberg Depression Rating Scale (MADRS) score, compared with citalopram and placebo. Both antidepressants produced significant improvements in the MADRS score after 30 days. Mild adverse events were twice as frequent in the desipramine group as in the other groups. A predominantly noradrenergic tricyclic antidepressant induced a more intense short‐term effect on parkinsonian depression than did an SSRI. However, desipramines lower tolerability may outweigh its slight short‐term clinical advantage.

Characteristics of apathy in Parkinson's disease

The objective of this study was to use the Lille Apathy Rating Scale to assess apathy in a large population of Parkinsons disease (PD) patients and identify several different apathy profiles. One hundred fifty‐nine patients with probable PD and 58 healthy controls participated in the study. Apathy was assessed using the Lille Apathy Rating Scale. Motor, cognitive, and depressive symptoms were rated on standardized scales. Data were analyzed using linear regression and multivariate analyses of variance. Thirty‐two percent of the PD patients were classified as apathetic. Apathy was more frequent in patients with dementia. The four apathy dimensions contributed differently to the overall severity of the apathetic condition. Action initiation and intellectual curiosity had a marked influence. Linear regression analysis revealed that the apathy level was mainly determined by cognitive impairment, not associated with the severity of motor symptoms, and only associated with the apathy subcomponent of the Montgomery and Asberg Depression Rating Scale. Apathy is highly prevalent in PD patients. Apathy profiles vary according to the clinical presentation of PD. The high prevalence of apathy in PD suggests the involvement of frontal–subcortical circuits. Although the neurochemical substrate of apathy remains poorly characterized, the strong link between apathy and cognitive impairment observed in several studies suggests the participation of nondopaminergic circuits.

Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson's disease †‡

The studies of duodenal infusion of a levodopa on small groups of parkinsonian patients have reported beneficial effects on motor complications. However, little is known about the patient profile and indications for duodenal levodopa infusion. The purpose of this study is to exhaustively investigate the clinical characteristics of the population and indication, efficacy and tolerability of duodenal levodopa infusion in natural care settings. Of the 102 patients treated with duodenal levodopa infusion since 2003, 91 were enrolled in a multicentre retrospective study. The mean age was 72.7 years, with average disease duration of 17 years. Patients were at advanced stage: 91% had gait disorders, 65% had visual hallucinations, and 50% were demented (MMSE: 23). Duodenal levodopa infusion was the last line of treatment for motor complications in 98% of the patients, due to failure of or contraindication for apomorphine pump and neurosurgical treatments. Long‐term treatment was observed by 73% of the population. Of these, >90% reported an improvement in motor fluctuations, quality of life, and autonomy. There were few severe adverse events. Technical problems were commonplace. Duodenal levodopa infusion seems to be an effective last‐line therapy for motor complications in Parkinsons disease. Hence, technical improvements and earlier introduction should be considered.

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.

Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson’s disease

Background: Therapeutic management of gait disorders in patients with advanced Parkinson’s disease (PD) can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus (STN) stimulation are more effective for limb-related parkinsonian signs than for gait disorders. Gait disorders could also be partly related to norepinephrine system impairment, and the pharmacological modulation of both dopamine and norepinephrine pathways could potentially improve the symptomatology. Aim: To assess the clinical value of chronic, high doses of methylphenidate (MPD) in patients with PD having gait disorders, despite their use of optimal dopaminergic doses and STN stimulation parameters. Methods: Efficacy was blindly assessed on video for 17 patients in the absence of l-dopa and again after acute administration of the drug, both before and after a 3-month course of MPD, using a Stand–Walk–Sit (SWS) Test, the Tinetti Scale, the Unified Parkinson’s Disease Rating Scale (UPDRS) part III score and the Dyskinesia Rating Scale. Results: An improvement was observed in the number of steps and time in the SWS Test, the number of freezing episodes, the Tinetti Scale score and the UPDRS part III score in the absence of l-dopa after 3 months of taking MPD. The l-dopa-induced improvement in these various scores was also stronger after the 3-month course of MPD than before. The Epworth Sleepiness Scale score fell dramatically in all patients. No significant induction of adverse effects was found. Interpretation: Chronic, high doses of MPD improved gait and motor symptoms in the absence of l-dopa and increased the intensity of response of these symptoms to l-dopa in a population with advanced PD.

Low levels of the vascular endothelial growth factor in CSF from early ALS patients

Deletion of the hypoxia-response element in the vascular endothelial growth factor (VEGF) promoter causes motor neuron degeneration in a mouse model. “At-risk” haplotypes with low circulating VEGF levels have been demonstrated in humans. Here the authors report low VEGF levels in the CSF of ALS patients during their first year of the disease, independently of VEGF promoter polymorphism. This finding early in ALS patients suggests a possible role for VEGF gene regulation in the pathogenesis of ALS.

Elevated IL-6 and TNF-α levels in patients with ALS: Inflammation or hypoxia?

Abnormal levels of interleukin (IL)-6 were described in patients with ALS, related to an inflammatory process. The authors compared IL-6 and tumor necrosis factor α (TNF-α) levels in CSF and sera from 10 hypoxemics and 10 normoxemics patients with ALS to those of 10 hypoxemics and 10 normoxemics neurologic controls. The same pattern exists in patients with ALS and controls: the highest levels are found in hypoxic conditions and undetectable levels are found in normoxemic conditions. Elevated IL-6 levels in ALS could correspond to a normal response to hypoxemia.

Exhaustive, one-year follow-up of subthalamic nucleus deep brain stimulation in a large, single-center cohort of parkinsonian patients.

OBJECTIVE To prospectively assess the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) at 12 months after surgery in a series of 100 consecutive patients treated in a single center. The primary objective was to describe the clinical outcome in terms of efficacy and tolerance in STN-DBS patients. A secondary objective was to discuss presurgery clinical characteristics a posteriori as a function of outcome. METHODS One hundred and three consecutive patients with severe Parkinsons disease received bilateral STN-DBS in our clinic between May 1998 and March 2003. Clinical assessment was performed before and 12 months after surgery and was based on the Unified Parkinsons Disease Rating Scale, Parts II, III, and IV A; the Schwab and England Scale; and cognitive evaluation. Patient-rated overall improvement was also evaluated. RESULTS Twelve months after surgery, the Unified Parkinsons Disease Rating Scale Part III score decreased by 43%, the Unified Parkinsons Disease Rating Scale Part II score (activities of daily living) fell by 34%, and the severity of dyskinesia-related disability decreased by 61%. The main surgical complications after STN-DBS were as follows: infection (n = 7), intracerebral hematoma (n = 5), electrode fracture (n = 4), and incorrect lead placement (n = 8). We observed cognitive decline and depression in 7.7 and 18% of the patients, respectively. The mean patient-rated overall improvement score was 70.7%. CONCLUSION The efficacy and safety of STN-DBS in our centers large cohort of Parkinsonian patients are generally similar to the results obtained by other groups, albeit at the lower limit of the range of reported values. In contrast to efficacy, the occurrence of adverse events cannot be predicted. Younger patients with Parkinsons disease (i.e., those younger than 60 yr) often show an excellent response to levodopa. However, in view of our data on overall patient satisfaction and the occurrence of adverse events, we suggest that older patients (but not those older than 70 yr) and less dopa-sensitive patients (but not those with a response <50%) should still be offered the option of STN-DBS.