Christelle Lagrange

Non-motor dopamine withdrawal syndrome after surgery for Parkinson’s disease: predictors and underlying mesolimbic denervation

Apathy has been reported to occur after subthalamic nucleus stimulation, a treatment of motor complications in advanced Parkinsons disease. We carried out a prospective study of the occurrence of apathy and associated symptoms, predictors and mechanisms in the year following subthalamic stimulation. Dopamine agonist drugs were discontinued immediately after surgery and levodopa was markedly reduced within 2 weeks. Apathy and depression were assessed monthly, using the Starkstein apathy scale and the Beck Depression Inventory. Dopamine agonists were re-introduced if patients developed apathy or depression. Preoperative non-motor fluctuations were evaluated using the Ardouin Scale. Depression, apathy and anxiety were evaluated both on and off levodopa. Analysis of predictors of apathy was performed using a Cox proportional hazard model. Twelve patients who developed apathy and a control group of 13 patients who did not underwent [11C]-raclopride positron emission tomography scanning before and after oral intake of methylphenidate. In 63 patients with Parkinsons disease treated with subthalamic stimulation, dopaminergic treatment was decreased by 82% after surgery. Apathy occurred after a mean of 4.7 (3.3-8.2) months in 34 patients and was reversible in half of these by the 12-month follow-up. Seventeen patients developed transient depression after 5.7 (4.7-9.3) months and these fell into the apathy group with one single exception. At baseline, fluctuations in depression, apathy and anxiety scores were greater in the group with apathy. Fluctuations in apathy, depression and anxiety ratings during a baseline levodopa challenge were also significant predictors of postoperative apathy in univariate analysis, but not motor and cognitive states or the level of reduction of dopaminergic medication. The multivariate model identified non-motor fluctuations in everyday life and anxiety score during the baseline levodopa challenge as two independent significant predictors of postoperative apathy. Without methylphenidate, [11C]-raclopride binding potential values were greater in apathetic patients bilaterally in the orbitofrontal, dorsolateral prefrontal, posterior cingulate and temporal cortices, left striatum and right amygdala, reflecting greater dopamine D2/D3 receptor density and/or reduced synaptic dopamine level in these areas. The variations of [11C]-raclopride binding potential values induced by methylphenidate were greater in non-apathetic patients in the left orbitofrontal cortex, dorsolateral prefrontal cortex, thalamus and internal globus pallidus and bilaterally in the anterior and posterior cingulate cortices, consistent with a more important capacity to release dopamine. Non-motor fluctuations are related to mesolimbic dopaminergic denervation. Apathy, depression and anxiety can occur after surgery as a delayed dopamine withdrawal syndrome. A varying extent of mesolimbic dopaminergic denervation and differences in dopaminergic treatment largely determine mood, anxiety and motivation in patients with Parkinsons disease, contributing to different non-motor phenotypes.

Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study

BACKGROUND We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood. METHODS We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis. FINDINGS Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed. INTERPRETATION Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study

BACKGROUND Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

Reliability of the Burke-Fahn-Marsden Scale in a Multicenter Trial for Dystonia

The multicenter SPIDY trial (pallidal stimulation for generalized, idiopathic dystonia) recently reported a marked improvement in dystonia which was assessed by the Burke‐Fahn‐Marsden (BFM) scale. However, the reliability of this tool has rarely been evaluated and its use in a multicenter study has never been assessed prospectively.

Effects of pulse width variations in pallidal stimulation for primary generalized dystonia.

BackgroundVarious pulse widths (from 60–450 μs) have been used for bilateral pallidal stimulation in generalized dystonia but, to date, no comparison of this parameter’s effects is available.ObjectiveTo provide an analysis of the differential effects of bilateral short, medium and long stimulus pulse width (PW) on clinical improvement in primary generalized dystonia.MethodsThe most effective therapeutic stimulation parameters were recorded in 22 patients using bilateral pallidal stimulation. Six months after surgery, the effects of bilateral pallidal short (60–90 μs), medium (120–150 μs) and long (450 μs) PWs were studied in 20 of those patients. The effect of the stimulation was assessed by reviewing videotaped sessions by an observer blinded to treatment status (Burke-Fahn-Marsden movement score). Patients were tested on separate days, in random order, for the stimulation conditions (acute effect with the stimulation condition lasting 10 hours). The same contact was used for each stimulation condition. All the electrodes were set at 130 Hz (monopolar stimulation) and the intensity was set individually 10% below the side effect threshold.ResultsMedian PWs of 60 (short), 120 (medium) and 450 μs (long) were compared,with a mean intensity of 4.46, 3.45 and 2.47 V, respectively. This study failed to demonstrate any significant difference in the movementscale dystonia mean scores depending on PW.ConclusionAccording to our findings, shortduration stimulus PWs are as effective as longer ones during a 10 hour period of observation. Confirmation of this finding for chronic use could be of importance in saving stimulator energy. Moreover, the use of smaller stimulus pulse widths are said to reduce charge injection and increase the therapeutic window between therapeutic effects and side effects.

Interruption of deep brain stimulation of the globus pallidus in primary generalized dystonia.

Stimulation (DBS) of the globus pallidus (GP) is effective to treat generalized dystonia. Little is known about the evolution of dystonia in case of arrest after a long period of stimulation. This study describes the course of dystonia during a 48 hours period without stimulation followed by a 24 hours period after turning ON the stimulator. 14 patients with generalized dystonia treated with bilateral GP DBS for 3 years or more were recruited. Blinded video‐based analysis was performed using Burke‐Fahn‐Marsden scale at (1) baseline (ON stimulation), (2) up to 48 hours after the stimulator was turned OFF, and (3) 24 hours after the stimulator was turned ON. 13 patients completed the 48 hours OFF‐stimulation period. The dystonia movement score progressively worsened from 24.3 ± 13.9 at baseline to 48.9 ± 19.8 after 48 hours (P < 0.00001). The disability score also worsened from 4.4 ± 1.2 at baseline to 5.7 ± 1.5 after 48 hours without stimulation (P < 0.001). When the neurostimulator was turned ON, the dystonia scores returned to baseline level after 10 hours. The interruption of GP DBS in dystonia results in a progressive worsening which is rapidly reversible once the neurostimulator is turned ON.

Levodopa Effects on Hand and Speech Movements in Patients with Parkinson’s Disease: A fMRI Study

Levodopa (L-dopa) effects on the cardinal and axial symptoms of Parkinson’s disease (PD) differ greatly, leading to therapeutic challenges for managing the disabilities in this patient’s population. In this context, we studied the cerebral networks associated with the production of a unilateral hand movement, speech production, and a task combining both tasks in 12 individuals with PD, both off and on levodopa (L-dopa). Unilateral hand movements in the off medication state elicited brain activations in motor regions (primary motor cortex, supplementary motor area, premotor cortex, cerebellum), as well as additional areas (anterior cingulate, putamen, associative parietal areas); following L-dopa administration, the brain activation profile was globally reduced, highlighting activations in the parietal and posterior cingulate cortices. For the speech production task, brain activation patterns were similar with and without medication, including the orofacial primary motor cortex (M1), the primary somatosensory cortex and the cerebellar hemispheres bilaterally, as well as the left- premotor, anterior cingulate and supramarginal cortices. For the combined task off L-dopa, the cerebral activation profile was restricted to the right cerebellum (hand movement), reflecting the difficulty in performing two movements simultaneously in PD. Under L-dopa, the brain activation profile of the combined task involved a larger pattern, including additional fronto-parietal activations, without reaching the sum of the areas activated during the simple hand and speech tasks separately. Our results question both the role of the basal ganglia system in speech production and the modulation of task-dependent cerebral networks by dopaminergic treatment.