Patrick Mertens

Neurostimulation for Parkinson's Disease with Early Motor Complications

BACKGROUND Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinsons disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinsons disease. METHODS In this 2-year trial, we randomly assigned 251 patients with Parkinsons disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinsons Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinsons Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS Subthalamic stimulation was superior to medical therapy in patients with Parkinsons disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

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 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.

Subthalamic nucleus stimulation in Parkinson’s disease

The aim of the present study was to assess the efficacy and safety of chronic subthalamic nucleus deep-brain stimulation (STN-DBS) in patients with Parkinsons disease (PD). 18 consecutive severely affected PD patients were included (mean age, SD: 56.9±6 years; mean disease duration: 13.5±4.4 years). All the patients were evaluated clinically before and 6 months after the surgical procedure using the Unified Parkinsons Disease Rating Scale (UPDRS). Additionally, a 12 months follow-up was available in 14 patients. The target coordinates were determined by ventriculography under stereotactic conditions, followed by electrophysiology and intraoperative stimulation. After surgery, continuous monopolar stimulation was applied bilaterally in 17 patients at 2.9±0.4 V through 1 (n = 31) or 2 contacts (n = 3). One patient had bilateral bipolar stimulation. The mean frequency of stimulation was 140±16 Hz and pulse width 68±13 μs. Off medication, the UPDRS part III score (max = 108) was reduced by 55 % during on stimulation (score before surgery: 44.9±13.4 vs at 6 months: 20.2±10; p < 0.001). In the on medication state, no difference was noted between the preoperative and the postoperative off stimulation conditions (scores were respectively: 17.9±9.2 and 23±12.6). The severity of motor fluctuations and dyskinesias assessed by UPDRS IV was reduced by 76 % at 6 months (scores were respectively: 10.3±3 and 2.5±3; p < 0.001). Off medication, the UPDRS II or ADL score was reduced by 52.8 % during on stimulation (26.9±6.5 preop versus 12.7±7 at 6 months). The daily dose of antiparkinsonian treatment was diminished by 65.5 % (levodopa equivalent dose – mg/D – was 1045 ± 435 before surgery and 360 ± 377 at 6 months; p < 0.01). These results remained stable at 12 months for the 14 patients studied. Side effects comprised lower limb phlebitis (n = 2), pulmonary embolism (n = 1), depression (n = 6), dysarthria and freezing (n = 1), sialorrhea and drooling (n = 1), postural imbalance (n = 1), transient paresthesias and dyskinesias. This study confirms the great value of subthalamic nucleus stimulation in the treatment of intractable PD. Some adverse events such as depression may be taken into account in the inclusion criteria and also in the post-operative outcome.

Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy.

&NA; Thirty‐one patients with medically refractory neuropathic pain were included in a prospective evaluation of motor cortex stimulation. The long‐term outcome was evaluated using five variables: (a) rate (percentage) of pain relief, (b) pain scores as assessed on VAS, (c) postoperative decrease in VAS scores, (d) reduction in analgesic drug intake, (e) a dichotomic (yes/no) response to the question whether the patient would accept, under similar circumstances, to be operated on again. Pain relief was rated as excellent (>70 % pain relief) in 10 % of cases, good (40‐69 %) in 42 %, poor (10‐39 %) in 35 % and negligible (0‐9 %) in 13 %. Intake of analgesic drugs was decreased in 52 % of patients and unchanged in 45 % (unavailable data in 3 %), with complete withdrawal of analgesic drugs in 36 % of patients. Twenty‐one patients (70 %) declared themselves favourable to re‐intervention if the same beneficial outcome could be guaranteed. Neither preoperative motor status, pain characteristics, type or localisation of lesions, quantitative sensory testing, Somatosensory Evoked Potentials, nor the interval between pain and surgery were found to predict the efficacy of MCS. The level of pain relief, as evaluated in the first month following implantation was a strong predictor of long‐term relief (regression analysis, R=0.744; p<0.0001). These results confirm that MCS can be a satisfactory and durable alternative to medical treatments in patients with refractory pain, and suggest that the efficacy of MCS may be predicted in the first month of therapy.

Motor cortex stimulation for pain control induces changes in the endogenous opioid system

Background: Motor cortex stimulation (MCS) for neuropathic pain control induces focal cerebral blood flow changes involving regions with high density of opioid receptors. We studied the possible contribution of the endogenous opioid system to MCS-related pain relief. Methods: Changes in opioid receptor availability induced by MCS were studied with PET scan and [11C]diprenorphine in eight patients with refractory neuropathic pain. Each patient underwent two preoperative (test–retest) PET scans and one postoperative PET scan acquired after 7 months of chronic MCS. Results: The two preoperative scans, performed at 2 weeks interval, did not show significant differences. Conversely, postoperative compared with preoperative PET scans revealed significant decreases of [11C]diprenorphine binding in the anterior middle cingulate cortex (aMCC), periaqueductal gray (PAG), prefrontal cortex, and cerebellum. Binding changes in aMCC and PAG were significantly correlated with pain relief. Conclusion: The decrease in binding of the exogenous ligand was most likely explained by receptor occupancy due to enhanced secretion of endogenous opioids. Motor cortex stimulation (MCS) may thus induce release of endogenous opioids in brain structures involved in the processing of acute and chronic pain. Correlation of this effect with pain relief in at least two of these structures supports the role of the endogenous opioid system in pain control induced by MCS.

Patterns of Bidirectional Communication between Cortex and Basal Ganglia during Movement in Patients with Parkinson Disease

Cortico-basal ganglia networks are considered to comprise several parallel and mostly segregated loops, where segregation is achieved in space through topographic connectivity. Recently, it has been suggested that functional segregation may also be achieved in the frequency domain, by selective coupling of related activities at different frequencies. So far, however, any coupling across frequency in the human has only been modeled in terms of unidirectional influences, a misplaced assumption given the looped architecture of the basal ganglia, and has been considered in static terms. Here, we investigate the pattern of bidirectional coupling between mesial and lateral cortical areas and the subthalamic nucleus (STN) at rest and during movement, with and without pharmacological dopaminergic input, in patients with Parkinsons disease. We simultaneously recorded scalp electroencephalographic activity and local field potentials from depth electrodes and deduced patterns of directed coherence between cortical and STN levels across three frequency bands [sub-β (3–13 Hz), β (14–35 Hz), γ (65–90 Hz)] in the different states. Our results show (1) asymmetric bidirectional coupling between STN and both mesial and lateral cortical areas with greater drives from cortex to STN at frequencies <35 Hz, (2) a drop of β band coupling driven from mesial cortex to STN during movement, and (3) an increase in symmetrical bidirectional drives between STN and mesial cortex and in lateral cortical drive to STN in the γ band after dopaminergic therapy. The results confirm a bidirectional pattern of cortico-basal ganglia communication that is differentially patterned across frequency bands and changes with movement and dopaminergic input.

Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviours

Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinsons disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinsons disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinsons Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinsons disease may be considered as new indications for subthalamic stimulation.

Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease >50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).

Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease: Five year follow-up

ObjectiveTo assess the long-term efficacy and safety of bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson’s disease (PD).Methods42 consecutive patients with idiopathic PD treated with bilateral STN stimulation were enrolled. Parkinsonian status, medication intake and neuropsychological evaluation were assessed preoperatively and at 1 and 5 years postoperatively in on and off medication/on and off stimulation conditions.Results23 patients could be followed-up 5 years after surgery. In the remaining cases, 5 died, 1 could not be assessed because of device removal for infection, 1 decided not to be stimulated, and 11 were lost of follow-up (one because of a liver carcinoma and the others because they refused the formal four conditions of assessment). STN stimulation reduced the UPDRS motor score by 55 % compared to baseline in the offmedication conditions. Tremor, rigidity, bradykinesia, postural stability, and gait improved by 74 %, 66 %, 59 %, 17 % and 37 %, respectively. UPDRS part II scores were reduced by 38 %. The dopaminergic treatment daily dose was reduced by 54.4 % after surgery. Axial dopa-unresponsive signs worsened in some patients. Among the 42 initial patients we observed the following: 2 brain hemorrhages, 3 infections of the device, 2 phlebitis and 1 pulmonary embolism. In addition, 2 patients needed a repositioning of the electrode. Among the 23 patients followed at 5 years, long lasting side effects consisted in dysarthria (56 %), depression (39 %), eyelid opening apraxia (30.4 %) and apathy (4.3 %).ConclusionsOur data confirm that bilateral STN stimulation is beneficial in the long-term for PD patients but does not prevent disease progression and the occurence of axial levodopa unresponsive signs in some patients.