Patricia Limousin

Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation

In monkeys rendered parkinsonian, lesions and electrical stimulation of the subthalamic nucleus reduce all major motor disturbances. The effect of electrical stimulation of the subthalamic nucleus was assessed in three patients with disabling akinetic-rigid Parkinsons disease and severe motor fluctuations. Quadripolar electrodes connected to a pulse generator were implanted in the subthalamic nuclei on both sides. Patients were evaluated with the unified Parkinsons disease rating scale and timed motor tests. 3 months after surgery, activities of daily living scores had improved by 58-88% and motor scores by 42-84%. This improvement was maintained for up to 8 months in the first patient operated upon. One patient was confused for 2 weeks after surgery, and another developed neuropsychological impairment related to a thalamic infarction which improved over 3 months. In one patient, stimulation could induce ballism that was stopped by reduction of stimulation. This is the first demonstration in human beings of the part played by the subthalamic nuclei in the pathophysiology of Parkinsons disease.

Adaptive Deep Brain Stimulation In Advanced Parkinson Disease

Brain–computer interfaces (BCIs) could potentially be used to interact with pathological brain signals to intervene and ameliorate their effects in disease states. Here, we provide proof‐of‐principle of this approach by using a BCI to interpret pathological brain activity in patients with advanced Parkinson disease (PD) and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered. Our goal was to demonstrate that by personalizing and optimizing stimulation in real time, we could improve on both the efficacy and efficiency of conventional continuous DBS.

Bilateral subthalamic or pallidal stimulation for Parkinson's disease affects neither memory nor executive functions: A consecutive series of 62 patients

There is a renewal of interest in surgical approaches including lesions and deep brain stimulation directed at motor subcorticofrontal loops. Bilateral lesioning presents a far greater risk of adverse effects, especially cognitive impairment. Furthermore, the main advantages of the stimulation procedure over lesioning are adaptability and reversibility of effects. The aim of this study was to assess the influence of bilateral stimulation of the subthalamic nucleus or internal globus pallidus on memory and executive functions in Parkinsons disease. Sixty‐two patients were assessed before and after 3 to 6 months of chronic bilateral stimulation of the subthalamic nucleus (n = 49) or internal globus pallidus (n = 13). The neuropsychological tests used were the Mattis Dementia Rating Scale, the Grober and Buschke Verbal Learning Test, the Wisconsin Card Sorting Test, category and literal fluency, graphic and motor series, the Stroop Test, and the Trail Making Test. Mood was evaluated by the Beck Depression Inventory. Only 4 of 25 cognitive variables were affected by deep brain stimulation. Under stimulation, performance improved for Parts A and B of the Trail Making Test, but there was a deterioration in literal and total lexical fluency. There was also a mild but significant improvement in mood. It may therefore be concluded that stimulation of the subthalamic nucleus or internal globus pallidus does not change the overall cognitive performance in Parkinsons disease and does not greatly affect the functioning of subcorticofrontal loops involved in cognition in humans. This relative absence of cognitive impairment in bilateral deep brain stimulation is likely because of the accurate positioning of the electrodes, allowing the effects of stimulation to be confined to sensorimotor circuits. Ann Neurol 1999;46:217–223

α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy?

We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype.

Resting oscillatory cortico-subthalamic connectivity in patients with Parkinson’s disease

Both phenotype and treatment response vary in patients with Parkinsons disease. Anatomical and functional imaging studies suggest that individual symptoms may represent malfunction of different segregated networks running in parallel through the basal ganglia. In this study, we use a newly described, electrophysiological method to describe cortico-subthalamic networks in humans. We performed combined magnetoencephalographic and subthalamic local field potential recordings in thirteen patients with Parkinsons disease at rest. Two spatially and spectrally separated networks were identified. A temporoparietal-brainstem network was coherent with the subthalamic nucleus in the alpha (7-13 Hz) band, whilst a predominantly frontal network was coherent in the beta (15-35 Hz) band. Dopaminergic medication modulated the resting beta network, by increasing beta coherence between the subthalamic region and prefrontal cortex. Subthalamic activity was predominantly led by activity in the cortex in both frequency bands. The cortical topography and frequencies involved in the alpha and beta networks suggest that these networks may be involved in attentional and executive, particularly motor planning, processes, respectively.

Exenatide and the treatment of patients with Parkinson’s disease

UNLABELLED BACKGROUND. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration. METHODS. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinsons disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months). RESULTS. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). CONCLUSION. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD. TRIAL REGISTRATION Clinicaltrials.gov NCT01174810. FUNDING Cure Parkinsons Trust.

Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review Clinical article

OBJECT Hemorrhagic complications carry by far the highest risk of devastating neurological outcome in functional neurosurgery. Literature published over the past 10 years suggests that hemorrhage, although relatively rare, remains a significant problem. Estimating the true incidence of and risk factors for hemorrhage in functional neurosurgery is a challenging issue. METHODS The authors analyzed the hemorrhage rate in a consecutive series of 214 patients undergoing image-guided deep brain stimulation (DBS) lead placement without microelectrode recording (MER) and with routine postoperative MR imaging lead verification. They also conducted a systematic review of the literature on stereotactic ablative surgery and DBS over a 10-year period to determine the incidence and risk factors for hemorrhage as a complication of functional neurosurgery. RESULTS The total incidence of hemorrhage in our series of image-guided DBS was 0.9%: asymptomatic in 0.5%, symptomatic in 0.5%, and causing permanent deficit in 0.0% of patients. Weighted means calculated from the literature review suggest that the overall incidence of hemorrhage in functional neurosurgery is 5.0%, with asymptomatic hemorrhage occurring in 1.9% of patients, symptomatic hemorrhage in 2.1% and hemorrhage resulting in permanent deficit or death in 1.1%. Hypertension and age were the most important patient-related factors associated with an increased risk of hemorrhage. Risk factors related to surgical technique included use of MER, number of MER penetrations, as well as sulcal or ventricular involvement by the trajectory. The incidence of hemorrhage in studies adopting an image-guided and image-verified approach without MER was significantly lower than that reported with other operative techniques (p < 0.001 for total number of hemorrhages, p < 0.001 for asymptomatic hemorrhage, p < 0.004 for symptomatic hemorrhage, and p = 0.001 for hemorrhage leading to permanent deficit; Fisher exact test). CONCLUSIONS Age and a history of hypertension are associated with an increased risk of hemorrhage in functional neurosurgery. Surgical factors that increase the risk of hemorrhage include the use of MER and sulcal or ventricular incursion. The meticulous use of neuroimaging-both in planning the trajectory and for target verification-can avoid all of these surgery-related risk factors and appears to carry a significantly lower risk of hemorrhage and associated permanent deficit.

Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease.

Excessive synchronization of neuronal activity at around 20 Hz is a common finding in the basal ganglia of patients with untreated Parkinsons disease (PD). Correlative evidence suggests, but does not prove, that this spontaneous activity may contribute to slowness of movement in this condition. Here we investigate whether externally imposed synchronization through direct stimulation of the region of the subthalamic nucleus at 20 Hz can slow motor performance in a simple unimanual tapping task and whether this effect is frequency selective. Tapping rates were recorded on 42 sides in 22 patients with PD after overnight withdrawal of medication. Tapping was performed without stimulation and during bilateral stimulation at 20 Hz, 50 Hz and 130 Hz. We found that tapping rates were slowed by 8.2+/-3.2% (p=0.014) during 20-Hz stimulation in subjects with relatively preserved baseline function in the task. This effect was frequency selective. The current data provide proof of the principle that excessive beta synchrony within the basal ganglia-cortical loop may contribute to the slowing of movements in Parkinsons disease.

Chronic stimulation of subthalamic nucleus improves levodopa-induced dyskinesias in Parkinson's disease.

Ventroposterior pallidotomy, and pallidal and subthalamic nucleus (STN) stimulation, are proposed to treat severe Parkinson’s disease (PD) with levodopa-induced motor complications. Pallidal surgery decreases levodopa-induced dyskinesias (LID). Parkinsonism evaluated by the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS) improves by about 30% after unilateral pallidotomy. STN stimulation can greatly improve parkinsonian disability, but its effects on LID are unknown because the first patients treated with STN stimulation were selected with mild or absent LID since spontaneous STN lesions can induce hemiballism. However, our initial experience with STN stimulation showed that stimulation-induced abnormal movements could be controlled by setting the stimulation voltage below the dyskinesia threshold. Moreover, the substantial decrease in levodopa dosage, which was made possible by the antiparkinsonian benefit, allowed a decrease in LID in the long-term. Thus, STN stimulation was also proposed for patients with severe LID. We selected all consecutive patients with young-onset PD, since this population is generally levodopa-sensitive and prone to develop severe LID. Eight patients with a mean age of 51 (SD 10) years and a mean disease duration of 16 (5) years were operated on bilaterally in the STN because of severe motor fluctuations (motor score on the UPDRS 57·5 [14·5] off-drug and 18·2 [10·6] on-drug). The study was approved by the Grenoble University ethical committee and all patients gave their written, informed consent. The surgical procedure has been described previously. 6 months after surgery, the motor score of the UPDRS improved from 58 (16) to 17 (8) (–71%) in the off-drug condition when stimulation was switched on. This improvement was seen in all the major parkinsonian symptoms. The dyskinesia score (six body parts, each scored 0–4, maximum score 24), assessed during the maximum motor response of a levodopa test with the same dose as preoperatively (early morning +50–100 mg), decreased from 11·4 (6·6) preoperatively to 6·8 (4·3) postoperatively onstimulation. Dyskinesia duration and disability (UPDRS items 32+33), which assess LID during activities of daily living under chronic stimulation, decreased from 4·0 (1·9) to 1·4 (0·9) (–65%). The antiparkinsonian drug dosage calculated as levodopa equivalent decreased from 1560 (930) to 680 (420) mg daily (–56%). With chronic STN stimulation, LID were greatly improved, in a similar percentage as with bilateral globus-pallidusinternus stimulation. With unilateral pallidotomy, contralateral LID are substantially improved although a big reduction of levodopa is not possible. Targeting the STN instead of the globus pallidus internus has the advantage of inducing a more pronounced antiakinetic effect. The decrease in LID induced by STN stimulation can be explained mainly by the decrease in levodopa dosage. This is why the improvement in dyskinesias is more obvious in activities of daily living than during the levodopa test with a dose identical to that given before surgery. Moreover, as highfrequency stimulation is supposed to act through neuroinhibition, the chronic inhibition of STN neurons can change the dyskinesia threshold with time, in the same way as the progressive abatement of hemiballism after a vascular lesion of the STN. Replacing the pulsatile levodopa-induced decrease of STN activity by a chronic stable decrease seems to improve dyskinesias. After 4 years of experience of STN stimulation, this surgical treatment improves LID with time, contrary to our initial fears. As the improvement in all the main parkinsonian motor symptoms is substantial in patients with a good levodopa response, the STN is suggested as the target of choice for the neurosurgical treatment of PD, even in patients with severe LID. However, randomised studies comparing different surgical procedures are required to better understand their respective value.

MRI-guided STN DBS in Parkinson's disease without microelectrode recording: efficacy and safety.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a commonly employed therapeutic procedure for patients with Parkinsons disease uncontrolled by medical therapies. This series describes the outcomes of 79 consecutive patients that underwent bilateral STN DBS at the National Hospital for Neurology and Neurosurgery between November 2002 and November 2008 using an MRI-guided surgical technique without microelectrode recording. Patients underwent immediate postoperative stereotactic MR imaging. The mean (SD) error in electrode placement was 1.3 (0.6) mm. There were no haemorrhagic complications. At a median follow-up period of 12 months, there was a mean improvement in the off-medication motor part of the Unified Parkinsons Disease Rating Scale (UPDRS III) of 27.7 points (SD 13.8) equivalent to a mean improvement of 52% (p<0.0001). In addition, there were significant improvements in dyskinesia duration, disability and pain, with a mean reduction in on-medication dyskinesia severity (sum of dyskinesia duration, disability and pain from UPDRS IV) from 3.15 (SD 2.33) pre-operatively, to 1.56 (SD 1.92) post-operatively (p=0.0001). Quality of life improved by a mean of 5.5 points (median 7.9 points, SD 17.3) on the Parkinsons disease Questionnaire 39 summary index. This series confirms that image-guided STN DBS without microelectrode recording can lead to substantial improvements in motor disability of well-selected PD patients with accompanying improvements in quality of life and most importantly, with very low morbidity.