Gustavo Polo

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.

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.

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.

Chorea induced by globus pallidus externus stimulation in a dystonic patient

Bilateral high‐frequency stimulation of the internal part of the pallidum has proven its efficacy in improving motor symptoms of dystonia. In Parkinsons disease, the stimulation of the external pallidum (GPe) can induce dyskinesias. This has never been described in dystonia. We report here a case of abnormal movements induced by the stimulation of GPe in a dystonic patient and discuss the pathophysiological mechanisms.

Relapse of tardive dystonia after globus pallidus deep-brain stimulation discontinuation.

Tardive dyskinesia and dystonia (TD) is a disabling condition caused by exposure to dopamine receptor blocking agents and encompasses a wide spectrum of abnormal movements, for which the effect of medical treatment is often disappointing [1]. High-frequency deep-brain stimulation (DBS), targeting the sensorimotor part of the internal globus pallidus (GPi), has shown, in open label studies, significant efficacy for severe TD [1, 2]. GPi DBS provides as well a clear benefit in primary dystonia and its discontinuation is usually followed by the rapid resurgence of sometimes life-threatening symptoms [3, 4]. However, some reports have suggested maintained clinical efficacy despite DBS interruption in primary or cervical dystonia, which questions the fact that DBS might have a diseasemodifying effect [5–7]. Such observation has never been made in TD. Here, we present a clinical observation of the re-occurrence of TD several weeks after GPi DBS interruption despite several years of stimulation. This 44-year-old woman was diagnosed with bipolar disorder at the age of 16 and had received several antipsychotic medications for many years (for long periods and sequentially: chlorpromazine, flupentixol, haloperidol, cyamemazine and for short periods: loxapine, alimemazine, risperidone and olanzapine). Severe cervical and axial dystonia started 3 years after neuroleptics onset, with left torticollis, antecollis and retrocaput associated with jerky movements, right shoulder antepulsion and extension of the dystonia to the trunk. Antipsychotic drugs suspension, tetrabenazine, clonazepam and botulinum toxin injections failed to improve the symptoms. Thus, bilateral ventroposterolateral GPi DBS was performed 15 years after disease onset. Bilateral monopolar stimulation was used (left side: contact 1 negative, case positive, 3.5 V/ 90 ls/130 Hz; right side: contact 9 negative, case positive, 3.5 V/90 ls/130 Hz). Hyperkinetic movements were rapidly suppressed, whereas dystonic postures improved more progressively as well as kyphoscoliosis. Abnormal Involuntary Movement Score (AIMS) decreased from 14 at baseline to 3 at 6 months postoperatively. The benefit was maintained for 10 years, and the patient remained free of any antipsychotic drugs. Then, 10 years after DBS onset, an infection of the internal pulse generator occurred after a second battery replacement, leading to stimulator removal (the electrodes were left in place) and stimulation arrest. No clinical worsening was observed during the first month after DBS cessation. Then, abnormal postures and jerks slowly reappeared and became more and more disabling with an AIMS score of 9 at 3 months after DBS cessation. Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7404-x) contains supplementary material, which is available to authorized users.

Do the effects measured by intraoperative and postoperative STN macrostimulation in Parkinson’s disease match?

The aim of our study was to compare the results obtained by intraoperative and postoperative subthalamic nucleus (STN) macrostimulation in Parkinson’s disease (PD). One hundred three PD patients implanted with bilateral STN stimulation were included. The thresholds for efficacy and side effects (motor contraction; paresthesias; oculomotor signs) observed on the same trajectory and at the same depth during the intraoperative evaluation and the first postoperative setting of STN stimulation parameters were collected. The level of improvement was divided into four categories depending on the degree of rigidity reduction: 0: no effect, A (mediocre efficacy): 20–50%, B (good efficacy): 60–100%, LL: lesion-like effect (disappearance of rigidity after implantation). Efficacy of STN stimulation was analyzed in 83 patients for a total of 664 contacts. For the best effects (B, LL), the results obtained in the operative room were concordant with those of the postoperative evaluation for 81% of the contacts. For the mediocre effects (A) and absence of efficacy, the results were only concordant in 20%. Side effects were analyzed in 103 patients for a total of 824 contacts. In 35% of the tested contacts paresthesias that were absent during surgery were observed postoperatively. This discrepancy was of 17% for the motor and of 10% for oculomotor side effects. Differences between the type of electrodes used, the stimulation parameters employed and the conditions of the assessment could explain these discrepancies.

Toe dystonia in Parkinson's disease: Impact of subthalamic nucleus deep brain stimulation

BACKGROUND Off state toe dystonia (TD) is a symptom frequently encountered in Parkinsons disease (PD), but little is known about its evolution after subthalamic nucleus deep brain stimulation (STN-DBS). OBJECTIVE To analyze the prevalence and the evolution of TD in PD patients candidate to STN-DBS. METHODS Individual data of consecutive 130 PD patients who underwent STN-DBS between 2010 and 2015 were collected. RESULTS Data were successfully collected in 95 patients. TD affect 45.3% of the patients in our cohort. TD was present in 32.7% of patients before surgery and was alleviated by STN-DBS in 48% of the cases. Motor improvement provided by STN-DBS, levodopa-equivalent treatment diminution after surgery, disease duration or age at the time of surgery were not predictive of TD evolution. A younger age at PD diagnosis was significantly associated with TD resolution. CONCLUSION STN-DBS is partially efficient for TD but its evolution seems independent of significant predictive factors.

Spinal Cord Stimulation for Intractable Pain

Spinal cord stimulation is a major treatment for chronic pain resistant to medications. The main established indications are neuropathic pain, failed back surgery syndrome, complex regional pain syndrome, peripheral vascular disease, and angina pectoris. Long-term effectiveness depends on strict selection of patients. Anatomical and functional integrity of the dorsal column fibers (i.e., from their body cells in the dorsal root ganglion up to the brainstem) is mandatory. Integrity can be checked, prior to decision-making of implantation, by using SSEPs, namely the central conduction time (CCT), i.e., the N13–N20 interval for the upper limb and the N22–P39 interval for the lower limb. In our study, when CCT was normal, long-term pain relief (>50 % on VAS) was achieved in 84 % of the patients, versus in none of the patients when CCT was significantly altered. Implantation can be performed percutaneously or by open surgery. Provided a strict selection of the patients and a rigorous location of the electrode (optimally, at the upper level of the painful territory), long-term results are satisfactory in most of the patients.