Dual Antiplatelet Therapy with Parenteral P2Y12 Inhibitors: Rationale, Evidence, and Future Directions.

Dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and an inhibitor of the platelet P2Y12 receptor for ADP, remains among the most investigated treatments in cardiovascular medicine. While a substantial amount of research initially stemmed from the observations of late and very late stent thrombosis events in the first-generation drug-eluting stent (DES) era, DAPT has been recently transitioning from a purely stent-related to a more systemic secondary prevention strategy. Oral and parenteral platelet P2Y12 inhibitors are currently available for clinical use. The latter have been shown to be extremely suitable in drug-naïve patients with acute coronary syndrome (ACS), mainly because oral P2Y12 inhibitors are associated with delayed efficacy in patients with STEMI and because pre-treatment with P2Y12 inhibitors is discouraged in NSTE-ACS, and in patients with recent DES implantation and in need of urgent cardiac and non-cardiac surgery. More definitive evidence is needed, however, about optimal switching strategies between parenteral and oral P2Y12 inhibitors and about newer potent subcutaneous agents that are being developed for the pre-hospital setting.

High Cervical Spinal Cord Stimulation: A One Year Follow-Up Study on Motor and Non-Motor Functions in Parkinson's Disease.

BACKGROUND: The present study investigated the effectiveness of stimulation applied at cervical levels on pain and Parkinson's disease (PD) symptoms using either tonic or burst stimulation mode. METHODS: Tonic high cervical spinal cord stimulation (T-HCSCS) was applied on six PD patients suffering from low back pain and failed back surgery syndrome, while burst HCSCS (B-HCSCS) was applied in twelve PD patients to treat primarily motor deficits. Stimulation was applied percutaneously with quadripolar or octapolar electrodes. Clinical evaluation was assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H&Y) scale. Pain was evaluated by a visual analog scale. Evaluations of gait and of performance in a cognitive motor task were performed in some patients subjected to B-HCSCS. One patient who also suffered from severe autonomic cardiovascular dysfunction was investigated to evaluate the effectiveness of B-HCSCS on autonomic functions. RESULTS: B-HCSCS was more effective and had more consistent effects than T-HCSCS in reducing pain. In addition, B-HCSCS improved UPDRS scores, including motor sub-items and tremor and H&Y score. Motor benefits appeared quickly after the beginning of B-HCSCS, in contrast to long latency improvements induced by T-HCSCS. A slight decrease of effectiveness was observed 12 months after implantation. B-HCSCS also improved gait and ability of patients to correctly perform a cognitive-motor task requiring inhibition of a prepared movement. Finally, B-HCSCS ameliorated autonomic control in the investigated patient. CONCLUSIONS: The results support a better usefulness of B-HCSCS compared to T-HCSCS in controlling pain and specific aspects of PD motor and non-motor deficits for at least one year.

Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Techniques, Side Effects, and Postoperative Imaging.

The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS.

The deep brain stimulation of the pedunculopontine tegmental nucleus.

Objective. The aim of the present study was to describe the surgical and clinical outcomes of the implantation and stimulation of the pedunculopontine tegmental nucleus in humans. Materials and Methods. Fourteen patients affected by movement disorders (12 Parkinson's disease and 2 progressive supranuclear palsy) underwent surgery for bilateral or monolateral implantation of stimulating electrodes in the pedunculopontine tegmental nucleus. The correct placement of electrodes was established and verified by combining angio-CT scans with magnetic resonance imaging. Intraoperative and postoperative evaluations were made to assess the clinical effectiveness of stimulation according to different Unified Parkinson's Disease Rating Scale items and neurophysiologic parameters. Results. No major complications occurred following the insertion of electrodes into the pedunculopontine tegmental nucleus. Neuroimaging showed that the electrode contacts were always correctly placed below the ponto-mesencephalic line. Stimulation of the pedunculopontine tegmental nucleus improved gait, posture, and speech, and modulated reflexes integrated at spinal or pontine levels. Conclusions. The surgical targeting of the pedunculopontine tegmental nucleus requires a careful adaptation of the traditional stereotactic approaches owing to the high variability of brainstem anatomy from one patient to another. The insertion of the leads in the pedunculopontine tegmental nucleus as well as their activation did not appear to induce serious adverse effects. The correct positioning of stimulating electrodes in pontine structures such as the pedunculopontine nucleus may be ascertained not only through neuroimaging techniques but also through clinical neurophysiology. The evolution of the surgical planning that we have developed emphasizes the limited value of single-unit recordings to identify the pedunculopontine tegmental nucleus and highlights the opportunities offered by functional evaluations of neurophysiologic parameters. As far as the clinical efficacy is concerned, our data suggest a promising outcome for simultaneous implantations of different basal ganglia nuclei in Parkinsonian and in progressive supranuclear palsy patients as well.

Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease.

Gait disturbances and akinesia are extremely disabling in advanced Parkinson's disease. It has been suggested that modulation of the activity of the pedunculopontine nucleus (PPN) may be beneficial in the treatment of these symptoms. We report the clinical affects of deep brain stimulation (DBS) in the PPN and subthalamic nucleus (STN). Six patients with unsatisfactory pharmacological control of axial signs such as gait and postural stability underwent bilateral implantation of DBS electrodes in the STN and PPN. Clinical effects were evaluated 2-6 months after surgery in the OFF- and ON-medication state, with both STN and PPN stimulation ON or OFF, or with only one target being stimulated. Bilateral PPN-DBS at 25 Hz in OFF-medication produced an immediate 45% amelioration of the motor Unified Parkinson's Disease Rating Scale (UPDRS) subscale score, followed by a decline to give a final improvement of 32% in the score after 3-6 months. In contrast, bilateral STN-DBS at 130-185 Hz led to about 54% improvement. PPN-DBS was particularly effective on gait and postural items. In ON-medication state, the association of STN and PPN-DBS provided a significant further improvement when compared to the specific benefit mediated by the activation of either single target. Moreover, the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities. These findings indicate that, in patients with advanced Parkinson's disease, PPN-DBS associated with standard STN-DBS may be useful in improving gait and in optimizing the dopamine-mediated ON-state, particularly in those whose response to STN only DBS has deteriorated over time. This combination of targets may also prove useful in extra-pyramidal disorders, such as progressive supranuclear palsy, for which treatments are currently elusive.

Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease.

The peduncolopontine nucleus modulates locomotor activity and dysfunction in this nucleus may be responsible for the gait and postural impairments seen in Parkinson's disease and other movement disorders. We report the first surgical exploration and implantation of deep brain stimulating electrodes of the peduncolopontine nucleus area in two Parkinson's disease patients to examine the safety and the potential benefit of chronic electrical stimulation at this site. Under local anesthesia, the peduncolopontine nucleus was approached from a coronal burr hole using a trajectory that was 78-80 degrees and 62-64 degrees on the coronal and sagittal planes. Microrecordings helped to identify neurons in peduncolopontine nucleus and the adjacent substantia nigra pars reticulata. Chronic deep brain stimulating electrodes were implanted within the peduncolopontine nucleus in a manner similar to that practiced with deep brain stimulating surgery at other targets. Peduncolopontine nucleus neurons were characterized by small and broad multiunits (230 muV, 2.5 ms, 14.6 Hz). Caudal to this area, neurons firing at higher frequency, approximately 70 Hz, characteristic of nigral neuronal discharges, were encountered, followed by 2 mm of cells similar to those recorded in the dorsal peduncolopontine nucleus area. After deep brain stimulating electrodes implantation, acute intraoperative stimulation (up to 3 V) was performed with two stimulation frequencies in each session. Stimulation at 80 Hz has little discernable effect. On the other hand, stimulation at 10 Hz fostered a subjective feeling of 'well-being' and a time-locked amelioration of the clinical scores. These findings demonstrate that the stereotactic approach of peduncolopontine nucleus is safe. The target may reliably be identified by microrecordings. Low-frequency stimulation may produce acute improvements in motor function.

Somatosensory evoked potential and clinical changes after electrode implant in basal ganglia of parkinsonian patients.

Median nerve somatosensory evoked potentials (SEPs) were recorded in three parkinsonian patients who underwent electrode implant in the subthalamic nucleus and/or globus pallidus for chronic deep brain stimulation (DBS). SEPs were evoked before surgery, in a medication-free condition, and after the functional stereotactic procedure, before beginning DBS. In order to evaluate the timing of the SEP changes after the electrode implant, in three further patients SEPs were recorded within the operating theater, before and immediately after the implantation. Patients' symptoms improved immediately after the electrode implant, and both N20 and N30 amplitudes increased in the postsurgical SEP recording. The clinical and neurophysiological effects observed after surgery, before commencing DBS, can be explained by microdamage in the target nucleus following the electrode implant. They occurred also in the patients studied in the operating theater, thus suggesting that they occur immediately after the stereotactic procedure. Our results suggest that the circuitries between the basal ganglia and the primary sensorimotor cortex may be modified not only by DBS but also by microdamage due to surgery and that they exert an important influence on SEP amplitude.

Oscillatory pallidal local field potential activity inversely correlates with limb dyskinesias in Parkinson's disease.

Levodopa induced dyskinesias (LIDs) are poorly understood and yet are a major cause of disability in Parkinson's disease (PD). The activity of neurons in the basal ganglia of patients with PD tends to be strongly synchronized at frequencies under 30 Hz, leading to oscillatory local field potentials (LFPs). As dopaminergic therapy acutely suppresses this synchronization, we investigated whether this suppression may contribute to LIDs. Accordingly, we sought an inverse correlation between oscillatory synchronization and dyskinesia activity across time. To this end, we recorded pallidal LFPs in two Parkinsonian subjects exhibiting LIDs following surgery for deep brain stimulation. We correlated LFP power with simultaneously recorded EMG from the dyskinetic contralateral upper limb. We found highly significant inverse correlations between the oscillatory LFP activity under 30 Hz and dyskinetic EMG (maximum r = -0.65, P < 0.001 and r = -0.33, P < 0.001 for activities over 13-30 Hz in each subject). The inverse relationship between oscillatory pallidal LFP activity and dyskinetic EMG was maintained over time periods of a few seconds and was focal. This observation links the suppression of oscillatory synchronization in the pallidum with dyskinetic muscle activity in PD.

Bilateral implantation in globus pallidus internus and in subthalamic nucleus in Parkinson's disease.

Introduction. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and of the pars interna of Globus Pallidus (GPi) is used to improve parkinsonian symptoms and attenuate levodopa-induced motor complications in Parkinson's disease (PD) (DBS for PD study group, 2001). It is still not clear what the best anatomic structures to stimulate are or what the physiologic effects of DBS are. Most of the studies regarding DBS for parkinsonian symptoms have been conducted in patients with STN implantation, and these studies reported significant improvement in motor function with a relatively low rate of complication. The large experience of ablative surgery associated with the DBS experience of some groups worldwide indicate that GPi is a possible and very promising target for the management of parkinsonian symptoms. Surgical procedures have become safer and it is now possible, in selected cases, to target both structures in the same patient by means of the stereotactic system, "3P Maranello" (CLS-SRL, Italy). Using this system we were able to evaluate the clinical effects of simultaneous stimulation of both STN and GPi as well as evaluate the effects of isolated stimulation of each target. As it is known that there is a high intersubject variability of DBS, it seems relevant to test all different combinations of DBS in the same patient. Methods. We assessed the effects of DBS in 13 cases of PD, immediately after (30 min) stimulation and during chronic stimulation (weeks or months). Patients fell into two groups. The first (n = 7) responded to both GPi and STN stimulation equally. The second group (n = 6) was preferentially stimulated with only one target (STN = 5, GPi = 1). Results. There was a good reduction in levodopa treatment following surgery. Most patients remained were chronically treated with bilateral stimulation of both targets. Conclusion. We conclude that DBS of STN and GPi was effective, with most patients treated chronically with both targets stimulated.