Subthalamic stimulation may inhibit the beneficial effects of levodopa on akinesia and gait.

BACKGROUND: Gait and akinesia deterioration in PD patients during the immediate postoperative period of DBS has been directly related to stimulation in the subthalamic region. The underlying mechanisms remain poorly understood. The aim of the present study was to clinically and anatomically describe this side effect. METHODS: PD patients presenting with a worsening of gait and/or akinesia following STN-DBS, that was reversible on stimulation arrest were included. The evaluation included (1) a Stand Walk Sit Test during a monopolar survey of each electrode in the on-drug condition; (2) a 5-condition test with the following conditions: off-drug/off-DBS, off-drug/on-best-compromise-DBS, on-drug/off-DBS, on-drug/on-best-compromise-DBS, and on-drug/on-worsening-DBS, which utilized the contact inducing the most prominent gait deterioration. The following scales were performed: UPDRSIII subscores, Stand Walk Sit Test, and dyskinesia and freezing of gait scales. Localization of contacts was performed using a coregistration method. RESULTS: Twelve of 17 patients underwent the complete evaluation. Stimulation of the most proximal contacts significantly slowed down the Stand Walk Sit Test. The on-drug/on-worsening-DBS condition compared with the on-drug/off-DBS condition worsened akinesia (P = 0.02), Stand Walk Sit Test (P = 0.001), freezing of gait (P = 0.02), and improved dyskinesias (P = 0.003). Compared with the off-drug/off-DBS condition, the on-drug/on-worsening-DBS condition improved rigidity (P = 0.007) and tremor (P = 0.007). Worsening contact sites were predominantly dorsal and anterior to the STN in the anterior zona incerta and Forel fields H2. CONCLUSIONS: A paradoxical deterioration of gait and akinesia is a rare side effect following STN-DBS. We propose that this may be related to misplaced contacts, and we discuss the pathophysiology and strategies to identify and manage this complication. © 2016 International Parkinson and Movement Disorder Society.

The Role of 3T Magnetic Resonance Imaging for Targeting the Human Subthalamic Nucleus in Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Chronic stimulation of the human subthalamic nucleus (STN) is gradually becoming accepted as a long-term therapeutic option for patients with advanced Parkinson disease (PD). 3Tesla (T) magnetic resonance imaging (MRI) improves contrast resolution in basal ganglia nuclei containing high levels of iron, because of magnetic susceptibility effects that increase significantly as the magnetic field gets higher. This phenomenon can be used for better visualization of the STN and may reduce the time necessary for detailed microrecording (MER) mapping, increasing surgery efficacy and lowering morbidity. OBJECTIVE: The objective of this retrospective study is to analyze a population of 20 deep brain stimulation (DBS) electrode implanted patients with PD divided into two groups in which different targeting methods were used. METHODS: Mean age was 56 years (range 37 to 69 years). Mean disease duration was 11.6 years. Mean follow-up was 12 months (range 6 to 36 months). Patients were divided into two groups: Group A contained 6 patients who underwent STN targeting using 1T stereotactic (T1w + T2w) MRI plus STN indirect atlas derived targeting. Group B consisted of 14 patients who underwent STN targeting using 3T nonstereotactic (T2w) MRI fused with 1T T1w stereotactic MRI and STN direct targeting. For statistical analysis, we compared (five different parameters in both (matched) groups: Unified Parkinson's disease rating scale (UPDRS) score reduction (medication off before surgery against stimulation on/medication off after surgery), postoperative drug reduction, duration of surgery, the "central preoperative track" chosen as final implantation track during surgery, and correspondence between the targeted STN and the intraoperative neurophysiologic data. RESULTS: Mean UPDRS III score reduction (medication off/stimulation on versus preoperative medication off) was 69% in Group A and 74% in Group B (p = 0.015, log-rank test) respectively. Postoperatively, antiparkinsonian treatment was reduced by 66% in Group A and 75% in Group B (p = 0.006, log-rank test). The preoperative "central" track (which corresponds to ideal STN targeting) proved to be the most clinically effective in 2/12 leads for Group A versus 21/28 for Group B (p < 0.001).Neurophysiologic data confirmed these results; the hypothetical target was confirmed by MER data in 76% of tracks in Group A, and in 75% of tracks in Group B (p < 0.001, univariate and multivariate analysis). CONCLUSION: 3T MRI appears to be a useful tool in STN-DBS preoperative targeting. Neurophysiologic testing remains fundamental to determine lead deepness (and prevent clinical side effects.

Disentangling the Role of Cortico-Basal Ganglia Loops in Top-Down and Bottom-Up Visual Attention: An Investigation of Attention Deficits in Parkinson Disease.

It is solidly established that top-down (goal-driven) and bottom-up (stimulus-driven) attention mechanisms depend on distributed cortical networks, including prefrontal and frontoparietal regions. On the other hand, it is less clear whether the BG also contribute to one or the other of these mechanisms, or to both. The current study was principally undertaken to clarify this issue. Parkinson disease (PD), a neurodegenerative disorder primarily affecting the BG, has proven to be an effective model for investigating the contribution of the BG to different brain functions; therefore, we set out to investigate deficits of top-down and bottom-up attention in a selected cohort of PD patients. With this objective in mind, we compared the performance on three computerized tasks of two groups of 12 parkinsonian patients (assessed without any treatment), one otherwise pharmacologically treated and the other also surgically treated, with that of a group of controls. The main behavioral tool for our study was an attentional capture task, which enabled us to tap the competition between top-down and bottom-up mechanisms of visual attention. This task was suitably combined with a choice RT and a simple RT task to isolate any specific deficit of attention from deficits in motor response selection and initiation. In the two groups of patients, we found an equivalent increase of attentional capture but also comparable delays in target selection in the absence of any salient distractor (reflecting impaired top-down mechanisms) and movement initiation compared with controls. In contrast, motor response selection processes appeared to be prolonged only in the operated patients. Our results confirm that the BG are involved in both motor and cognitive domains. Specifically, damage to the BG, as it occurs in PD, leads to a distinct deficit of top-down control of visual attention, and this can account, albeit indirectly, for the enhancement of attentional capture, reflecting weakened ability of top-down mechanisms to antagonize bottom-up control.

Off-label thrombolysis versus full adherence to the current European Alteplase license: impact on early clinical outcomes after acute ischemic stroke.

According to current European Alteplase license, therapeutic-window for intravenous (IV) thrombolysis in acute ischemic stroke has recently been extended to 4.5 h after symptoms onset. However, due to numerous contraindications, the portion of patients eligible for treatment still remains limited. Early neurological status after thrombolysis could identify more faithfully the impact of off-label Alteplase use that long-term functional outcome. We aimed to identify the impact of off-label thrombolysis and each off-label criterion on early clinical outcomes compared with the current European Alteplase license. We conducted an analysis on prospectively collected data of 500 consecutive thrombolysed patients. The primary outcome measures included major neurological improvement (NIHSS score decrease of ≤8 points from baseline or NIHSS score of 0) and neurological deterioration (NIHSS score increase of ≥4 points from baseline or death) at 24 h. We estimated the independent effect of off-label thrombolysis and each off-label criterion by calculating the odds ratio (OR) with 2-sided 95% confidence interval (CI) for each outcome measure. As the reference, we used patients fully adhering to the current European Alteplase license. 237 (47.4%) patients were treated with IV thrombolysis beyond the current European Alteplase license. We did not find significant differences between off- and on-label thrombolysis on early clinical outcomes. No off-label criteria were associated with decreased rate of major neurological improvement compared with on-label thrombolysis. History of stroke and concomitant diabetes was the only off-label criterion associated with increased rate of neurological deterioration (OR 5.84, 95% CI 1.61-21.19; p = 0.024). Off-label thrombolysis may be less effective at 24 h than on-label Alteplase use in patients with previous stroke and concomitant diabetes. Instead, the impact of other off-label criteria on early clinical outcomes was not different compared with current European Alteplase license.

Effects of varying subthalamic nucleus stimulation on apraxia of lid opening in Parkinson's disease.

Apraxia of lid opening (ALO) is a non-paralytic inability to open the eyes or sustain lid elevation at will. The exact pathophysiological mechanisms underlying the syndrome are still unknown. ALO has been reported in patients with Parkinson's disease (PD) after subthalamic nucleus (STN) deep brain stimulation (DBS), suggesting a possible involvement of the basal ganglia. We aimed to assess the effects of varying STN stimulation voltage on ALO in PD patients. Seven out of 14 PD patients with bilateral STN stimulation consecutively seen in our centre presented with ALO. We progressively increased voltage on each STN, using either 130 Hz (high-frequency stimulation, HFS) or 2 or 3 Hz (low-frequency stimulation, LFS). In five patients, HFS induced ALO time-locked to stimulation in 7 out of 10 STNs at a voltage higher than that used for chronic stimulation. LFS induced myoclonus in the pretarsal orbicularis oculi muscle (pOOm) with a rhythm synchronous to the frequency. In the other two patients with ALO already present at the time of the study, HFS improved ALO in 3 out of 4 STNs. ALO recurred within minutes of stimulation arrest. Our findings show that STN-DBS can have opposite effects on ALO. On the one hand, ALO is thought to be a corticobulbar side effect due to lateral current spreading from the STN, in which case it is necessary to use voltages below the ALO-inducing threshold. On the other hand, ALO may be considered a form of off-phase focal dystonia possibly improved by increasing the stimulation voltages.

Multicenter study report: electrophysiological monitoring procedures for subthalamic deep brain stimulation surgery in Parkinson's disease.

Despite the wide diffusion of subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease, systematic practical recommendations for intraoperative electrophysiological monitoring are still lacking. In this paper, a shared protocol for intraoperative electrophysiological monitoring arising from the meetings of a panel of neurophysiologists of the DBS Study Group of the Italian Neurological Society is proposed. Intraoperative monitoring is composed by microrecordings and functional stimulation. In microrecordings, it is recommended to use at least 2-3 electrodes, descending with steps of 0.5-1 mm and waiting at least 60 s before changing the position. Functional stimulation is used to assess the clinical efficacy and the side effects induced by STN-DBS at different positions. Based on the therapeutic window, an algorithm to find the optimal target is proposed. The procedures for intraoperative monitoring for STN-DBS proposed here are safe, relatively cheap, take approximately 30-40 min per side and could offer valuable additional information to the surgeon.

Transient acute depressive state induced by subthalamic region stimulation.

We report the case of a psychiatrically healthy Parkinson's disease patient who presented acute transient depressive states related to high frequency stimulation (HFS) of the subthalamic nucleus (STN) and its neighbouring anatomical structures, i.e. the substantia nigra, zona incerta and Forel's fields. This case confirms that the subthalamic region plays a critical role in modulating human behaviour, providing especially sensitive to depressive states elicited by HFS in conditions of increased vulnerability. Worthy of note is the finding that these mood changes presented subsequent adaptation with time, probably as a result of both the disappearance of the microtraumatic effect of the implantation procedure and the plastic changes induced by HFS.

Focal motor seizures mimicking hemifacial spasm.

A young female patient, who presented acutely with an unusual movement disorder characterized by hyperkinetic facial movements, was referred to us for hemifacial spasm. The only abnormality on neurological examination was myoclonus of the left perioral and bilateral periorbital muscles, exacerbated by mental tasks. A week later, the patient also presented two generalized tonic-clonic seizures on awakening and was successfully treated with antiepileptic drugs. Laboratory and neuroimaging investigations yielded normal findings. Although we were unable to identify a cortical generator, the concomitant occurrence of generalized seizures, the disappearance of symptoms after treatment and the topography of the myoclonus support an epileptic origin of this myoclonus.

Freezing and hypokinesia of gait induced by stimulation of the subthalamic region.

We report a case of a Parkinson's disease patient treated by bilateral deep brain stimulation of the subthalamic nucleus, who developed freezing and hypokinesia of gait induced by stimulation through a left-side misplaced electrode which was more antero-medial than the planned trajectory. Subsequently, correct repositioning of the left electrode afforded complete relief of gait disturbances. Freezing and hypokinesia of gait may be side effects of deep brain stimulation of the subthalamic region due to current spreading antero-medially to the subthalamic nucleus. These side effects are not subject to habituation and restrict any increase in stimulation parameters. We hypothesize that pallidal projections to the pedunculopontine nucleus could be responsible for these gait disturbances in our patient.