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BACKGROUND Delayed facial palsy (DFP) after resection of vestibular schwannomas (VS) is worsening of facial nerve function after an initially normal postoperative result. OBJECTIVE To characterize different types of DFP, compare recovery rates, and review of series of outcomes in patients following resection of VS. METHODS Between 2001 and 2017, 434 patients (51% female) with VS underwent resection. We categorized the patients who developed facial palsy into groups based on timing of onset after surgery, immediate facial palsy (IFP), early-onset DFP (within 48 h), and late-onset DFP (after 48 h). Introduction of facial nerve motor-evoked potentials (fMEP) in 2002 and a change of practice utilizing perioperative minocycline in 2005 allowed for historical analysis of these interventions. RESULTS Mean age of study cohort was 49.1 yr (range 13-81 yr), with 19.8% developing facial palsy. The late-onset DFP group demonstrated a significantly faster recovery than the early-onset DFP group (2.8 ± 0.5 vs 47 ± 8 wk, P

BackgroundFreezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson’s Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted.MethodsAs part of an open-label Phase 1 clinical study, one PD patient with predominantly axial symptoms and severe FOG refractory to levodopa therapy was implanted with directional DBS electrodes (Boston Science Vercise CartesiaTM) targeting the CnF bilaterally. Since the CnF is a poorly defined reticular nucleus, targeting was guided both by diffusion tensor imaging (DTI) tractography and anatomical landmarks. Intraoperative stimulation and microelectrode recordings were performed near the targets with leg EMG surface recordings in the subject.ResultsPost-operative imaging revealed accurate targeting of both leads to the designated CnF. Intraoperative stimulation near the target at low thresholds in the awake patient evoked involuntary electromyography (EMG) oscillations in the legs with a peak power at the stimulation frequency, similar to observations with CnF DBS in animals. Oscillopsia was the primary side effect evoked at higher currents, especially when directed posterolaterally. Directional DBS could mitigate oscillopsia.ConclusionDTI-based targeting and intraoperative stimulation to evoke limb EMG activity may be useful methods to help target the CnF accurately and safely in patients. Long term follow-up and detailed gait testing of patients undergoing CnF stimulation will be necessary to confirm the effects on FOG.Clinical Trial RegistrationClinicaltrials.gov identifier: NCT04218526.

Background Freezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson’s disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG, was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive mesencephalic locomotor region (MLR) preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation. Methods We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow-up. Discussion This paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target. Trial registration ClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020)

Background: Freezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson’s Disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive MLR preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation.Methods: We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow up.Discussion: This paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target.Trial Registration: Clinicaltrials.gov Identifier: NCT04218526 (registered January 6, 2020), https://www.clinicaltrials.gov/ct2/show/NCT04218526

Aberrant regulation of programmed cell death (PCD) has been tied to an array of human pathologies ranging from cancers to autoimmune disorders to diverse forms of neurodegeneration. Pharmacologic modulation of PCD signalling is therefore of central interest to a number of clinical and biomedical applications. A key component of PCD signalling involves the modulation of pro‐ and anti‐apoptotic Bcl‐2 family members. Among these, Bax translocation represents a critical regulatory phase in PCD. In the present study, we have employed a high‐content high‐throughput screen to identify small molecules which inhibit the cellular process of Bax re‐distribution to the mitochondria following commitment of the cell to die. Screening of 6246 Generally Recognized As Safe compounds from four chemical libraries post‐induction of cisplatin‐mediated PCD resulted in the identification of 18 compounds which significantly reduced levels of Bax translocation. Further examination revealed protective effects via reduction of executioner caspase activity and enhanced mitochondrial function. Consistent with their effects on Bax translocation, these compounds exhibited significant rescue against in vitro and in vivo cisplatin‐induced apoptosis. Altogether, our findings identify a new set of clinically useful small molecules PCD inhibitors and highlight the role which cAMP plays in regulating Bax‐mediated PCD.

Background: Stimulation parameters are crucial for the efficacy and safety of motor cortex stimulation (MCS). Motor threshold (MT) can be defined as the lowest voltage that produces motor contraction. The final stimulation parameters are always a smaller percentage of MT in order to avoid seizures. We determined how patient position and activity affect MT. Methods: Prospective MT measurements were made while patients were either lying down or sitting up, and in a resting state or while actively contracting the target muscle. Paired 1-tailed t tests were performed to assess for statistically significant differences between MT measurements made under the 4 different combinations of position and activity. Results: The MT was lower when the target muscle was being actively contracted compared to resting in both supine and upright positions (both p < 0.001). The MT was also lower when upright compared to supine in both resting and active states of muscle contraction (both p < 0.001). The mean difference between supine resting and upright active states is 0.79 V. Conclusion: When selecting final stimulation parameters for MCS, clinicians should be aware that the lowest MT is elicited while patients are seated upright and actively contracting the target muscle. Using this method of determining the MT when calculating the final stimulation parameters could reduce the chance of MCS-induced seizures.

Introduction Stereotactic mesencephalotomy is an ablative procedure which lesions the pain pathways (spinothalamic and trigeminothalamic tracts) at the midbrain level to treat medically refractory, nociceptive, contralateral pain. Sparsely reported in contemporary English language literature, this operation is at risk of being lost from the modern-day neurosurgical practice. Methods We present a case report and brief review of the literature on stereotactic mesencephalotomy. A 17-year-old girl with cervical cord glioblastoma and medically refractory unilateral head and neck pain was treated with contralateral stereotactic mesencephalotomy. The lesion was placed at the level of the inferior colliculus, half way between the lateral edge of the aqueduct and lateral border of the midbrain. Results The patient had no head and neck pain immediately after the procedure and remained pain-free for the remainder of her life (five months). She was weaned off her pre-operative narcotics and was able to leave hospital, meeting her palliative care goals. Conclusions Cancer-related unilateral head and neck nociceptive pain in the palliative care setting can be successfully treated with stereotactic mesencephalotomy. We believe that stereotactic mesencephalotomy is the treatment of choice for a small number of patients typified by our case. The authors make a plea to the palliative care and neurosurgical communities to rediscover this operation.

Objectives No widely accepted programming guidelines for motor cortex stimulation (MCS) exist. We propose that an individual's effective stimulation voltage can be predicted as their percentage of motor threshold (PMT). Materials and Methods Seven patients already successfully treated with MCS for neuropathic pain were included. Patients received stimulation that was the same as their baseline PMT (“medium”), 10% higher (“high”) or 10% lower (“low”) in a blinded, randomized study. Outcome was assessed after 14 days with the visual analogue scale for pain, the McGill pain questionnaire, and the SF-36 questionnaire. Results The best treatment response (mean VAS 3.4) was seen with the medium setting which was at a mean of 62% PMT. High and low settings both resulted in a significant increase in pain compared with the medium setting (mean VAS 6.0 and 6.3, respectively) and a significant decrease in SF-36 scores. No significant difference in pain control was observed between the high and low settings. The mean time from changes in treatment settings to reported change in pain level was 2.9 days (±1.0 day). Conclusions We propose that the PMT represents an important parameter that measures the degree to which MCS may be affecting the motor cortex. A mean PMT of 62% was required for effective pain relief. Higher settings did not result in increased therapeutic efficacy but rather in a significant increase in pain. Targeting therapy to a PMT level may speed initial programming, allow more consistent longitudinal follow-up, and be a basis for a standardized programming paradigm.