Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects.

Background: Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs. Methods: Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested. Results: Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure. Conclusion: We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.

Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke.

BACKGROUND AND PURPOSE: The potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke. METHODS: We examined the effect of PAS in fourteen participants with chronic hemiparetic stroke at five time-points in a within-subjects repeated measures design study: baseline off-drug, and following a week of orally administered memantine at doses of 5, 10, 15, and 20 mg, comprising a total of seventy sessions. Each week, MEP amplitude pre and post-PAS was assessed in the contralesional hemisphere as a marker of enhanced or diminished plasticity. Strength and dexterity were recorded each week to monitor motor-specific clinical status across the study period. RESULTS: We found that MEP amplitude was significantly larger after PAS in baseline sessions off-drug, and responsiveness to PAS in these sessions was associated with increased clinical severity. There was no observed increase in MEP amplitude after PAS with memantine at any dose. Motor threshold (MT), strength, and dexterity remained unchanged during the study. CONCLUSION: Paired associative stimulation successfully induced corticospinal excitability enhancement in chronic stroke subjects at the group level. However, this response did not occur in all participants, and was associated with increased clinical severity. This could be an important way to stratify patients for future PAS-drug studies. PAS was suppressed by memantine at all doses, regardless of responsiveness to PAS off-drug, indicating CNS engagement.

Frameless robot-assisted stereoelectroencephalography for refractory epilepsy in pediatric patients: accuracy, usefulness, and technical issues.

BACKGROUND: Stereoelectroencephalography (SEEG) is an effective technique to help to locate and to delimit the epileptogenic area and/or to define relationships with functional cortical areas. We intend to describe the surgical technique and verify the accuracy, safety, and effectiveness of robot-assisted SEEG in a newly created SEEG program in a pediatric center. We focus on the technical difficulties encountered at the early stages of this program. METHODS: We prospectively collected SEEG indication, intraoperative events, accuracy calculated by fusion of postoperative CT with preoperative planning, complications, and usefulness of SEEG in terms of answering preimplantation hypothesis. RESULTS: Fourteen patients between the ages of 5 and 18 years old (mean 10 years) with drug-resistant epilepsy were operated on between April 2016 and April 2018. One hundred sixty-four electrodes were implanted in total. The median entry point localization error (EPLE) was 1.57 mm (1-2.25 mm) and the median target point localization error (TPLE) was 1.77 mm (1.2-2.6 mm). We recorded seven intraoperative technical issues. Two patients suffered complications: meningitis without demonstrated germ in one patient and a right frontal hematoma in the other. In all cases, the SEEG was useful for the therapeutic decision-making. CONCLUSION: SEEG has been useful for decision-making in all our pediatric patients. The robotic arm is an accurate tool for the insertion of the deep electrodes. Nevertheless, it is an invasive technique not risk-free and many problems can appear at the beginning of a robotic arm-assisted SEEG program that must be taken into account beforehand.

Frameless robot-assisted pallidal deep brain stimulation surgery in pediatric patients with movement disorders: precision and short-term clinical results.

OBJECTIVE: The purpose of this study was to verify the safety and accuracy of the Neuromate stereotactic robot for use in deep brain stimulation (DBS) electrode implantation for the treatment of hyperkinetic movement disorders in childhood and describe the authors' initial clinical results. METHODS: A prospective evaluation of pediatric patients with dystonia and other hyperkinetic movement disorders was carried out during the 1st year after the start-up of a pediatric DBS unit in Barcelona. Electrodes were implanted bilaterally in the globus pallidus internus (GPi) using the Neuromate robot without the stereotactic frame. The authors calculated the distances between the electrodes and their respective planned trajectories, merging the postoperative CT with the preoperative plan using VoXim software. Clinical outcome was monitored using validated scales for dystonia and myoclonus preoperatively and at 1 month and 6 months postoperatively and by means of a quality-of-life questionnaire for children, administered before surgery and at 6 months' follow-up. We also recorded complications derived from the implantation technique, "hardware," and stimulation. RESULTS: Six patients aged 7 to 16 years and diagnosed with isolated dystonia ( DYT1 negative) (3 patients), choreo-dystonia related to PDE2A mutation (1 patient), or myoclonus-dystonia syndrome SGCE mutations (2 patients) were evaluated during a period of 6 to 19 months. The average accuracy in the placement of the electrodes was 1.24 mm at the target point. At the 6-month follow-up, patients showed an improvement in the motor (65%) and functional (48%) components of the Burke-Fahn-Marsden Dystonia Rating Scale. Patients with myoclonus and SGCE mutations also showed an improvement in action myoclonus (95%-100%) and in functional tests (50%-75%) according to the Unified Motor-Rating Scale. The Neuro-QOL score revealed inconsistent results, with improvement in motor function and social relationships but worsening in anxiety, cognitive function, and pain. The only surgical complication was medial displacement of the first electrode, which limited intensity of stimulation in the lower contacts, in one case. CONCLUSIONS: The Neuromate stereotactic robot is an accurate and safe tool for the placement of GPi electrodes in children with hyperkinetic movement disorders.