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Marta San Luciano, Amy Robichaux-Viehoever, Kristen A. Dodenhoff, Melissa L. Gittings, Aaron C. Viser, Caroline A. Racine, Ian O. Bledsoe, Christa Watson Pereira, Sarah S. Wang, Philip A. Starr, and Jill L. Ostrem

OBJECTIVE

The aim of this study was to evaluate the feasibility and preliminary efficacy and safety of combined bilateral ventralis oralis posterior/ventralis intermedius (Vop/Vim) deep brain stimulation (DBS) for the treatment of acquired dystonia in children and young adults. Pallidal DBS is efficacious for severe, medication-refractory isolated dystonia, providing 50%–60% long-term improvement. Unfortunately, pallidal stimulation response rates in acquired dystonia are modest and unpredictable, with frequent nonresponders. Acquired dystonia, most commonly caused by cerebral palsy, is more common than isolated dystonia in pediatric populations and is more recalcitrant to standard treatments. Given the limitations of pallidal DBS in acquired dystonia, there is a need to explore alternative brain targets. Preliminary evidence has suggested that thalamic stimulation may be efficacious for acquired dystonia.

METHODS

Four participants, 3 with perinatal brain injuries and 1 with postencephalitic symptomatic dystonia, underwent bilateral Vop/Vim DBS and bimonthly evaluations for 12 months. The primary efficacy outcome was the change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) scores between the baseline and 12-month assessments. Video documentation was used for blinded ratings. Secondary outcomes included evaluation of spasticity (Modified Ashworth Scale score), quality of life (Pediatric Quality of Life Inventory [PedsQL] and modified Unified Parkinson’s Disease Rating Scale Part II [UPDRS-II] scores), and neuropsychological assessments. Adverse events were monitored for safety.

RESULTS

All participants tolerated the procedure well, and there were no safety concerns or serious adverse events. There was an average improvement of 21.5% in the BFMDRS motor subscale score, but the improvement was only 1.6% according to the BADS score. Following blinded video review, dystonia severity ratings were even more modest. Secondary outcomes, however, were more encouraging, with the BFMDRS disability subscale score improving by 15.7%, the PedsQL total score by 27%, and the modified UPDRS-II score by 19.3%. Neuropsychological assessment findings were unchanged 1 year after surgery.

CONCLUSIONS

Bilateral thalamic neuromodulation by DBS for severe, medication-refractory acquired dystonia was well tolerated. Primary and secondary outcomes showed highly variable treatment effect sizes comparable to those of pallidal stimulation in this population. As previously described, improvements in quality of life and disability were not reflected in dystonia severity scales, suggesting a need for the development of scales specifically for acquired dystonia.

Clinical trial registration no.: NCT03078816 (clinicaltrials.gov)

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Jill L. Ostrem, Nathan Ziman, Nicholas B. Galifianakis, Philip A. Starr, Marta San Luciano, Maya Katz, Caroline A. Racine, Alastair J. Martin, Leslie C. Markun, and Paul S. Larson

OBJECT

The ClearPoint real-time interventional MRI-guided methodology for deep brain stimulation (DBS) lead placement may offer advantages to frame-based approaches and allow accurate implantation under general anesthesia. In this study, the authors assessed the safety and efficacy of DBS in Parkinson’s disease (PD) using this surgical method.

METHODS

This was a prospective single-center study of bilateral DBS therapy in patients with advanced PD and motor fluctuations. Symptom severity was evaluated at baseline and 12 months postimplantation using the change in Unified Parkinson’s Disease Rating Scale (UPDRS) Part III “off” medication score as the primary outcome variable.

RESULTS

Twenty-six PD patients (15 men and 11 women) were enrolled from 2010 to 2013. Twenty patients were followed for 12 months (16 with a subthalamic nucleus target and 4 with an internal globus pallidus target). The mean UPDRS Part III “off” medication score improved from 40.75 ± 10.9 to 24.35 ± 8.8 (p = 0.001). “On” medication time without troublesome dyskinesia increased 5.2 ± 2.6 hours per day (p = 0.0002). UPDRS Parts II and IV, total UPDRS score, and dyskinesia rating scale “on” medication scores also significantly improved (p < 0.01). The mean levodopa equivalent daily dose decreased from 1072.5 ± 392 mg to 828.25 ± 492 mg (p = 0.046). No significant cognitive or mood declines were observed. A single brain penetration was used for placement of all leads, and the mean targeting error was 0.6 ± 0.3 mm. There were 3 serious adverse events (1 DBS hardware-related infection, 1 lead fracture, and 1 unrelated death).

CONCLUSIONS

DBS leads placed using the ClearPoint interventional real-time MRI-guided method resulted in highly accurate lead placement and outcomes comparable to those seen with frame-based approaches.

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Steven W. Cheung, Caroline A. Racine, Jennifer Henderson-Sabes, Carly Demopoulos, Annette M. Molinaro, Susan Heath, Srikantan S. Nagarajan, Andrea L. Bourne, John E. Rietcheck, Sarah S. Wang, and Paul S. Larson

OBJECTIVE

The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.

METHODS

Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint.

RESULTS

The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event.

CONCLUSIONS

Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%–80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.

Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

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Eduardo Caverzasi, Shawn L. Hervey-Jumper, Kesshi M. Jordan, Iryna V. Lobach, Jing Li, Valentina Panara, Caroline A. Racine, Vanitha Sankaranarayanan, Bagrat Amirbekian, Nico Papinutto, Mitchel S. Berger, and Roland G. Henry

OBJECT

Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping.

The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection.

METHODS

The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery.

RESULTS

This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005).

CONCLUSIONS

The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits.

Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits.