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Ellen L. Air, Jill L. Ostrem, Terence D. Sanger, and Philip A. Starr

Object

Deep brain stimulation (DBS) is an established technique for the treatment of several movement disorders in adults. However, the technical approach, complications, and results of DBS in children have not been well documented.

Methods

A database of DBS implantations performed at a single institution, prospectively established in 1998, was reviewed for patients who received DBS prior to the age of 18. Diagnoses, surgical technique, and complications were noted. Outcomes were assessed using standard rating scales of neurological function.

Results

Of 815 patients undergoing DBS implantation over a 12-year period, 31 were children (mean age at surgery 13.2 years old, range 4–17 years old). Diagnoses included the following: DYT1 primary dystonia (autosomal dominant, Tor1AΔGAG mutation, 10 cases), non-DYT1 primary dystonia (3 cases), secondary dystonia (11 cases), neurodegeneration with brain iron accumulation (NBIA, 3 cases), levodopa-responsive parkinsonism (2 cases), Lesch-Nyhan disease (1 case), and glutaric aciduria Type 1 (1 case). Six children ages 15–17 years old underwent awake microelectrode-guided surgery. For 25 children operated under general anesthesia, the surgical technique evolved from microelectrode-guided surgery to image-guided surgeries using real-time intraoperative MR imaging or CT for lead location confirmation. Complications included 5 hardware infections, all in children younger than 10 years old. At 1 year after implantation, patients with DYT1 dystonia had a mean improvement in the Burke-Fahn-Marsden Dystonia Rating Scale movement subscore of 75%, while those with secondary dystonia had only small improvements. Outcomes in the 3 children with NBIA were disappointing.

Conclusions

Results of DBS in children with primary and secondary dystonias were similar to those in adults, with excellent results for DYT1 dystonia in children without fixed orthopedic deformity and much more modest results in secondary dystonia. In contrast to reported experience in adults with NBIA, these results in children with NBIA were poor. Infection risk was highest in the youngest patients.

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Philip A. Starr, Nicholas M. Barbaro, Neil H. Raskin, and Jill L. Ostrem

Object

Cluster headache (CH) is the most severe of the primary headache disorders. Based on the finding that regional cerebral blood flow is increased in the ipsilateral posterior hypothalamic region during a CH attack, a novel neurosurgical procedure for CH was recently introduced: hypothalamic deep brain stimulation (DBS). Two small case series have been described. Here, the authors report their technical approach, intraoperative physiological observations, and 1-year outcomes after hypothalamic DBS in four patients with medically intractable CHs.

Methods

Patients underwent unilateral magnetic resonance (MR) imaging–guided stereotactic implantation of a Medtronic DBS (model 3387) lead and Soletra pulse generator system. Intended tip coordinates were 3 mm posterior, 5 mm inferior, and 2 mm lateral to the midcommissural point. Microelectrode recording and intraoperative test stimulation were performed. Lead locations were measured on postoperative MR images. The intensity, frequency, and severity of headaches throughout a 1-week period were tracked in patient diaries immediately prior to surgery and after 1 year of continuous stimulation.

At the 1-year follow-up examination, DBS had produced a greater than 50% reduction in headache intensity or frequency in two of four cases. Active contacts were located 3 to 6 mm posterior to the mammillothalamic tract. Neurons in the target region showed low-frequency tonic discharge.

Conclusions

In two previously published case series, headache relief was obtained in many but not all patients. The results of these open-label studies justify a larger, prospective trial but do not yet justify widespread clinical application of this technique.

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Alastair J. Martin, Paul S. Larson, Nathan Ziman, Nadja Levesque, Monica Volz, Jill L. Ostrem, and Philip A. Starr

OBJECTIVE

The objective of this study was to assess the incidence of postoperative hardware infection following interventional (i)MRI–guided implantation of deep brain stimulation (DBS) electrodes in a diagnostic MRI scanner.

METHODS

A diagnostic 1.5-T MRI scanner was used over a 10-year period to implant DBS electrodes for movement disorders. The MRI suite did not meet operating room standards with respect to airflow and air filtration but was prepared and used with conventional sterile procedures by an experienced surgical team. Deep brain stimulation leads were implanted while the patient was in the magnet, and patients returned 1–3 weeks later to undergo placement of the implantable pulse generator (IPG) and extender wire in a conventional operating room. Surgical site infections requiring the removal of part or all of the DBS system within 6 months of implantation were scored as postoperative hardware infections in a prospective database.

RESULTS

During the 10-year study period, the authors performed 164 iMRI-guided surgical procedures in which 272 electrodes were implanted. Patients ranged in age from 7 to 78 years, and an overall infection rate of 3.6% was found. Bacterial cultures indicated Staphylococcus epidermis (3 cases), methicillin-susceptible Staphylococcus aureus (2 cases), or Propionibacterium sp. (1 case). A change in sterile practice occurred after the first 10 patients, leading to a reduction in the infection rate to 2.6% (4 cases in 154 procedures) over the remainder of the procedures. Of the 4 infections in this patient subset, all occurred at the IPG site.

CONCLUSIONS

Interventional MRI–guided DBS implantation can be performed in a diagnostic MRI suite with an infection risk comparable to that reported for traditional surgical placement techniques provided that sterile procedures, similar to those used in a regular operating room, are practiced.

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Camilla Kilbane, Adolfo Ramirez-Zamora, Elena Ryapolova-Webb, Salman Qasim, Graham A. Glass, Philip A. Starr, and Jill L. Ostrem

OBJECT

Holmes tremor (HT) is characterized by irregular, low-frequency (< 4.5 Hz) tremor occurring at rest, with posture, and with certain actions, often affecting proximal muscles. Previous reports have tended to highlight the use of thalamic deep brain stimulation (DBS) in cases of medication-refractory HT. In this study, the authors report the clinical outcome and analysis of single-unit recordings in patients with medication-refractory HT treated with globus pallidus internus (GPi) DBS.

METHODS

The authors retrospectively reviewed the medical charts of 4 patients treated with pallidal DBS for medication-refractory HT at the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center. Clinical outcomes were measured at baseline and after surgery using an abbreviated motor-severity Fahn-Tolosa-Marin (FTM) tremor rating scale. Intraoperative microelectrode recordings were performed with patients in the awake state. The neurophysiological characteristics identified in HT were then also compared with characteristics previously described in Parkinson's disease (PD) studied at the authors' institution.

RESULTS

The mean percentage improvement in tremor motor severity was 78.87% (range 59.9%–94.4%) as measured using the FTM tremor rating scale, with an average length of follow-up of 33.75 months (range 18–52 months). Twenty-eight GPi neurons were recorded intraoperatively in the resting state and 13 of these were also recorded during contralateral voluntary arm movement. The mean firing rate at rest in HT was 56.2 ± 28.5 Hz, and 63.5 ± 19.4 Hz with action, much lower than the GPi recordings in PD. GPi unit oscillations of 2–8 Hz were prominent in both patients with HT and those with PD, but in HT, unlike PD, these oscillations were not suppressed by voluntary movement.

CONCLUSIONS

The efficacy of GPi DBS exceeded that reported in prior studies of ventrolateral thalamus DBS and suggest GPi may be a better target for treating HT. These clinical and neurophysiological findings help illuminate evolving models of HT and highlight the importance of cerebellar–basal ganglia interactions.

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Editorial

Deep brain stimulation for Parkinson disease

Andres M. Lozano

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Philip A. Starr, Alastair J. Martin, Jill L. Ostrem, Pekka Talke, Nadja Levesque, and Paul S. Larson

Object

The authors discuss their method for placement of deep brain stimulation (DBS) electrodes using interventional MR (iMR) imaging and report on the accuracy of the technique, its initial clinical efficacy, and associated complications in a consecutive series of subthalamic nucleus (STN) DBS implants to treat Parkinson disease (PD).

Methods

A skull-mounted aiming device (Medtronic NexFrame) was used in conjunction with real-time MR imaging (Philips Intera 1.5T). Preoperative imaging, DBS implantation, and postimplantation MR imaging were integrated into a single procedure performed with the patient in a state of general anesthesia. Accuracy of implantation was assessed using 2 types of measurements: the “radial error,” defined as the scalar distance between the location of the intended target and the actual location of the guidance sheath in the axial plane 4 mm inferior to the commissures, and the “tip error,” defined as the vector distance between the expected anterior commissure–posterior commissure (AC-PC) coordinates of the permanent DBS lead tip and the actual AC-PC coordinates of the lead tip. Clinical outcome was assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS III), in the off-medication state.

Results

Twenty-nine patients with PD underwent iMR imaging–guided placement of 53 DBS electrodes into the STN. The mean (± SD) radial error was 1.2 ± 0.65 mm, and the mean absolute tip error was 2.2 ± 0.92 mm. The tip error was significantly smaller than for STN DBS electrodes implanted using traditional frame-based stereotaxy (3.1 ± 1.41 mm). Eighty-seven percent of leads were placed with a single brain penetration. No hematomas were visible on MR images. Two device infections occurred early in the series. In bilaterally implanted patients, the mean improvement on the UPDRS III at 9 months postimplantation was 60%.

Conclusions

The authors' technical approach to placement of DBS electrodes adapts the procedure to a standard configuration 1.5-T diagnostic MR imaging scanner in a radiology suite. This method simplifies DBS implantation by eliminating the use of the traditional stereotactic frame and the subsequent requirement for registration of the brain in stereotactic space and the need for physiological recording and patient cooperation. This method has improved accuracy compared with that of anatomical guidance using standard frame-based stereotaxy in conjunction with preoperative MR imaging.

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Philip A. Starr, Robert S. Turner, Geoff Rau, Nadja Lindsey, Susan Heath, Monica Volz, Jill L. Ostrem, and William J. Marks Jr.

Object

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a promising new procedure for the treatment of dystonia. The authors present their technical approach for placement of electrodes into the GPi in awake patients with dystonia, including the methodology used for electrophysiological mapping of the GPi in the dystonic state, clinical outcomes and complications, and the location of electrodes associated with optimal benefit.

Methods

Twenty-three adult and pediatric patients who had various forms of dystonia were included in this study. Baseline neurological status and improvement in motor function resulting from DBS were measured using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Implantation of the DBS lead was performed using magnetic resonance (MR) imaging–based stereotaxy, single-cell microelectrode recording, and intraoperative test stimulation to determine thresholds for stimulation-induced adverse effects. Electrode locations were measured on computationally reformatted postoperative MR images according to a prospective protocol.

Conclusions

Physiologically guided implantation of DBS electrodes in patients with dystonia is technically feasible in the awake state in most cases, with low morbidity rates. Spontaneous discharge rates of GPi neurons in dystonia are similar to those of globus pallidus externus neurons, such that the two nuclei must be distinguished by neuronal discharge patterns rather than by rates. Active electrode locations associated with robust improvement (> 50% decrease in BFMDRS score) were located near the intercommissural plane, at a mean distance of 3.7 mm from the pallidocapsular border. Patients with juvenile-onset primary dystonia and those with the tardive form benefited greatly from this procedure, whereas benefits for most secondary dystonias and the adult-onset craniocervical form of this disorder were more modest.

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Fedor Panov, Emily Levin, Coralie de Hemptinne, Nicole C. Swann, Salman Qasim, Svjetlana Miocinovic, Jill L. Ostrem, and Philip A. Starr

OBJECTIVE

Contemporary theories of the pathophysiology of movement disorders emphasize abnormal oscillatory activity in basal ganglia-thalamocortical loops, but these have been studied in humans mainly using depth recordings. Recording from the surface of the cortex using electrocorticography (ECoG) provides a much higher amplitude signal than depth recordings, is less susceptible to deep brain stimulation (DBS) artifacts, and yields a surrogate measure of population spiking via “broadband gamma” (50–200 Hz) activity. Therefore, a technical approach to movement disorders surgery was developed that employs intraoperative ECoG as a research tool.

METHODS

One hundred eighty-eight patients undergoing DBS for the treatment of movement disorders were studied under an institutional review board–approved protocol. Through the standard bur hole exposure that is clinically indicated for DBS lead insertion, a strip electrode (6 or 28 contacts) was inserted to cover the primary motor or prefrontal cortical areas. Localization was confirmed by the reversal of the somatosensory evoked potential and intraoperative CT or 2D fluoroscopy. The ECoG potentials were recorded at rest and during a variety of tasks and analyzed offline in the frequency domain, focusing on activity between 3 and 200 Hz. Strips were removed prior to closure. Postoperative MRI was inspected for edema, signal change, or hematoma that could be related to the placement of the ECoG strip.

RESULTS

One hundred ninety-eight (99%) strips were successfully placed. Two ECoG placements were aborted due to resistance during the attempted passage of the electrode. Perioperative surgical complications occurred in 8 patients, including 5 hardware infections, 1 delayed chronic subdural hematoma requiring evacuation, 1 intraparenchymal hematoma, and 1 venous infarction distant from the site of the recording. None of these appeared to be directly related to the use of ECoG.

CONCLUSIONS

Intraoperative ECoG has long been used in neurosurgery for functional mapping and localization of seizure foci. As applied during DBS surgery, it has become an important research tool for understanding the brain networks in movement disorders and the mechanisms of therapeutic stimulation. In experienced hands, the technique appears to add minimal risk to surgery.

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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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Philip A. Starr, Leslie C. Markun, Paul S. Larson, Monica M. Volz, Alastair J. Martin, and Jill L. Ostrem

Object

The placement of deep brain stimulation (DBS) leads in adults is traditionally performed using physiological confirmation of lead location in the awake patient. Most children are unable to tolerate awake surgery, which poses a challenge for intraoperative confirmation of lead location. The authors have developed an interventional MRI (iMRI)–guided procedure to allow for real-time anatomical imaging, with the goal of achieving very accurate lead placement in patients who are under general anesthesia.

Methods

Six pediatric patients with primary dystonia were prospectively enrolled. Patients were candidates for surgery if they had marked disability and medical therapy had been ineffective. Five patients had the DYT1 mutation, and mean age at surgery was 11.0 ± 2.8 years. Patients underwent bilateral globus pallidus internus (GPi, n = 5) or sub-thalamic nucleus (STN, n = 1) DBS. The leads were implanted using a novel skull-mounted aiming device in conjunction with dedicated software (ClearPoint system), used within a 1.5-T diagnostic MRI unit in a radiology suite, without physiological testing. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) was used at baseline, 6 months, and 12 months postoperatively. Further measures included lead placement accuracy, quality of life, adverse events, and stimulation settings.

Results

A single brain penetration was used for placement of all 12 leads. The mean difference (± SD) between the intended target location and the actual lead location, in the axial plane passing through the intended target, was 0.6 ± 0.5 mm, and the mean surgical time (leads only) was 190 ± 26 minutes. The mean percent improvement in the BFMDRS movement scores was 86.1% ± 12.5% at 6 months (n = 6, p = 0.028) and 87.6% ± 19.2% at 12 months (p = 0.028). The mean stimulation settings at 12 months were 3.0 V, 83 μsec, 135 Hz for GPi DBS, and 2.1 V, 60 μsec, 145 Hz for STN DBS). There were no serious adverse events.

Conclusions

Interventional MRI–guided DBS using the ClearPoint system was extremely accurate, provided real-time confirmation of DBS placement, and could be used in any diagnostic MRI suite. Clinical outcomes for pediatric dystonia are comparable with the best reported results using traditional frame-based stereotaxy. Clinical trial registration no.: NCT00792532 (ClinicalTrials.gov).