An 86-year-old right-handed man with medically refractory essential tremor was treated using left-sided MRI-guided focused ultrasound (MRgFUS) thalamotomy targeting the dentatorubrothalamic tract (DRTT) at its intersection with the ventral intermediate nucleus of the thalamus, with immediate symptomatic improvement and immediate postprocedure imaging demonstrating disruption of the DRTT. The patient experienced a partial return of symptoms 9 weeks following the procedure, and MRI demonstrated retraction of the left thalamic ablation site. The patient underwent repeat left-sided MRgFUS thalamotomy 4 months after initial treatment, resulting in reduced tremor. MR thermometry temperature measurements during the second MRgFUS procedure were unreliable with large fluctuations and false readings, likely due to susceptibility effects from the initial MRgFUS procedure. Final sonications were therefore monitored using the amount of energy delivered. The patient fared well after the second procedure and had sustained improvement in tremor control at the 12-month follow-up. This is the first report to describe the technical challenges of repeat MRgFUS with serial imaging.
Elizabeth K. Weidman, Michael G. Kaplitt, Kristin Strybing and J. Levi Chazen
Michael Pourfar, Chengke Tang, Tanya Lin, Vijay Dhawan, Michael G. Kaplitt and David Eidelberg
The authors investigated whether the insertion of deep brain stimulation electrodes into the subthalamic nucleus can alter regional brain metabolism in the absence of stimulation.
Six patients with Parkinson disease (PD) underwent preoperative FDG PET scanning, and again after STN electrode implantation with stimulation turned off.
Compared with baseline values, glucose utilization was reduced in the postoperative off-stimulation scans in the putamen/globus pallidus and in the ventral thalamus (p < 0.01), and there was increased metabolism in the sensorimotor cortex and cerebellum (p < 0.005). The expression of a specific PD-related spatial covariance pattern measured in the FDG PET data did not change after electrode implantation (p = 0.36), nor was there a significant change in clinical motor ratings (p = 0.44). Differences in PD-related spatial covariance pattern expression among the patients after electrode implantation did, however, correlate with the number of microelectrode recording trajectories placed during surgery (r = –0.82, p < 0.05).
These findings suggest that electrode implantation can impart a microlesion effect on regional brain function. Nonetheless, these local changes did not cross the threshold of network modulation needed to achieve clinical benefit.
Mihaela A. Stavarache, Nicholas Petersen, Eric M. Jurgens, Elizabeth R. Milstein, Zachary B. Rosenfeld, Douglas J. Ballon and Michael G. Kaplitt
Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain.
Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses.
Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%–75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons.
This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.
Whitney E. Parker, Elizabeth K. Weidman, J. Levi Chazen, Sumit N. Niogi, Rafael Uribe-Cardenas, Michael G. Kaplitt and Caitlin E. Hoffman
The authors tested the feasibility of magnetic resonance–guided focused ultrasound (MRgFUS) ablation of mesial temporal lobe epilepsy (MTLE) seizure circuits. Up to one-third of patients with mesial temporal sclerosis (MTS) suffer from medically refractory epilepsy requiring surgery. Because current options such as open resection, laser ablation, and Gamma Knife radiosurgery pose potential risks, such as infection, hemorrhage, and ionizing radiation, and because they often produce visual or neuropsychological deficits, the authors developed a noninvasive MRgFUS ablation strategy for mesial temporal disconnection to mitigate these risks.
The authors retrospectively reviewed 3-T MRI scans obtained with diffusion tensor imaging (DTI). The study group included 10 patients with essential tremor (ET) who underwent pretreatment CT and MRI prior to MRgFUS, and 2 patients with MTS who underwent MRI. Fiber tracking of the fornix-fimbria pathway and inferior optic radiations was performed, ablation sites mimicking targets of open posterior hippocampal disconnection were modeled, and theoretical MRgFUS surgical plans were devised. Distances between the targets and optic radiations were measured, helmet angulations were prescribed, and the numbers of available MRgFUS array elements were calculated.
Tractograms of fornix-fimbria and optic radiations were generated in all ET and MTS patients successfully. Of the 10 patients with both the CT and MRI data necessary for the analysis, 8 patients had adequate elements available to target the ablation site. A margin (mean 8.5 mm, range 6.5–9.8 mm) of separation was maintained between the target lesion and optic radiations.
MRgFUS offers a noninvasive option for seizure tract disruption. DTI identifies fornix-fimbria and optic radiations to localize optimal ablation targets and critical surrounding structures, minimizing risk of postoperative visual field deficits. This theoretical modeling study provides the necessary groundwork for future clinical trials to apply this novel neurosurgical technique to patients with refractory MTLE and surgical contraindications, multiple prior surgeries, or other factors favoring noninvasive treatment.
J. Levi Chazen, Harini Sarva, Philip E. Stieg, Robert J. Min, Douglas J. Ballon, Kane O. Pryor, Paul M. Riegelhaupt and Michael G. Kaplitt
The objective of this study was to evaluate the utility of diffusion tensor imaging (DTI) tractography–based targeting of the dentatorubrothalamic tract (DRT) for magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy in patients with essential tremor (ET) and correlate postprocedural tract disruption with clinical outcomes.
Four patients received preprocedural and immediate postprocedural DTI in addition to traditional anatomical MRI sequences for MRgFUS thalamotomy. Optimal ablation sites were selected based on the patient-specific location of the DRT as demonstrated by DTI (direct targeting) and correlated with traditional atlas-based measurements for thalamic ventral intermediate nucleus (Vim) lesioning (indirect targeting). Fiber tracts were displayed three-dimensionally during the procedure and used in conjunction with clinical signs of tremor control for fine correction of the ablation site. Immediately following the conclusion of the procedure, the MRgFUS head frame was removed and patients were placed in a 32-channel MRI head coil for follow-up DTI and anatomical MRI sequences.
All patients had excellent postoperative tremor control and successful pre- and postprocedural DTI fiber tracking of the corticospinal tract, medial lemniscus, and DRT. Immediate postprocedure DTI failed to track the DRT ipsilateral to the lesion site with a preserved contralateral DRT, coincident with substantial resolution of contralateral tremor.
DTI can reliably identify the optimal ablation target and demonstrates tract disruption on immediate postprocedural imaging. A clinical improvement of ET was observed immediately following the procedure, correlating with DRT disruption and suggesting that interruption of the DRT is a consequence of clinically successful MRgFUS thalamotomy. These findings may have utility for both MRgFUS procedure planning in surgically naive patients and retreatment of patients who have previously undergone unsuccessful thalamic Vim lesioning.
Sepideh Amin-Hanjani, Nicholas C. Bambakidis, Fred G. Barker II, Bob S Carter, Kevin M. Cockroft, Rose Du, Justin F. Fraser, Mark G. Hamilton, Judy Huang, John A. Jane Jr., Randy L. Jensen, Michael G. Kaplitt, Anthony M. Kaufmann, Julie G. Pilitsis, Howard A. Riina, Michael Schulder, Michael A. Vogelbaum, Lynda J. S. Yang and Gabriel Zada
Mark M. Souweidane, Justin F. Fraser, Lisa M. Arkin, Dolan Sondhi, Neil R. Hackett, Stephen M. Kaminsky, Linda Heier, Barry E. Kosofsky, Stefan Worgall, Ronald G. Crystal and Michael G. Kaplitt
The authors conducted a phase I study of late infantile neuronal ceroid lipofuscinosis using an adenoassociated virus serotype 2 (AAV2) vector containing the deficient CLN2 gene (AAV2CUhCLN2). The operative technique, radiographic changes, and surgical complications are presented.
Ten patients with late infantile neuronal ceroid lipofuscinosis disease each underwent infusion of AAV2CUhCLN2 (3 × 1012 particle units) into 12 distinct cerebral locations (2 depths/bur hole, 75 minutes/infusion, and 2 μl/minute). Innovative surgical techniques were developed to overcome several obstacles for which little or no established techniques were available. Successful infusion relied on preoperative stereotactic planning to optimize a parenchymal target and diffuse administration. Six entry sites, each having 2 depths of injections, were used to reduce operative time and enhance distribution. A low-profile rigid fixation system with 6 integrated holding arms was utilized to perform simultaneous infusions within a practical time frame. Dural sealant with generous irrigation was used to avoid CSF egress with possible subdural hemorrhage or altered stereotactic registration.
Radiographically demonstrated changes were seen in 39 (65%) of 60 injection sites, confirming localization and infusion. There were no radiographically or clinically defined complications.
The neurosurgical considerations and results of this study are presented to offer guidance and a basis for the design of future gene therapy or other clinical trials in children that utilize direct therapeutic delivery.
Marissa D’Souza, Kevin S. Chen, Jarrett Rosenberg, W. Jeffrey Elias, Howard M. Eisenberg, Ryder Gwinn, Takaomi Taira, Jin Woo Chang, Nir Lipsman, Vibhor Krishna, Keiji Igase, Kazumichi Yamada, Haruhiko Kishima, Rees Cosgrove, Jordi Rumià, Michael G. Kaplitt, Hidehiro Hirabayashi, Dipankar Nandi, Jaimie M. Henderson, Kim Butts Pauly, Mor Dayan, Casey H. Halpern and Pejman Ghanouni
Skull density ratio (SDR) assesses the transparency of the skull to ultrasound. Magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy in essential tremor (ET) patients with a lower SDR may be less effective, and the risk for complications may be increased. To address these questions, the authors analyzed clinical outcomes of MRgFUS thalamotomy based on SDRs.
In 189 patients, 3 outcomes were correlated with SDRs. Efficacy was based on improvement in Clinical Rating Scale for Tremor (CRST) scores 1 year after MRgFUS. Procedural efficiency was determined by the ease of achieving a peak voxel temperature of 54°C. Safety was based on the rate of the most severe procedure-related adverse event. SDRs were categorized at thresholds of 0.45 and 0.40, selected based on published criteria.
Of 189 patients, 53 (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40. There was no significant difference in improvement in CRST scores between those with an SDR ≥ 0.45 (58% ± 24%), 0.40 ≤ SDR < 0.45 (i.e., SDR ≥ 0.40 but < 0.45) (63% ± 27%), and SDR < 0.40 (49% ± 28%; p = 0.0744). Target temperature was achieved more often in those with an SDR ≥ 0.45 (p < 0.001). Rates of adverse events were lower in the groups with an SDR < 0.45 (p = 0.013), with no severe adverse events in these groups.
MRgFUS treatment of ET can be effectively and safely performed in patients with an SDR < 0.45 and an SDR < 0.40, although the procedure is more efficient when SDR ≥ 0.45.