LABORATORY INVESTIGATION J Neurosurg 125:1080–1086, 2016 Convection-enhanced delivery improves MRI visualization of basal ganglia for stereotactic surgery Aaron E. Bond, MD, PhD,1 Robert F. Dallapiazza, MD, PhD,1 M. Beatriz Lopes, MD, PhD,2 and W. Jeffrey Elias, MD1 Departments of 1Neurosurgery and 2Neuropathology, University of Virginia Health Sciences Center, Charlottesville, Virginia OBJECTIVE Stereotactic deep brain stimulation surgery is most commonly performed while patients are awake. This allows for intraoperative clinical assessment and electrophysiological target verification, thereby promoting favorable outcomes with few side effects. Intraoperative CT and MRI have challenged this concept of clinical treatment validation. Image-guided surgery is capable of delivering electrodes precisely to a planned, stereotactic target; however, these methods can be limited by low anatomical resolution even with sophisticated MRI modalities. The authors are developing a novel method using convection-enhanced delivery to safely manipulate the extracellular space surrounding common anatomical targets for surgery. By altering the extracellular content of deep subcortical structures and their associated white matter tracts, the MRI visualization of the basal ganglia can be improved to better define the anatomy. This tech- nique could greatly improve the accuracy and success of stereotactic surgery, potentially eliminating the reliance on awake surgery. METHODS Observations were made in the clinical setting where vasogenic and cytotoxic edema improved the MRI visualization of the basal ganglia. These findings were replicated in the experimental setting using an FDA-approved intracerebral catheter that was stereotactically inserted into the thalamus or basal ganglia of 7 swine. Five swine were infused with normal saline, and 2 were infused with autologous CSF. Flow rates varied between 1 μl/min to 6 μl/min to achieve convective distributions. Concurrent MRI was performed at 15-minute intervals to monitor the volume of infusion and observe the imaging changes of the deep subcortical structures. The animals were then clinically observed, and necropsy was performed within 48 hours, 1 week, or 1 month for histological analysis. RESULTS In all animals, the white matter tracts became hyperintense on T2-weighted imaging as compared with basal ganglia nuclei, enabling better definition of the deep brain anatomy. The volume of distribution and infusion (Vd/Vi ratio) ranged from 2.5 to 4.5. There were no observed clinical effects from the infusions. Histological analysis demonstrated mild neuronal effects from saline infusions but no effects from CSF infusions. CONCLUSIONS This work provides the initial foundation for a novel approach to improve the visualization of deep brain anatomy during MRI-guided, stereotactic procedures. Convective infusions of CSF alter the extracellular fluid content of the brain for improved MRI without evidence of clinical or toxic effects. http://thejns.org/doi/abs/10.3171/2015.10.JNS151154 KEY WORDS convection-enhanced delivery; basal ganglia; MRI; stereotactic neurosurgery; image-guided; functional neurosurgery TEREOTACTIC surgery is commonly used to treat Image-guided techniques have been developed to posi- chronic neurological disorders such as Parkinson’s tion a stimulating or lesioning electrode with a mean vec- disease, tremor, epilepsy, and psychiatric diseases. tor error as low as 1.59 mm with intraoperative CT-guided SLesioning, stimulation, and local delivery of drugs9,22 all techniques4 and 0.14–0.86 mm with intraoperative MRI.5 rely on the ability to treat specific brain regions that are Current methods for targeting these structures also of- often small, deep, and indistinct on conventional MRI. ten include referencing a stereotactic atlas, with potential Validation of their placement typically requires clinical errors due to patient-specific variations from the atlas.27 testing or electrophysiological mapping with microelec- Richter et al. reviewed 35 subthalamic nuclei (STN) in 18 trode recordings (MERs), or both of these.8,18,29,32–35 patients and compared their location based on T2-weight- ABBREVIATIONS CED = convection-enhanced delivery; DBS = deep brain stimulation; MER = microelectrode recording; MW = molecular weight; STN = subthalamic nuclei; UPDRS = Unified Parkinson’s Disease Rating Scale; Vd = volume of distribution; Vi = volume of infusion SUBMITTED May 20, 2015. ACCEPTED October 19, 2015. INCLUDE WHEN CITING Published online February 5, 2016; DOI: 10.3171/2015.10.JNS151154. 1080 J Neurosurg Volume 125 • November 2016 ©AANS, 2016 Unauthenticated | Downloaded 09/29/21 06:53 PM UTC CED enhancement of basal ganglia on MRI ed MRI. They then compared the T2-weighted MRI loca- the right DBS electrode tract to the subthalamus (Fig. 1). tions to locations as depicted in the Talairach and Tourn- The remainder of the DBS system was explanted, and the oux, and Schaltenbrand and Wahren atlases and found the infection was cleared after several weeks of intravenous anterior border of the STN to vary from 4.1 mm to 3.7 mm aztreonam therapy. A second bilateral subthalamic DBS from the midcommissural point, posterior border 4.2 mm system was eventually reimplanted 1 year after the first. to 10 mm, medial border 7.9 mm to 12.1 mm, and lateral The presumed vasogenic edema around the infected border 12.3 mm to 15.4 mm.26,27,31 There have been ad- electrode highlighted the boundaries of the right STN and vances in the use of MRI including coregistering multiple adjacent deep brain anatomy in contrast to the unaffected, sequences,35 7-T imaging, 8,32,34 9.4-T imaging,18 fast gray contralateral, left side (Fig. 1). This observation led to the matter acquisition T1 inversion recovery,29 and others.33 To premise of this study, where we believe that the extracellu- date, a practical and widely adoptable solution to easily lar space could be manipulated experimentally to improve identify these deep subcortical nuclei remains elusive and MRI visualization. results in widespread reliance on awake neurosurgery. We first observed a patient with vasogenic edema Additional Clinical Observations around an STN deep brain stimulation (DBS) electrode After we recognized improved MRI visualization of that dramatically improved the MRI visualization of the the anatomy surrounding an infected DBS electrode, we deep brain anatomy. This observation was then confirmed noted similar incidences of edema in the deep brain re- by MRI in other patients with edema from a variety of gions from a variety of pathologies (Fig. 2). These shared a pathologies extending into the basal ganglia. Because va- common pathophysiology where vasogenic edema extend- sogenic edema represents an increase in the extracellular ed into surrounding tissues as evidenced by T2-weighted water content, we sought to replicate this experimentally MRI. These cases served as further clinical evidence in an animal model with convection-enhanced delivery that an alteration in extracellular fluid content changed (CED). The preclinical study presented here demonstrates the characteristics of T2-weighted MRI. The enhanced a technique for convecting an infusate to improve the definition of deep brain anatomy, and particularly the visualization of deep brain structures with conventional boundaries between nuclei and white matter tracts, was MRI. We envision that this technique potentially can be observed in patients with sarcoma metastasis, thalamic used in combination with MRI-guided surgery to improve glioblastoma, sarcoidosis of the basal ganglia, large B-cell stereotactic targeting and obviate the need for awake sur- lymphoma, clear cell meningioma, gliomatosis cerebri, gery with MER or stimulation mapping. stereotactic thalamotomy for tremor, central glioblastoma, and stereotactic pallidotomy for cerebral palsy athetosis Methods and dystonia. Case Observation Swine Model of CED-Enhanced MRI Visualization A 59-year-old retired psychologist presented for con- Following approval from the University of Virginia In- sideration of DBS surgery. He had been diagnosed 5 years stitutional Animal Care and Use Committee, Sus scrofa earlier with Parkinson’s disease when he presented with domestica (Yorkshire) female pigs weighing approxi- a stooped posture and diminished facial expressions. He mately 25 pounds were acquired and acclimated in the developed severe motor fluctuations, short duration re- vivarium facility for 3 days. Swine nuclei are smaller than sponses, and peak dose dyskinesia on a medication regi- men consisting of levodopa 25/100 every 2 hours, 5 daily doses of 200 mg of entacapone, and 1.5 mg of pramipexole 3 times a day. The unmedicated (off) motor examination was notable for mild hypophonia with hypomimia, mod- erately increased tone (especially in the patient’s neck), and significant bradykinesia in the absence of tremor. He was able to independently stand with effort to a stooped posture, and his gait was slowed with delayed initiation and a diminished arm swing. A formal neuropsychologi- cal assessment deemed that he was a good candidate for surgery, because he experienced no mood issues and a preservation of cognition. He underwent successful surgery consisting of bilat- eral STN DBS with microelectrode mapping and a staged pulse generator implantation. Unfortunately, he developed a Pseudomonas infection involving the pulse generator, which required explantation of the pulse generator and the FIG. 1. Axial T2-weighted MR images. Left: Patient who had