Middlebrooks, Erik H.

Objective With a growing appreciation for interindividual anatomical variability and patient‐specific brain connectivity, advanced imaging sequences offer the opportunity to directly visualize anatomical targets for deep brain stimulation (DBS). The lack of quantitative evidence demonstrating their clinical utility, however, has hindered their broad implementation in clinical practice. Methods Using fast gray matter acquisition T1 inversion recovery (FGATIR) sequences, the present study identified a thalamic hypointensity that holds promise as a visual marker in DBS. To validate the clinical utility of the identified hypointensity, we retrospectively analyzed 65 patients (26 female, mean age = 69.1 ± 12.7 years) who underwent DBS in the treatment of essential tremor. We characterized its neuroanatomical substrates and evaluated the hypointensity's ability to predict clinical outcome using stimulation volume modeling and voxelwise mapping. Finally, we determined whether the hypointensity marker could predict symptom improvement on a patient‐specific level. Results Anatomical characterization suggested that the identified hypointensity constituted the terminal part of the dentatorubrothalamic tract. Overlap between DBS stimulation volumes and the hypointensity in standard space significantly correlated with tremor improvement ( R 2 = 0.16, p = 0.017) and distance to hotspots previously reported in the literature ( R 2 = 0.49, p = 7.9e‐4). In contrast, the amount of variance explained by other anatomical atlas structures was reduced. When accounting for interindividual neuroanatomical variability, the predictive power of the hypointensity increased further ( R 2 = 0.37, p = 0.002). Interpretation Our findings introduce and validate a novel imaging‐based marker attainable from FGATIR sequences that has the potential to personalize and inform targeting and programming in DBS for essential tremor. ANN NEUROL 2022;91:613–628

Introduction: Patients with carotid stenosis may have silent cerebrovascular disease due to chronic hypoperfusion and atheroembolism. If so, progression of silent disease may be preventable through revascularization. We aim to evaluate the association between carotid stenosis/occlusion and cerebral small vessel disease (SVD) burden ipsilateral to the cervical carotid stenosis. Methods: Patients age ≥40 years with carotid stenosis or occlusion on carotid ultrasound who underwent MRI brain and intracranial angiogram with gradable SVD on MRI from 2011-2015 were included. Severity of carotid stenosis was defined using NASCET criteria as 50-69% (moderate), 70-99% (high-grade), or occluded. WMH volume was quantified using an automated artificial intelligence algorithm applied to axial T2 FLAIR images. Images were also scored for presence of chronic lacune, cerebral microbleeds (CMB), and silent infarcts using STRIVE criteria. Differences in WMD volume between hemispheres ipsilateral and contralateral to the carotid stenosis were calculated, and prevalence of SVD and silent infarct were compared across severities of carotid stenosis. Results: Of the 183 patients, mean age was 71±10 years and 38% were female. Moderate and severe stenosis was present in 36% and 46.5%, respectively, and 18% had carotid occlusion. Mean WMH volume was 7271±522mm 3 . Patients with carotid stenosis had greater WMH volume ipsilateral to the side of carotid stenosis than the contralateral side (mean difference 224±206mm 3 ), and higher severity of stenosis was associated with greater hemispheric difference in WMH volume (moderate vs high; 164±274mm 3 vs 743±309 mm 3 , p=0.009). Silent infarcts were more prevalent in high-grade carotid stenosis than moderate grade (moderate vs high, 10.8% vs 36.5%; p=0.002). There were no differences in either lacunae or CMBs across severities. Conclusions: Greater than one third of patients with high-grade carotid stenosis had ipsilateral silent brain infarction, and the volume of WMH was greater on the side of carotid stenosis. Future analyses should consider the potential yield of screening for carotid atherosclerosis in patients with varying degrees of hemispheric WMH asymmetry.

While abnormalities of the hippocampus have been well characterized in temporal lobe epilepsy, various additional temporal lobe abnormalities have also been described. One poorly understood entity, the so-called temporal pole blurring (TPB), is one of the more frequently described neocortical abnormalities in TLE and is thought to represent dysmyelination and axonal loss due to chronic electrical perturbations in early age-onset temporal lobe epilepsy. In this study, we describe the first reported cases of TPB diagnosed by a recently described MRI sequence known as 3D Edge-Enhancing Gradient Echo (3D-EDGE), which has an effective “myelin weighting” making it exquisitely sensitive to this temporal pole dysmyelination. The value of detection of TPB lies in lateralizing seizure onset, as well as predicting a lower baseline neuropsychological performance compared to temporal lobe epilepsy without TPB. Additionally, it is critical to not mistake TPB for alternative diagnoses, such as focal cortical dysplasia or neoplasm.

OBJECTIVE Multiple meningiomas (MMs) occur in as many as 18% of patients with meningioma, and data on progression-free survival (PFS) are scarce. The objective of this study was to explore the influence of the number of lesions and clinical characteristics on PFS in patients with WHO grade I meningiomas. METHODS The authors retrospectively reviewed the records of all adults diagnosed with a meningioma at their three main sites from January 2009 to May 2020. Progression was considered the time from diagnosis until radiographic growth of the originally resected meningioma. A secondary analysis was performed to evaluate the time of diagnosis until the time to second intervention (TTSI). Univariable and multivariable analyses were conducted to assess whether the number of lesions or any associated variables (age, sex, race, radiation treatment, tumor location, and extent of resection) had a significant impact on PFS and TTSI. RESULTS Eight hundred thirty-eight patients were included. Use of a log-rank test to evaluate PFS and TTSI between a single and multiple lesions showed a significantly shorter progression for MM (p < 0.001 and p < 0.001, respectively). Multivariable Cox regression analysis showed significantly inferior PFS on MM compared to a single lesion (hazard ratio [HR] 2.262, 95% confidence interval [CI] 1.392–3.677, p = 0.001) and a significantly inferior TTSI for patients with MM when compared to patients with a single meningioma (HR 2.377, 95% CI 1.617–3.494, p = 0.001). By testing the number of meningiomas as a continuous variable, PFS was significantly inferior for each additional meningioma (HR 1.350, 95% CI 1.074–1.698, p = 0.010) and TTSI was significantly inferior as well (HR 1.428, 95% CI 1.189–1.716, p < 0.001). African American patients had an inferior PFS when compared to non-Hispanic White patients (HR 3.472, 95% CI 1.083–11.129, p = 0.036). CONCLUSIONS The PFS of meningiomas appears to be influenced by the number of lesions present. Patients with MM also appear to be more prone to undergoing a second intervention for progressive disease. Hence, a closer follow-up may be warranted in patients who present with multiple lesions. These results show a decreased PFS for each additional lesion present, as well as a shorter PFS for MM compared to a single lesion. When assessing associated risk factors, African American patients showed an inferior PFS, whereas older age and adjuvant therapy with radiation showed an improved PFS.

Abstract INTRODUCTION Multiple meningiomas (MM) occurs in up to 18% of meningioma patients and progression data are scarce. The objective of this study is to explore the influence of number of lesions and clinical characteristics on progression-free survival (PFS) and time to a second intervention (TTSI) in patients with WHO grade 1 meningiomas. METHODS We retrospectively reviewed records of all adults diagnosed with a meningioma at our three main sites from January 2009 to May 2020. Progression was considered as time from diagnosis until radiographic progression of the originally resected meningioma. A secondary analysis was carried to evaluate the time from diagnosis to time of a second intervention. Univariable and multivariable analyses were conducted to assess whether number of lesions or any associated variables (age, sex, race, radiation, location, and extent of resection) had a significant impact on PFS and TTSI. RESULTS 838 patients were included. Log-rank test evaluating PFS and TTSI between single and multiple lesions showed significantly shorter progression for MM (p&lt; 0.001 and p&lt; 0.001, respectively). Multivariable Cox regression showed significantly inferior PFS on MM vs. single lesion (HR 2.262 [CI 95%, 1.392-3.677], p=0.001) and a significantly inferior TTSI for patients with MM vs. single meningioma (HR 2.377 [CI 95%, 1.617 – 3.494], p=0.001). When input as a continuous variable, PFS was significantly inferior for each additional meningioma (HR 1.350 [CI 95% 1.074-1.698], p=0.010) and TTSI is significantly inferior as well (HR 1.428 [CI 95% 1.189 – 1.716], p&lt; 0.001). African-Americans had an inferior PFS when compared to Non-Hispanic White patients (HR 3.472 [CI 95% 1.083-11.129], p=0.036). CONCLUSION The PFS of meningiomas is influenced by the number of lesions present. Patients with MM are more prone to undergo a second intervention for progressive disease. Hence, a closer follow-up may be warranted in patients who present with multiple lesions.

Abstract BACKGROUND Intraoperative detection of residual tumor and isocitrate dehydrogenase (IDH) mutations can assist in maximizing surgical resection beyond contrast enhancing margins and guide intraoperative surgical decision making for glioma patients. We aimed to evaluate the use of desorption electrospray ionization-mass spectrometry (DESI-MS) for intraoperative assessment of IDH mutations and estimation of tumor cell percentage (TCP). METHODS This is a prospective study using intraoperative DESI-MS analysis of freshly obtained tissue samples to evaluate IDH mutations via 2-hydroxyglutarate (2-HG) intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles. These IDH mutation and TCP estimates were subsequently validated by a senior neuropathologist. RESULTS A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of TCP in 203 margin and core biopsies based on NAA intensity yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP assessment based on characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Further validation of the methodology is being performed in an ongoing collaboration with Mayo Clinic-Jacksonville, where we have collected 178 biopsies from 24 patients. Preliminary results of IDH mutation assessments indicate 100% sensitivity, specificity, and accuracy. DISCUSSION/CONCLUSION We present a novel system to allow intraoperative evaluation of IDH status and to guide surgical resection by TCP measurement from tissue biopsies. Prospectively, we propose to modify our DESI-MS system by placing a surgical material (e.g. cottonoid) along the surgical margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. This will allow the retention of the spatial distribution of diagnostic molecules while analyzing a wall of the surgical cavity without the need for biopsy.

OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3) 2/3 × (6.106/[V T2 1/1 − V T1 1/1 ]) 2 , where V T2 and V T1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.

Abstract Introduction/Objective Maximizing surgical resection in gliomas, while avoiding compromising non-infiltrated tissue, is associated with survival benefit. Current methodologies are suboptimal in providing rapid, intraoperative molecular characterization of tissue. We address this unmet need by using desorption electrospray ionization mass spectrometry (DESI-MS) for the intraoperative molecular assessment of gliomas. Methods/Case Report This prospective study uses intraoperative DESI-MS analysis of fresh tissue to evaluate IDH mutations via 2-hydroxyglutarate intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles in less than three minutes. Blinded review of the tissue smears by a neuropathologist is used to validate IDH mutation status and TCP estimates. Results (if a Case Study enter NA) Presently, 529 biopsies from 85 enrolled patients have been collected and analyzed at two institutions. TCP assessment based on NAA intensity in 203 biopsies at the first institution yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP estimates via characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Ongoing validation of the methodology is being performed at a second institution, where we have collected 282 biopsies from 36 patients. IDH mutation assessment of the first 15 patients indicate 100% sensitivity, specificity, and accuracy. Conclusion This study represents the first and largest study using DESI-MS for the intraoperative evaluation of IDH status and TCP measurement in gliomas. Prospectively, we propose to modify our DESI-MS system to allow estimation of IDH mutation status and TCP in surgical cavities without the need for a biopsy by placing a surgical material along the margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. We envision molecular analysis by DESI-MS as a complementary technique to histopathology capable of providing additional clinical information in near real-time.

Abstract BACKGROUND Brain mapping is the most reliable intraoperative tool for identifying surrounding functional cortical and subcortical brain parenchyma. Brain mapping procedures are nuanced and require a multidisciplinary team and a well-trained neurosurgeon. Current training methodology involves real-time observation and operation, without widely available surgical simulation. OBJECTIVE To develop a patient-specific, anatomically accurate, and electrically responsive biomimetic 3D-printed model for simulating brain mapping. METHODS Imaging data were converted into a 2-piece inverse 3D-rendered polyvinyl acetate shell forming an anatomically accurate brain mold. Functional and diffusion tensor imaging data were used to guide wire placement to approximate the projection fibers from the arm and leg areas in the motor homunculus. Electrical parameters were generated, and data were collected and processed to differentiate between the 2 tracts. For validation, the relationship between the electrical signal and the distance between the probe and the tract was quantified. Neurosurgeons and trainees were interviewed to assess the validity of the model. RESULTS Material testing of the brain component showed an elasticity modulus of 55 kPa (compared to 140 kPa of cadaveric brain), closely resembling the tactile feedback a live brain. The simulator's electrical properties approximated that of a live brain with a voltage-to-distance correlation coefficient of r 2 = 0.86. Following 32 neurosurgeon interviews, ∼96% considered the model to be useful for training. CONCLUSION The realistic neural properties of the simulator greatly improve representation of a live surgical environment. This proof-of-concept model can be further developed to contain more complicated tractography, blood and cerebrospinal fluid circulation, and more in-depth feedback mechanisms.