Serial MRI Research Articles

A novel reconstructive approach of the lumbar vertebral column from 2D MRI to 3D models

IntroductionLow back pain (LBP), arising from the lumbar vertebral column (LVC), is a global burden, ranking highest in terms of disability. In the United Arab Emirates (UAE), there is a high prevalence of LBP in the adult population. As MRI has emerged as the mainstay in assessment of LVC-related conditions, this study aimed to reconstruct reproducible 3D LVC MRI models from 2D MRI scans. MethodsFollowing the extraction of serial 2D MRI scan slices from an existing image database, fifty 3D MRI models (n = 50) were retrospectively reconstructed (Mimics Innovation Suite ®) and analyzed through the bootstrapping technique. ResultsLumbar vertebral bodies depicted kidney and oval shapes, with an increasing frequency of the former traced from L1 to L5. Traction (10%) and claw (14%) osteophyte types were noted. The inferior rims of L2 (2%) and L4 (4%) presented with the co-existence of both osteophyte types, which was reflective of the same degenerative process. Morphometric dimensions of L1 were also determined: Anterior vertebral height: 29.6 ± 3.5 mm (28.6–30.5 mm); Posterior vertebral height: 26.8 ± 3.1 mm (25.9–29.6 mm); Superior vertebral width: 40.6 ± 3.8 mm (39.6–41.6 mm); Intervertebral disc height between L1 and L2: 15.9 ± 6.3 mm (14.3–17.7 mm). ConclusionA proof-of-concept in the reconstructive approach of the LVC was established, which introduces a process through which a normative simulated dataset can be obtained in the extended population. Additionally, these values will assist to detect structural disproportions and changes and contribute to pre-operative planning and artificial intervertebral disc implant design.

ODP359 Thyrotropin secreting pituitary microadenoma and lung adenocarcinoma treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) Erlotinib and Osimertinib: a case report

Abstract Background Thyrotropin secreting pituitary adenoma (TSHoma) of the pituitary specific transcription factor-1 (PIT-1) lineage, is the rarest subtype of pituitary neuroendocrine tumours (pitNETs). TSHomas must be discriminated from primary hyperthyroidism and can cause morbidity through thyrotoxicosis or local mass effect. Serum alpha-subunit level may be used as a marker of tumour activity, as 50-85% of TSHoma patients have high serum alpha-subunit levels. First line treatment is surgical resection of the tumour. Medical therapy with somatostatin analogues or radiotherapy may be used for tumour control. Epidermal growth factor receptor (EGFR) expression has been demonstrated in pitNETs including corticotrophs, gonadotrophs, lactotrophs and somatotrophs. EGFR inhibiting agent, Lapatinib, has been investigated for treatment of prolactinomas and EGFR expression is implicated in tumorigenesis of corticotrophs. EGFR targeting tyrosine kinase inhibitors (TKIs) can be used first line to treat metastatic adenocarcinoma of the lung harbouring activating EGFR mutations. Case Report A non-smoking 53-year-old male of Middle Eastern heritage was seen in clinic with secondary hyperthyroidism on a background of metastatic adenocarcinoma of the lung and hypertension. The patient had no symptoms of hyperthyroidism and had no personal or family history of thyroid dysfunction. No new headaches or visual disturbance were reported. Physical exam showed brisk reflexes, no specific signs of hyperthyroidism or thyromegaly were seen. Thyroid function tests demonstrated a persistently elevated TSH 5.1mIU/L (0.4-4. 0), T4 21.8pmol/L (9-19) and T3 6.4pmol/L (2.6-6. 0) with negative anti- thyroid receptor, thyroperoxidase and thyroglobulin antibodies. Ultrasound of the thyroid was unremarkable. MRI revealed a well-circumscribed left anterior pituitary lesion of 5.4×6.8mm in size. Surgery was deferred as 3 months prior, he was diagnosed with stage 4 intrapulmonary adenocarcinoma of the lung with an exon-19 deletion mutation in the EGFR gene. He received stereotactic radiotherapy and EGFR targeted therapy using 100mg of Erlotinib daily, which increased to 200mg 6 months later. After 1 year of therapy, his adenocarcinoma progressed and he was transitioned to the 3 rd generation EGFR-TKI Osimertinib. Instead of undergoing the risk of pituitary surgery, a trial of EGFR therapy for its pleiotropic pituitary adenoma effects was decided. During the EGFR-TKI treatment period, alpha subunit levels have remained stable and serial MRI imaging at 1 year showed no interval pituitary adenoma growth. Conclusion This is a rare case of TSHoma identified during treatment of lung cancer with EGFR-TKIs. EGFR signalling is implicated in prolactinomas and corticotrophs though there is a paucity of data regarding TSHomas. To date, our patient has achieved radiological and biochemical stability in his TSHoma, with hyperthyroidism control on EGFR-TKI therapy, suggestive of a therapeutic benefit from EGFR signal blockade. Further studies are needed in larger cohorts to quantify EGFR expression in TSHomas and evaluate its possible role in pathogenesis. Presentation: No date and time listed

A quantitative and comparative evaluation of stereotactic spine radiosurgery local control: proposing a consistent measurement methodology.

Stereotactic body radiotherapy (SBRT) is a precise and conformal treatment modality used in the management of metastatic spine tumors. Multiple studies have demonstrated its safety and efficacy for pain and tumor control. However, no uniform quantitative imaging methodology exists to evaluate response to treatment in these patients. This study presents radiographic local control rates post-SBRT, systematically compares measurements acquired according to WHO and Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and explores the relationship to patient outcome. The authors performed a retrospective review of prospectively obtained data from a cohort of 59 consecutive patients (81 metastatic isocenters) treated with SBRT and followed with serial MRI scans. Measurements were performed by a neuroradiologist blinded to the patients' clinical course. Local control status was determined according to both WHO and RECIST measurements, and agreement between the measuring methodologies was calculated and reported. Eighty-one isocenters (111 vertebral bodies) were treated with SBRT. The mean treatment dose was 13.96 Gy and the median follow-up duration was 10.8 months, during which 408 MRI scans were evaluated with both WHO and RECIST criteria for each scan point. Imaging demonstrated a mean unidimensional size decrease of 0.2 cm (p = 0.14) and a mean area size decrease of 0.99 cm2 (p = 0.03). Although 88% of the case classifications were concordant and the agreement was significant, WHO criteria were found to be more sensitive to tumor size change. The local control rates according to WHO and RECIST were 95% and 98%, respectively. Although WHO volumetric measurements are admittedly superior for tumor size measurement, RECIST is simpler, reproducible, and for the first time is shown here to be comparable to WHO criteria. Thus, the application of RECIST methodology appears to be a suitable standard for evaluating post-SBRT treatment response. Moreover, using comprehensive and consistent measuring approaches, this study substantiates the efficacy of SBRT in the treatment of spine metastases.

Assessment of Interfraction Change in Gross Tumor Volume of Anal Carcinoma Patients Undergoing Curative Chemoradiotherapy

<h3>Purpose/Objective(s)</h3> Radiation with concurrent chemotherapy (CRT) represents standard definitive therapy for anal cancer. CRT protocols result in excellent local control but are associated with significant acute and late morbidity. Adaptive planning techniques may allow for decrease in treatment volume and reduce toxicity. In this study, we used serial MRI scans to assess changes in gross tumor volume (GTV) during curative CRT. <h3>Materials/Methods</h3> Since 2019, we have instituted a REB-approved prospective registry study of de-escalated radiotherapy for patients undergoing CRT for anal cancer. Patients received a total dose of 45-63 Gy in 25-35 fractions with concurrent Capecitabine and a single dose of Mitomycin-C on day 1. In addition to pre-treatment (pre-tx) CT and MR simulation, patients also underwent MR simulation at fraction 11 (fx11) and fraction 21 (fx21). The GTV was contoured separately on individual axial T2 sequences. Median (inter-quartile-range) was used for descriptive statistics and the Mann-Whitney-Wilcoxon was used between groups of interfractional contours to determine statistically significant differences in tumor size between fractions. The Kruskal-Wallace test was used to determine significance between all 3 GTV volumes. P-values of <0.05 were considered statistically significant. <h3>Results</h3> A total of 24 patients were accrued. All patient completed RT without interruptions. All 24 had pre-tx MRI. During CRT course, 22 had a second MRI scan (fx11), and 19 had a third (fx21) scan. Table 1 shows the median (IQR) pre-tx GTV and the absolute and percent reduction in the GTV at fx11 and fx21 compared to pre-treatment GTV. Median (IQR) reduction in GTV between pre-tx and fx11 and fx21 MRI was 6.1cc (3.8-12.1) and 7.8cc (5.7-14.6), respectively. Median reduction in GTV between fx11 and fx21 was 2.9cc (1.3-6.6). After normalizing volumes as the percentage of pre-tx GTV, median (IQR) volume was 62.5% (51.6-69.7) (p<0.001) at fx11 and 43.6% (34.2-55.6) (p<0.001) at fx21. Based on Kruskal-Wallace test, overall change between GTVs at all 3 time points was found to be significant, p=0.042. <h3>Conclusion</h3> For patients undergoing CRT for anal cancer, there appears to be an early and significant reduction in the tumor volume over time. This study helps define planning adaptation parameters using serial MRI during CRT and will inform strategies to reduce normal tissue exposure

Impact of ATM Mutations on Brain Metastasis Control and Radionecrosis in Non-Small Cell Lung Cancer Patients Undergoing SRS

<h3>Purpose/Objective(s)</h3> While Ataxia Telangectasia Mutated gene (ATM) variants have been associated with improved local control after radiation, adverse radiation events have been reported following conventional radiotherapy for extracranial tumors. It remains unknown whether ATM variants affect rates of radiation necrosis (RN) and local intracranial progression (LIP) following stereotactic radiosurgery (SRS) for brain metastases. We questioned whether pathologic ATM variants increase rates of RN and/or decrease rates of LIP following SRS for brain metastasis in non-small cell lung cancer (NSCLC) patients. <h3>Materials/Methods</h3> Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified at our institution. RN and LIP were determined by either biopsy or multi-disciplinary serial MRI review. Cumulative incidence of RN and LIP were estimated via the Kaplan Meier method. Cox proportional hazards testing was performed for variant classification (not detected [ND] vs variant of unknown significance [VUS] or pathogenic variant [PV]). A power analysis estimated that 34 events would need to be observed to detect a >4-fold hazard ratio for event. <h3>Results</h3> 541 patients completed SRS for brain metastasis secondary to NSCLC, of which 260 completed molecular profiling. Comprehensive Genomic Profiling (CGP) was performed on cell free circulating tumor DNA (61%), primary tumor (17%), extracranial metastasis (17%), and brain tumor (18%), including ≥2 sites for 33 (13%) patients. Availability of CGP data was significantly associated with more recent year of SRS completion (2018-20, 64% vs 2015-17, 25%; p<0.001), younger age at brain metastasis diagnosis (64.8 years [IQR 57.1-72.8] vs 67.8 years [IQR 59.6-72.8]; p=0.036), no prior tobacco use (22% vs 10%; p<0.001), adenocarcinoma histology (84% vs 73%; p=0.002), and metastatic disease at initial diagnosis (73% vs 63%; p=0.017). ATM variants were identified in 36 cases (13.8%; 13 PV, 23 VUS). For all patients with CPG, RN incidence was 4.9% (95% CI 1.6 – 8.2%) at 6 months and 9.9% (95% CI 4.8 - 15.0%) at 12 months and LIP was 5.4% (95% CI 2.4 – 8.4%) at 6 months and 9.8% (5.5 – 14.1%) at 12 months. For patients with ATM variants, RN incidence was 5.3% (0.0 - 15.3%) at both 6 and 12 months, with 2 total RN events at 5.7 months and 13.9 months following SRS, respectively; LIP was 3.1% (0.0 - 9.1%) at both 6 and 12 months, with one total LIP event at 2.0 months following SRS (P=0.46 and P=0.26 for RN and LIP, respectively). <h3>Conclusion</h3> We did not detect significant differences in RN or LIP risk following SRS for NSCLC brain metastases associated with ATM variants. These results suggest that at this time, ATM status should not inform SRS use when otherwise indicated for NSCLC brain metastases. This dataset additionally allowed us to estimate the number of patients needed to detect a given magnitude of relative risk for RN or LIP associated with a given variant. These data can inform future studies as CGP data accumulate.

Risk of Late or Recurrent Radiation Necrosis beyond 5 Years from Stereotactic Radiosurgery

<h3>Purpose/Objective(s)</h3> Radiation necrosis (RN) is a well-recognized complication most commonly occurring within 1-3 years of stereotactic radiosurgery (SRS). However, the incidence of late RN after this period is poorly described. This study characterizes the incidence of and risk factors for late or recurrent RN occurring five years after SRS. <h3>Materials/Methods</h3> This single-institution, retrospective analysis included patients treated with LINAC-based SRS (any indication) who were followed for over five years clinically and with serial MRI imaging. Late or recurrent RN was defined as any imaging changes with corresponding neurologic symptoms or deficits occurring after five years from treatment not attributable to disease recurrence. Associations with late RN were analyzed using Pearson coefficients, Mann-Whitney U tests, and Fisher's exact test. Univariate and multivariate analyses were performed using Cox proportional hazards model. <h3>Results</h3> We identified 219 patients who were treated to a cumulative 297 lesions over 246 SRS courses to a median dose of 17.0 Gy (range: 12-35 Gy). 290 (97.3%) were treated in a single fraction with 64 (21.5%) of the lesions having been adjuvantly following resection. The median follow-up time was 7.4 years (range: 5.1-16.1 years), and late or recurrent RN occurred in 19 (12.9%) patients and in 23 (7.7%) lesions at a median 6.1 years (range: 5.1-13.9 years) from SRS. 15 of the 23 (65.2%) lesions with late RN were managed successfully with steroids, bevacizumab, and/or anti-epileptic drugs. The remaining 8 (34.8%) were refractory to medical therapy and required resection, and histopathology confirmed necrosis without disease recurrence in each. Late or recurrent RN was more common among brain metastases and arterial-venous malformations or fistulas (Table 1). The mean dose in lesions that developed late RN was higher than for lesions that did not (18.5 ±1.5 Gy vs. 16.5± 4.1 Gy; p<0.001). Gross tumor volume >1.5cc (HR: 4.6, 95% CI: 1.8-11.6; p=0.001), PTV margins >1mm (HR: 3.1; 95%CI: 1.1-9.0, p=0.040), brain V12 Gy >5cc (HR: 18.7, 95% CI: 5.5-63.2; p<0.001), and a history or early, resolved RN (HR: 13.7, 95% CI: 5.1-36.8; p<0.001) were all associated with late or recurrent RN. On multivariate analysis, only brain V12 Gy >5cc (HR: 4.6 95% CI: 1.0-20.5; p=0.046) and a history of early, resolved RN (HR: 4.0; 95% CI: 1.2-12.7; p=0.021) remained significantly associated with late or recurrent RN. <h3>Conclusion</h3> This is the first study, to our knowledge, describing the risk of late or recurrent RN beyond five years from SRS. While uncommon, late or recurrent RN was associated with brain V12 Gy >5 cc a history of early RN, suggesting that closer long-term follow-up may be warranted for these select patients.

Local Control of Brain Metastases with Osimertinib Alone in Patients with EGFR-Mutant Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Osimertinib has emerged as a new standard of care in the treatment of EGFR-mutant metastatic non-small cell lung cancer (NSCLC). However, data on lesion-level control and durability of intracranial response to osimertinib is limited. We aim here to describe longitudinal lesion-level outcomes of brain metastases treated with osimertinib alone. <h3>Materials/Methods</h3> We retrospectively reviewed charts of patients with EGFR-mutant NSCLC with at least one untreated brain metastasis at the time of initiation of osimertinib at our institution from 2006-2021. An FDA-approved brain tumor segmentation tool, VBrain, was used to identify, track, and measure brain metastases larger than 5 mm on serial MRI brain scans. Patients with leptomeningeal disease were excluded. Cumulative incidence of local failure (LF) was calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow up. LF was defined as a ≥20% increase in the maximum diameter of a brain lesion using linear measurements on serial imaging. LF was calculated on a per-lesion basis, and univariable and multivariable analysis was conducted with competing risks regression used to identify predictors for LF. Overall survival (OS) was analyzed using Kaplan-Meier. <h3>Results</h3> A total of 73 patients with 284 untreated brain metastases larger than 5 mm were identified. Median follow-up time was 17 months (range 1.3-50.6 months). Median age at brain metastases diagnosis was 60 years old (range 30-90); 68.5% were female. Median number of prior systemic therapies received was 0 (range 0-6), with 32.9%, 27.4%, and 15.1% of patients receiving prior tyrosine kinase inhibitors, chemotherapy, and immunotherapy, respectively. The median size of brain metastases was 6.9 mm (range 5.0-33.6 mm) and the median number of brain metastases larger than 5 mm per patient was 1 (range 0-43). Median OS was 24.4 months (95% confidence interval [CI] 17.6-34.9). The 1-year cumulative incidence of LF was 12.1% (95% CI 8.8-16.1). On univariable analysis, uncontrolled primary tumor (hazard ratio [HR] 3.78, 95% CI 1.87-7.66; <i>p</i><0.001), increasing number of prior systemic therapies before osimertinib (HR 2.12, 95% CI 1.49-3.04; <i>p</i><0.001), and higher ECOG score (HR 7.8, 95% CI 1.99-31.81; <i>p</i>=0.003) was associated with LF. These factors remained significant in multivariable analysis. Median duration on osimertinib was 14.8 months (range 0.2-48.3 months), and 26% of patients experienced toxicities from osimertinib that required either a change in systemic therapy or a dose reduction. 9.6% and 18.6% of patients underwent salvage whole brain radiation therapy and salvage stereotactic radiosurgery, respectively. <h3>Conclusion</h3> Although NSCLC patients have excellent response of untreated intracranial metastases on osimertinib alone, over 10% of metastases will progress locally at 1 year. Further studies are needed to identify the brain metastases at risk for local failure to guide optimal intracranial management in these patients.

Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia.

Behavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain's glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more conspicuous on MRI. Therefore, enlarged PVS may be a useful biomarker of disease severity and progression in neurodegenerative proteinopathies such as bvFTD. This study aimed to determine the utility of PVS as a biomarker of disease progression in patients with bvFTD. Serial baseline and week 52 MRIs acquired from ten patients with bvFTD prospectively recruited and followed in a Phase 1b open label trial of sodium selenate for bvFTD were used in this study. An automated algorithm quantified PVS on MRI, which was visually inspected and validated by a member of the study team. The number and volume of PVS were extracted and mixed models used to assess the relationship between PVS burden and other measures of disease (cognition, carer burden scale, protein biomarkers). Additional exploratory analysis investigated PVS burden in patients who appeared to not progress over the 12 months of selenate treatment (i.e., "non-progressors"). Overall, PVS cluster number (ß = -3.27, CI [-7.80 - 1.27], p = 0.267) and PVS volume (ß = -36.8, CI [-84.9 - 11.3], p = 0.171) did not change over the paired MRI scans 12 months apart. There was association between cognition total composite scores and the PVS burden (PVS cluster ß = -0.802e-3, CI [9.45e - 3 - -6.60e - 3, p ≤ 0.001; PVS volume ß = -1.30e - 3, CI [-1.55e - 3 - -1.05e - 3], p ≤ 0.001), as well as between the change in the cognition total composite score and the change in PVS volume (ß = 4.36e - 3, CI [1.33e - 3 - 7.40e - 3], p = 0.046) over the trial period. There was a significant association between CSF t-tau and the number of PVS clusters (ß = 2.845, CI [0.630 - 5.06], p = 0.036). Additionally, there was a significant relationship between the change in CSF t-tau and the change in the number of PVS (ß = 1.54, CI [0.918 - 2.16], p < 0.001) and PVS volume (ß = 13.8, CI [6.37 - 21.1], p = 0.003) over the trial period. An association was found between the change in NfL and the change in PVS volume (ß = 1.40, CI [0.272 - 2.52], p = 0.045) over time. Within the "non-progressor" group (n = 7), there was a significant relationship between the change in the CSF total-tau (t-tau) levels and the change in the PVS burden (PVS cluster (ß = 1.46, CI [0.577 - 2.34], p = 0.014; PVS volume ß = 14.6, CI [3.86 - 25.4], p = 0.032) over the trial period. Additionally, there was evidence of a significant relationship between the change in NfL levels and the change in the PVS burden over time (PVS cluster ß = 0.296, CI [0.229 - 0.361], p ≤ 0.001; PVS volume ß = 3.67, CI [2.42 - 4.92], p = 0.002). Analysis of serial MRI scans 12 months apart in patients with bvFTD demonstrated a relationship between PVS burden and disease severity as measured by the total cognitive composite score and CSF t-tau. Further studies are needed to confirm PVS as a robust marker of neurodegeneration in proteinopathies.

MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes

BackgroundWe investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients.MethodsFrom an institutional cohort, we analysed adult patients with MOGAE followed-up for...

Evaluating the use of synthetic T1-w images in new T2 lesion detection in multiple sclerosis.

The assessment of disease activity using serial brain MRI scans is one of the most valuable strategies for monitoring treatment response in patients with multiple sclerosis (MS) receiving disease-modifying treatments. Recently, several deep learning approaches have been proposed to improve this analysis, obtaining a good trade-off between sensitivity and specificity, especially when using T1-w and T2-FLAIR images as inputs. However, the need to acquire two different types of images is time-consuming, costly and not always available in clinical practice. In this paper, we investigate an approach to generate synthetic T1-w images from T2-FLAIR images and subsequently analyse the impact of using original and synthetic T1-w images on the performance of a state-of-the-art approach for longitudinal MS lesion detection. We evaluate our approach on a dataset containing 136 images from MS patients, and 73 images with lesion activity (the appearance of new T2 lesions in follow-up scans). To evaluate the synthesis of the images, we analyse the structural similarity index metric and the median absolute error and obtain consistent results. To study the impact of synthetic T1-w images, we evaluate the performance of the new lesion detection approach when using (1) both T2-FLAIR and T1-w original images, (2) only T2-FLAIR images, and (3) both T2-FLAIR and synthetic T1-w images. Sensitivities of 0.75, 0.63, and 0.81, respectively, were obtained at the same false-positive rate (0.14) for all experiments. In addition, we also present the results obtained when using the data from the international MSSEG-2 challenge, showing also an improvement when including synthetic T1-w images. In conclusion, we show that the use of synthetic images can support the lack of data or even be used instead of the original image to homogenize the contrast of the different acquisitions in new T2 lesions detection algorithms.

The interplay between prenatal liver growth and lung development in congenital diaphragmatic hernia.

ObjectiveLiver herniation is a known risk factor for increased severity in CDH and is associated with clinically significant pulmonary hypoplasia and pulmonary hypertension. Better studies are needed to understand the growth of the herniated liver compared to the liver that remains in the abdomen and how this liver growth then affects lung development. Serial hi-resolution fetal MRI enables characterization of liver growth throughout gestation and examination of macroscopic features that may regulate liver growth. Here, we hypothesized that the nature of liver herniation affects liver growth and, in turn, affects lung growth.MethodsClinical data were retrospectively collected from consecutive cases of prenatally diagnosed isolated left-sided or right-sided CDH from June 2006 to August 2021. Only those cases with MRI lung volumetry for both mid-gestation and late-gestation time points were recruited for analysis. Cases with fetal chromosomal abnormalities and other major structural abnormalities were excluded. Fractional liver volume and liver growth was indexed to estimated fetal weight and compared to lung growth.ResultsData was collected from 28 fetuses with a left liver-down CDH (LLD), 37 left liver-up CDH (LLU) and 9 right liver-up CDH (RLU). Overall, RLU fetuses had greater overall and fractional (intra-thoracic vs. intra-abdominal) liver growth when compared to LLD and LLU fetuses. Additionally, intra-thoracic liver growth was consistently slower than intra-abdominal liver growth for either right- or left-sided CDH. When the liver was not herniated, a positive correlation was seen between liver growth and lung growth. However, when the liver was herniated above the diaphragm, this positive correlation was lost.ConclusionRight-sided CDH fetuses exhibit greater liver growth compared to left-sided CDH. Liver herniation disrupts the normal positive correlation between liver and lung growth that is seen when the liver is entirely within the abdomen.

What happens to brain outside the thermal ablation zones? An assessment of needle-based therapeutic ultrasound in survival swine

Background In stereotactic radiosurgery, isodose lines must be considered to determine how surrounding tissue is affected. In thermal ablative therapy, such as laser interstitial thermal therapy (LITT), transcranial MR-guided focused ultrasound (tcMRgFUS), and needle-based therapeutic ultrasound (NBTU), how the surrounding area is affected has not been well studied. Objective We aimed to quantify the transition zone surrounding the ablation core created by magnetic resonance-guided robotically-assisted (MRgRA) delivery of NBTU using multi-slice volumetric 2-D magnetic resonance thermal imaging (MRTI) and subsequent characterization of the resultant tissue damage using histopathologic analysis. Methods Four swine underwent MRgRA NBTU using varying duration and wattage for treatment delivery. Serial MRI images were obtained, and the most representative were overlaid with isodose lines and compared to brain tissue acquired postmortem which underwent histopathologic analysis. These results were also compared to predicted volumes using a finite element analysis model. Contralateral brain tissue was used for control data. Results Intraoperative MRTI thermal isodose contours were characterized and comprehensively mapped to post-operative MRI images and qualitatively compared with histological tissue sections postmortem. NBTU 360° ablations induced smaller lesion volumes (33.19 mm3; 120 s, 3 W; 30.05 mm3, 180 s, 4 W) versus 180° ablations (77.20 mm3, 120 s, 3 W; 109.29 mm3; 180 s; 4 W). MRTI/MRI overlay demonstrated the lesion within the proximal isodose lines. The ablation-zone was characterized by dense macrophage infiltration and glial/neuronal loss as demonstrated by glial fibrillary acidic protein (GFAP) and neurofilament (NF) absence and avid CD163 staining. The transition-zone between lesion and normal brain demonstrated decreased macrophage infiltration and measured ∼345 microns (n − 3). We did not detect overt hemorrhages or signs of edema in the adjacent spared tissue. Conclusion We successfully performed MRgRA NBTU ablation in swine and demonstrated minimal histologic changes extended past the ablation-zone. The lesion was characterized by macrophage infiltration and glial/neuronal loss which decreased through the transition-zone.

P03.05.A Radiation-induced leukoencephalopathy (RIL) in glioma: unique injury dynamics following proton vs photon beam radiotherapy

Abstract Background White matter injury after brain-directed radiotherapy (RT), aka radiation-induced leukoencephalopathy (RIL), is common in brain tumor patients. Differentiation from progressive disease can be challenging. Dosimetric advantages of protons (PRT) over photons (XRT) minimize radiation to healthy brain tissue, potentially limiting radiotoxic sequelae including RIL. We characterized RIL during periods of progression-free survival (PFS) in glioma patients irradiated with either PRT or XRT, hypothesizing that PRT would result in reduced RIL outside of the target field. Material and Methods 34 patients (19 male; mean age = 40.10y) with grade 2/3 gliomas and a history of partial cranial RT were stratified by RT modality [XRT (n=17) vs PRT (n=17)] and matched on 11 criteria [age, sex, tumor type/location/laterality, mutational status (IDH; 1p19q deletion), concurrent/adjuvant chemotherapy, radiation dose/fractions] for retrospective analysis. RIL development was characterized longitudinally for up to 3 years post-RT via analysis of serial MRI T2/FLAIR sequences. A novel RIL scoring system with embedded Fazekas scale was designed to quantify injury severity at both global (whole brain) and hemispheric levels. Results Matched groups did not differ significantly on any demographic or clinical characteristics. Median PFS post-RT was 4.7 (XRT) and 5.1 (PRT) years. The novel RIL scoring system was reliable (intraclass correlation coefficient &amp;gt;0.9). There was a significant increase in global RIL in both XRT [F(3, 57)=8.63, p&amp;lt; .001] and PRT [F(3, 61)=4.69, p&amp;lt; .005] groups over time, relative to baseline (1-month post-RT). A majority [62% (XRT) and 72% (PRT)] developed moderate or severe RIL within 3 years, with the ipsilesional hemisphere more severely affected. Analysis of RIL injury dynamics (i.e., average % change between 1 and 3 years post-RT) at hemispheric level identified radiation modality-specific differences: XRT resulted in greater contralesional hemispheric injury than PRT [F(1, 31)=4.32, p&amp;lt;.05]. This effect was not observed in ipsilesional hemispheres. Conclusion RIL is common in glioma patients and quantifiable by characteristic imaging features, including early onset post-RT, greater ipsilesional injury burden, and progression over time. RIL injury dynamics appear to be radiation modality-specific, whereby XRT causes greater delayed injury in the remote, contralesional hemisphere. These findings may reflect dosimetric differences between protons and photons. The impact of such sequelae on cognitive function is subject of current investigation.

Conservative treatment for patients with massive prolapsed lumber intervertebral discs

&lt;p&gt;&lt;strong&gt;Background:&lt;/strong&gt; The natural history of Lumber hernia of nucleus pulpous is not fully known and absolute indications for surgical intervention cannot be established. Several studies have shown that the most giant discs appear to have the greatest tendency to resolve with conservative treatment. The objective of this study is to investigate whether massive prolapsed discs can be safely managed conservatively once clinical improvement has occurred.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Thirty-five patients were studied by clinical assessments and serial magnetic imaging over 3 years. Patients present with intense sciatica but began to show clinical improvement despite massive disc prolapsed. Clinical assessment included the Lasegue test and neurological improvement. The Oswestry disability index was used to measure function and changes in function. Serial MRI studies allowed the measurement of volume changes of the prolapsed disc material over some time. &lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Initial follow-up at an average of 13.2 months showed that 87% had complete and sustained recovery at the initial follow-up. Only four patients required surgery. The average Oswestry disability index improved from 63% to 20%. Volumetric analysis of serial MRI scans showed an average reduction of 69% in disc size. &lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;A massive disc prolapsed can pursue a favourable course. If early progress is shown, the long-term prognosis is very good and even massive disc prolapses can be treated conservatively.&lt;/p&gt;

Elevated intraspinal pressure drives edema progression after acute compression spinal cord injury in rabbits

Elevated intraspinal pressure (ISP) following traumatic spinal cord injury (tSCI) can be an important factor for secondary SCI that may result in greater tissue damage and functional deficits. Our present study aimed to investigate the dynamic changes in ISP after different degrees of acute compression SCI in rabbits with closed canals and explore its influence on spinal cord pathophysiology. Closed balloon compression injuries were induced with different inflated volumes (40 μl, 50 μl or no inflation) at the T7/8 level in rabbits. ISP was monitored by a SOPHYSA probe at the epicenter within 7 days post-SCI. Edema progression, spinal cord perfusion and damage severity were evaluated by serial multisequence MRI scans, somatosensory evoked potentials (SEPs) and behavioral scores. Histological and blood spinal cord barrier (BSCB) permeability results were subsequently analyzed. The results showed that the ISP waveforms comprised three peaks, significantly increased after tSCI, peaked at 72 h (21.86 ± 3.13 mmHg) in the moderate group or 48 h (31.71 ± 6.02 mmHg) in the severe group and exhibited “slow elevated and fast decreased” or “fast elevated and slow decreased” dynamic changes in both injured groups. Elevated ISP after injury was correlated with spinal cord perfusion and edema progression, leading to secondary lesion enlargement. The secondary damage aggravation can be visualized by diffusion tensor tractography (DTT). Moreover, the BSCB permeability was significantly increased at the epicenter and rostrocaudal segments at 72 h after SCI; by 14 days, notable permeability was still observed at the caudal segment in the severely injured rabbits. Our results suggest that the ISP of rabbits with closed canals increased after acute compression SCI and exhibited different dynamic change patterns in moderately and severely injured rabbits. Elevated ISP exacerbated spinal cord perfusion, drove edema progression and led to secondary lesion enlargement that was strongly associated with BSCB disruption. For severe tSCI, early intervention targeting elevated ISP may be an indispensable choice to rescue spinal cord function.

Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson’s disease

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n= 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.

Improved Brain Pathology and Progressive Peripheral Neuropathy in a 15 Year Old Survivor of Infantile Krabbe Disease Treated With Umbilical Cord Transplantation.

ObjectiveKrabbe disease is a fatal leukodystrophy caused by deficiency in galactocerebrosidase enzyme activity. The only currently available therapy is hematopoietic stem cell transplantation with bone marrow or umbilical cord blood (UCBT), which leads to increased lifespan and functional abilities when performed in the preclinical stage. While stabilization of white matter disease has been seen on serial MRI studies, neuropathological changes following transplantation have not been documented so far.Materials and MethodsWe report the first postmortem examination of a 15-year-old female patient with infantile Krabbe disease after UCBT in infancy.ResultsIn contrast to an untreated Krabbe disease brain, which showed severe myelin and oligodendrocyte loss with occasional globoid cells, the transplanted brain displayed markedly improved myelin preservation, but not reaching normal myelination levels. Consistent with the transplanted patient’s clinical presentation of pronounced deficits in gross motor skills, corticospinal tracts were most severely affected. No globoid cells or evidence of active demyelination were observed in the central nervous system, indicative of at least partially successful functional restoration. This was corroborated by the identification of male donor-derived cells in the brain by in situ hybridization. Unlike the observed disease stabilization in the central nervous system, the patient experienced progressive peripheral neuropathy. While diminished macrophage infiltration was seen postmortem, peripheral nerves exhibited edema, myelin and axon loss and persistent Schwann cell ultrastructural inclusions.ConclusionUmbilical cord blood transplantation was able to alter the natural disease progression in the central but less so in the peripheral nervous system, possibly due to limited cross-correction of Schwann cells.

Hearing Preservation in Observed Sporadic Vestibular Schwannoma: A Systematic Review.

To characterize the natural history of hearing loss for patients presenting with serviceable hearing (SH) who undergo a wait-and-scan approach for sporadic vestibular schwannoma (VS) using aggregate time-to-event survival analysis. Systematic review. Published international English literature, January 1, 2000 to May 31, 2020. Patients with sporadic VS entering a wait-and-scan approach with SH at diagnosis. Observation with serial MRI and audiometry. In total, 3,652 patients from 26 studies were included for analysis. Mean age at diagnosis was 58.8 years (SD, 4.1). Mean follow-up was 49.2 months (SD, 26.5). In total, 755 patients (21%) failed conservative treatment and underwent radiosurgery or microsurgery at the time of last follow-up. The average loss to follow-up was 6.9% (SD, 11.1). A total of 1,674 patients had SH at the time of diagnosis. Survival rates for maintaining SH were 96% at 1 year, 77% at 3 years, 62% at 5 years, and 42% at 10 years following diagnosis. In this systematic review, aggregate data from 3,652 patients across 26 studies show consistent patterns in progression of hearing loss during observation for patients with sporadic VS as a function of time. As an easy-toremember conservative benchmark for those presenting with SH at diagnosis: approximately 75% retain SH at 3 years, 60% at 5 years, and 40% at 10 years.

Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice.

Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.

Disease progression and brain atrophy in NMDAR encephalitis: Associated factor &amp; clinical implication

ObjectiveWe investigated the longitudinal pattern, determining factors, and clinical implications of brain volume changes in N‐methyl d‐aspartate receptor‐antibody (NMDAR) encephalitis.MethodsBaseline clinical profiles, treatment profiles, and outcome measured using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and modified Rankin scale (mRS) were obtained from a long‐term clinical database documenting an NMDAR encephalitis cohort. In serial MRI, the change in the normalized volume of different brain regions from the baseline evaluation was measured. At each MRI evaluation time point, the cumulative disease burden (CASE score × months) and the cumulative duration of status epilepticus were also evaluated.ResultsThirty‐six patients were followed‐up for 28.5 months (range 12–63 months). The volume ratio at last MRI to baseline was the lowest in the cerebellum (94.4 ± 5.7%, p < 0.001). Once developed, cerebellar volume reduction followed a progressive course until 2 years from disease onset. The degree of cerebellar volume reduction was positively correlated with mRS and total CASE scores (all, p < 0.001), and CASE scores in the domains of memory, language, and psychiatric problems, gait instability/ataxia, and weakness (all, p < 0.01). In linear mixed model analyses, the degree of cerebellar volume reduction was associated with cumulative disease burden up to 2 years (p < 0.001) and duration of status epilepticus (p < 0.001), and delayed removal of teratoma for ≥1 month (p = 0.006).InterpretationIn NMDAR encephalitis, cerebellar volume reduction was progressive once developed. Cerebellar volume reduction might reflect disease burden and extent of progression and be associated with poor outcomes in multiple functional domains.