Optical coherence tomography-guided Brillouin microscopy highlights regional tissue stiffness differences during anterior neural tube closure in the Mthfd1l murine mutant.

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos was significantly lower than that of wild-type embryos. Additionally, exogenous formate supplementation improved tissue stiffness and gross embryonic morphology in nullizygous and heterozygous embryos. Our results demonstrate the significance of proper tissue stiffness in normal NTC and pave the way for future studies on the mechanobiology of normal and abnormal embryonic development.

Disruption of Fuz in mouse embryos generates hypoplastic hindbrain development and reduced cranial nerve ganglia.

BACKGROUND: The brain and spinal cord formation is initiated in the earliest stages of mammalian pregnancy in a highly organized process known as neurulation. Environmental or genetic interferences can impair neurulation, resulting in clinically significant birth defects known collectively as neural tube defects. The Fuz gene encodes a subunit of the CPLANE complex, a macromolecular planar polarity effector required for ciliogenesis. Ablation of Fuz in mouse embryos results in exencephaly and spina bifida, including dysmorphic craniofacial structures due to defective cilia formation and impaired Sonic Hedgehog signaling. RESULTS: We demonstrate that knocking Fuz out during embryonic mouse development results in a hypoplastic hindbrain phenotype, displaying abnormal rhombomeres with reduced length and width. This phenotype is associated with persistent reduction of ventral neuroepithelial stiffness in a notochord adjacent area at the level of the rhombomere 5. The formation of cranial and paravertebral ganglia is also impaired in these embryos. CONCLUSIONS: This study reveals that hypoplastic hindbrain development, identified by abnormal rhombomere morphology and persistent loss of ventral neuroepithelial stiffness, precedes exencephaly in Fuz ablated murine mutants, indicating that the gene Fuz has a critical function sustaining normal neural tube development and neuronal differentiation.

Reverberant optical coherence elastography using multifocal acoustic radiation force.

In this study, we introduce a multifocal acoustic radiation force source that combines an ultrasound transducer and a 3D-printed acoustic lens for application in reverberant optical coherence elastography (Rev-OCE). An array of plano-concave acoustic lenses, each with an 11.8 mm aperture diameter, were used to spatially distribute the acoustic energy generated by a 1 MHz planar ultrasound transducer, producing multiple focal spots on a target plane. These focal spots generate reverberant shear wave fields detected by the optical coherence tomography (OCT) system. The effectiveness of the multifocal Rev-OCE system in probing mechanical properties with high resolution is demonstrated in layered gelatin phantoms.

Multimodal imaging system combining optical coherence tomography and Brillouin microscopy for neural tube imaging.

To understand the dynamics of tissue stiffness during neural tube formation and closure in a murine model, we have developed a multimodal, coaligned imaging system combining optical coherence tomography (OCT) and Brillouin microscopy. Brillouin microscopy can map the longitudinal modulus of tissue but cannot provide structural images. Thus, it is limited for imaging dynamic processes such as neural tube formation and closure. To overcome this limitation, we have combined Brillouin microscopy and OCT in one coaligned instrument. OCT provided depth-resolved structural imaging with a micrometer-scale spatial resolution to guide stiffness mapping by Brillouin modality. 2D structural and Brillouin frequency shift maps were acquired of mouse embryos at gestational day (GD) 8.5, 9.5, and 10.5 with the multimodal system. The results demonstrate the capability of the system to obtain structural and stiffness information simultaneously.

Device-Assisted and Neuromodulatory Therapies for Parkinson's Disease: A Network Meta-Analysis.

BACKGROUND: Device-assisted and neuromodulatory therapies are the standard of care for Parkinson's disease (PD) with disabling motor complications. We aimed to compare and rank the currently available advanced therapies for PD on patient relevant outcomes. METHODS: We searched various databases for randomized controlled trials that studied subthalamic nucleus deep brain stimulation (STN-DBS), globus pallidus interna (GPi) DBS, pallidotomy, subthalamotomy, continuous subcutaneous apomorphine infusion (CSAI), or intrajejunal levodopa infusion (IJLI), in patients with PD and motor complications. Primary outcome was the quality of life (QOL) at 6 months. Secondary outcomes included Unified Parkinson's Disease Rating Scale III and II, ON time, OFF time, levodopa equivalent daily doses, and adverse events (AE). Data were pooled using a Bayesian network meta-analysis, summarized as mean difference (MD) with 95% credibility intervals (CrI) and visualized in forest plots/league tables. Surface under the cumulative ranking curve plots determined the ranking probability. RESULTS: We identified 6745 citations and included 26 trials. STN-DBS (MD, -8.0; 95% CrI, -11, -5.8), GPi-DBS (MD, -7.1; 95% CrI, -11, -2.9), and IJLI (MD, -7.0; 95% CrI, -12, -1.8) led to better QOL than medical therapy alone, without significant differences among them. STN-DBS had the highest probability of being ranked the best treatment for QOL (79.6%), followed by IJLI (63.5%) and GPi-DBS (62.8%). CONCLUSIONS: In advanced PD, STN-DBS alleviates more patient and clinician relevant outcomes, followed by GPi-DBS and IJLI. In resource limited settings, unilateral pallidotomy may improve motor symptoms and activities of daily living, although overall QOL may not be improved. © 2022 International Parkinson and Movement Disorder Society.

Ga-68 PSMA PET/CT in recurrent high-grade gliomas: evaluating PSMA expression in vivo.

PURPOSE: We planned this prospective study to evaluate PSMA expression in recurrent high-grade gliomas (rHGG), including anaplastic astrocytoma and glioblastoma using Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68 (HBED-CC)]- (Ga-68 PSMA) positron emission tomography (PET), with its theranostic potential in mind. METHODS: This was a prospective study enrolling patients with clinical and MRI evidence of rHGG on follow-up. Three treated cases of HGG with RN on MRI were also included as negative controls. Abnormal tracer accumulation in the brain parenchyma, more than the contralateral hemisphere was interpreted as positive study. For semiquantitative analysis, a 3D spherical region of interest (ROI) was drawn around the site of the abnormal Ga-68 PSMA uptake, and the ratio of SUVmax of tumor (T) to SUVmax of the contralateral corresponding area (TBR) was calculated. Each patients' PSMA brain PET was fused to the corresponding MRI and reviewed for concordance. RESULTS: Thirty patients were included in the study, a total of 49 lesions were detected on MRI, and fused PET/MR images showed increased Ga-68 PSMA uptake in all these lesions. Multifocal lesions were better appreciated on fused PET-MR images, and concordance between MRI and PET was 100 % for patient and lesion-wise detection. Recurrent glioma lesions showed SUVmax and SUVmean values (median and IQR) 6.0 (4.4-8.2) and 3.3 (2.8-3.7), respectively. Lesions labeled as radiation necrosis on MRI did not show tracer accumulation. CONCLUSION: Ga-68 PSMA has potential utility for evaluating recurrence in HGG and its potential for theranostics would encourage its use in the evaluation of these patients.

Introduction to optical coherence elastography: tutorial.

Optical coherence elastography (OCE) has seen rapid growth since its introduction in 1998. The past few decades have seen tremendous advancements in the development of OCE technology and a wide range of applications, including the first clinical applications. This tutorial introduces the basics of solid mechanics, which form the foundation of all elastography methods. We then describe how OCE measurements of tissue motion can be used to quantify tissue biomechanical parameters. We also detail various types of excitation methods, imaging systems, acquisition schemes, and data processing algorithms and how various parameters associated with each step of OCE imaging can affect the final quantitation of biomechanical properties. Finally, we discuss the future of OCE, its potential, and the next steps required for OCE to become an established medical imaging technology.

Mission impossible: chemotherapy in the intensive care for pineal region germ cell tumor.

Pineal region tumors are rare and a heterogenous group of primary central nervous system tumors which are primarily classified as germ cell tumors and non-germ cell tumors. Chemotherapy and radiotherapy as the primary treatment modalities have been reported to result in good outcomes. We discuss the case of a young girl who presented to our emergency department in an unconscious state and had a large lesion in the posterior third ventricular region, but without any associated hydrocephalus which could explain her stuporous state. Given the rapid decline in her sensorium, we were faced with the difficult choice between surgical decompression of the tumor and a trial of rescue chemotherapy following histopathological confirmation through biopsy. She underwent an open biopsy followed by chemotherapy in a neurosurgical intensive care unit despite her poor Karnofsky performance score. She improved after chemotherapy and her tumor decreased in size significantly over time. We highlight the role of chemotherapy administered in the neurosurgical ICU to an unconscious patient with a large chemoresponsive tumor leading to rapid shrinkage of the lesion and gradual improvement in the sensorium of the patient.

Comparison of a bolt-connected external ventricular drain with a tunneled external ventricular drain - a narrative review and meta-analysis.

External ventricular drain (EVD) is one of the most commonly performed neurosurgical procedures. EVD can be associated with high rates of complications like misplacement, iatrogenic hemorrhage, and CSF infection. Several modifications have been proposed in the EVD insertion techniques to decrease the risk of these complications. Bolt-connected EVD, one of these modifications which involves insertion of a bolt in the burr hole, has been proposed to have better chances of optimal placement of EVD tip, lesser risk of CSF infection, and accidental pullout. A comprehensive search of different databases was performed to retrieve studies comparing the bolt-connected EVD with tunneled EVD and meta-analysis was done. Seven studies met inclusion criteria and were included in the meta-analysis. Our analysis revealed that bolt-connected EVD is associated with significantly better chances of optimal placement than traditional tunneled EVD (MH OR-1.65, 95% CI 1.14 to 2.40, p = 0.008). We also observed that bolt-connected EVD is associated with significantly decreased risk of CSF infection (MH OR-0.60, 95% CI 0.39 to 0.94, p = 0.026), EVD malfunction (MH OR-0.31, 95% CI 0.16 to 0.58, p = 0.0003), and accidental disconnection (MH OR-0.09, 95% CI 0.03 to 0.26, p < 0.0001) as compared to traditional tunneled EVD. The difference between the two techniques was not statistically significant for complications, multiple punctures done for insertion of EVD, iatrogenic intracranial, and need of reoperation. Bolt-connected external ventricular drain is associated with significantly more chances of optimal placement and lesser chances of accidental discontinuation and CSF infection than tunneled EVD. There was no statistically significant difference noted between the two techniques for multiple punctures done for insertion of EVD, iatrogenic intracranial hemorrhage and need of reoperation. However, most of the included studies were retrospective. Thus, the results from the meta-analysis should be interpreted with caution as further prospective high-quality studies are needed.

Bilateral pallidotomy for acquired or heredodegenerative generalized dystonia in children.

OBJECTIVE: Dystonias are relatively rare disorders characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Generalized dystonia is a therapeutic challenge because medications are unable to control dystonia adequately in most patients. These patients may be candidates for surgical therapy. The commonly used surgical procedures in these patients are pallidotomy and deep brain stimulation. Limited studies are available on the role of pallidotomy in children with acquired/heredodegenerative generalized dystonia. The objective of this study was to describe the authors' experience with bilateral pallidotomy in this group of patients. METHODS: The authors retrospectively reviewed all pediatric patients (less than 18 years of age) with acquired/heredodegenerative generalized dystonia who underwent bilateral simultaneous pallidotomy at their center between January 2014 and January 2021. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores before and after surgery were recorded. Complications arising after the procedure were recorded as well. RESULTS: Ten patients (8 male and 2 female) with a mean (range) age of 11.1 (5-17) years were included in this study. The mean duration between disease onset and surgical intervention was 3.9 years. Two patients presented in status dystonicus. The mean ± SD (range) preoperative BFMDRS score of the patients without status dystonicus (n = 8) was 80 ± 18.9 (59.5-108). The mean ± SD BFMDRS score at the time of discharge from the hospital after surgery was 58.8 ± 37.9. Three patients had more than 20% change in BFMDRS score at the time of discharge from the hospital. The mean improvement was 25.5% at the end of 1 year. Of 5 surviving patients in the non-status dystonicus group, 3 patients had more than 40% change in BFMDRS score while the other 2 patients developed recurrence at the last follow-up (4.5 years). Status dystonicus abated after bilateral pallidotomy in both patients. Permanent bulbar complications were seen in 2 patients. CONCLUSIONS: Bilateral pallidotomy may result in clinically significant improvement in children with acquired/heredodegenerative generalized dystonia, although the benefits should be closely weighed against the risk of irreversible bulbar dysfunction. It is a viable option for children in resource-limited settings.

Effect of topical and intraventricular antibiotics used during ventriculoperitoneal shunt insertion on the rate of shunt infection-a meta-analysis.

INTRODUCTION: The ventriculoperitoneal shunt is one of the most commonly performed neurosurgical procedures. One of the avoidable complications of shunt surgery is shunt infection. This PRISMA-compliant meta-analysis analysed the effectiveness of topical and/or intraventricular antibiotics in preventing shunt infections in patients undergoing shunt surgery. METHODS: Four databases were searched from inception to 30th June 2021. Only original articles comparing the rate of shunt infection with and without antibiotics were included. Random-effects meta-analysis was used to compare the effect of the use of antibiotics in preventing infection and subgroup analysis for finding differences in various antibiotics. RESULTS: The rate of shunt infection was 2.24% (53 out of 2362) in the topical antibiotic group in comparison to 5.24% (145 out of 2764) in the control group (p = 0.008). Subgroup analysis revealed that there is no significant difference between the antibiotics used. CONCLUSIONS: Our meta-analysis found that the risk of shunt infection is significantly reduced with the use of topical and intraventricular antibiotics without any serious adverse effect. No side effects of topical or intraventricular antibiotics were reported in the included studies. Further prospective studies are required to establish the safety and optimal dosage of topical antibiotics for them to be used routinely in neurosurgical practice. They can be used in patients at high risk of developing shunt infections till such studies are available.

Assessment of Prevalence and Associated Risk Factors of NAFLD in People Living with Diabetes in India: A Retrospective, Multicenter, Electronic Medical Records Based Study.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease worldwide. The prevalence of NAFLD varies depending on population studied and type of diagnostic tools used to screen or diagnose the patients. There is a strong relationship between metabolic syndrome components and NAFLD prevalence. This study aims to understand the prevalence of NAFLD along with the associated risk factors and their interaction with other comorbidities among people living with diabetes in Indian context. MATERIALS AND METHODS: It is a retrospective, observational study based on data retrieved from electronic medical records (EMRs) of people living with diabetes from more than 250 individual diabetes centers located in more than 30 cities across 14 states in India. Medical records of 171,996 adults living with diabetes were included in the analysis. The assessment of prevalence of NAFLD in diabetes was done using algorithm based on alanine transaminase (ALT) and aspartate aminotransferase (AST). RESULTS: Overall, 44.48% of people living with diabetes were found to have NAFLD. A significantly higher proportion of males (58.64%) had NAFLD compared to females (36.91%) (p<0.001). Nonalcoholic fatty liver disease prevalence was >50% in seven of the states. People living with diabetes along with dyslipidemia and hypertension had a significantly higher prevalence of NAFLD (p<0.001). Obesity (57.1%), dyslipidemia (59.1%), and hypertriglyceridemia (42.3%) had significantly higher odds of NAFLD among people living with diabetes. CONCLUSION: This study highlighted high-risk categories for NAFLD in diabetes, like young, obese, hypertriglyceridemia, poor glycemic control, etc. This information will help health care providers in prioritizing screening among high-risk diabetes population.

Ultra-fast dynamic line-field optical coherence elastography.

In this work, we present an ultra-fast line-field optical coherence elastography system (LF-OCE) with an 11.5 MHz equivalent A-line rate. The system was composed of a line-field spectral domain optical coherence tomography system based on a supercontinuum light source, Michelson-type interferometer, and a high-speed 2D spectrometer. The system performed ultra-fast imaging of elastic waves in tissue-mimicking phantoms of various elasticities. The results corroborated well with mechanical testing. Following validation, LF-OCE measurements were made in in situ and in in vivo rabbit corneas under various conditions. The results show the capability of the system to rapidly image elastic waves in tissues.

Multimodal high-resolution embryonic imaging with light sheet fluorescence microscopy and optical coherence tomography.

A high-resolution imaging system combining optical coherence tomography (OCT) and light sheet fluorescence microscopy (LSFM) was developed. LSFM confined the excitation to only the focal plane, removing the out of plane fluorescence. This enabled imaging a murine embryo with higher speed and specificity than traditional fluorescence microscopy. OCT gives information about the structure of the embryo from the same plane illuminated by LSFM. The co-planar OCT and LSFM instrument was capable of performing co-registered functional and structural imaging of mouse embryos simultaneously.

Micro Air-Pulse Spatial Deformation Spreading Characterizes Degree of Anisotropy in Tissues.

In optical coherence elastography (OCE), air-pulse stimulation has been widely used to produce propagation of mechanical waves for elastic characterization of tissues. In this paper, we propose the use of spatial deformation spreading (SDS) on the surface of samples produced by air-pulse stimulation for the OCE of transverse isotropic tissues. Experiments in isotropic tissue-mimicking phantoms and anisotropic chicken tibialis muscle were conducted using a spectral-domain optical coherence tomography system synchronized with a confocal air-pulse stimulation. SDS measurements were compared with wave speeds values calculated at different propagation angles. We found an approximately linear relationship between shear wave speed and SDS in isotropic phantoms, which was confirmed with predictions made by the numerical integration of a wave propagation model. Experimental measurements in chicken muscle show a good agreement between SDS and surface wave speed taken along and across the axis of symmetry of the tissues, also called degree of anisotropy. In summary, these results demonstrated the capabilities of SDS produced by the air-pulse technique in measuring the shear elastic anisotropy of transverse isotropic tissues.

A Scientometric Analysis of the 100 Most Cited Articles on Pallidotomy.

BACKGROUND: Pallidotomy is the oldest stereotactically performed neurosurgical procedure for movement disorders. Consequently, there is a wealth of literature available on the topic. OBJECTIVES: The aim of this analysis was to identify the top-cited articles on pallidotomy in order to discern the origins, spread, the current trends, and the future directions of this surgical procedure. METHODS: We performed a search of the Web of Science database on 19 October 2020 using the keyword "pallidotomy." The top-100 cited articles found were arranged in descending order on the basis of citation count (CC) and citation per year (CY). Relevant conclusions were derived. RESULTS: The 100 top-cited articles were published between 1961 and 2017, in 24 journals. The average CC and CY were 118.1 (range - 856-46) and 5.326 (range - 29.52-2.09), respectively. The 3 most prolific authors were Lang AE (Neurologist - Toronto), Lozano AM (Neurosurgeon - Toronto), and Vitek JL (Neurologist - Atlanta). The Journal of Neurosurgery published the highest number of top-cited articles [Neurology. 1960;10:61-9]. The maximum articles were from the USA. University of Toronto and Emory University were the most productive institutions. CONCLUSIONS: Pallidotomy has gone through several ebbs and flows. Unilateral pallidotomy is currently recommended for the treatment of motor symptoms of Parkinson's disease and dystonia. The need for further research and improved technology to make the technique safer and prove its efficacy is highlighted, especially keeping in mind a large number of populations to which the prohibitively expensive deep brain stimulation is unavailable.

Spontaneous external rupture of hydrocephalus after fontanelle closure: a case report and review of literature.

We report a 2-year-old child with congenital hydrocephalus who presented with a frontal meningocoele due to ventriculo-subgaleal fistula secondary to hydrocephalus (internal rupture), which gradually ruptured spontaneously through the skin. This case is unique given its association with occipital encephalocele and is only the second case to present with external rupture beyond the age of 1 year. Further, the ventricles have ruptured through the skull, after the closure of anterior fontanelle, into the subgaleal space. It challenges the present understanding that external rupture occurs only through an open anterior fontanelle.

C19MC amplification and expression of Lin28A and Olig2 in the classification of embryonal tumors of the central nervous system: A 14-year retrospective study from a tertiary care center.

INTRODUCTION: CNS embryonal tumors (CET) other than medulloblastomas (MB) and atypical teratoid/rhabdoid tumors (AT/RTs), previously designated as 'central nervous system primitive neuroectodermal tumors' ('CNS PNETs'), are a heterogenous subset of tumors with poorly defined diagnostic criteria. Other than the subset of embryonal tumor with multilayered rosettes (ETMR) defined by C19MC amplification, most CETs are diagnosed by exclusion of other molecularly defined entities and histological mimics including MB, AT/RTs, and high-grade gliomas, and termed as CET, not otherwise specified (NOS) in the 2016 WHO classification. AIM: To reclassify 'CNS PNETs' as per WHO 2016, and estimate the true proportion of CET, NOS in a tertiary healthcare setting, and to evaluate the diagnostic utility of C19MC amplification, Lin28A and Olig2 expression in the subclassification of CETs. METHODS: Previously diagnosed cases of 'CNS PNETs' (2002-2016) were first evaluated by immunohistochemistry (IHC) for MIC2, RelaA, L1CAM, IDH1R132H, H3K27M, H3G34R, H3G34V, INI1, and BRG1 proteins and by fluorescence in-situ hybridization (FISH) for EWSR1 translocation to exclude histological mimics. The selected CETs (case cohort) and 79 histological mimics (comparison cohort) comprising of MB, AT/RT, pineal parenchymal tumors, Ewing sarcoma, esthesioneuroblastoma, intraocular medulloepithelioma, and H3G34R mutant high-grade glioma were subject to IHC for Olig2 and Lin28A, and FISH for C19MC amplification. RESULTS: Twenty-two cases of 'CNS PNETs' were retrieved, all of which were negative for the first panel of markers and showed retained INI-1/BRG1 expression. Three of them (3/22, 13.6%) showed C19MC amplification (ETMR, C19MC-altered) with ETMR histology, Lin28A positivity, and Olig2 negativity. Among the remaining 19 CETs, one showed medulloepithelioma histology (Medulloepithelioma, NOS) and remaining were non-descript small round cell tumors (CET, NOS), all negative for Lin28A. Olig2 was positive in only 3 CETs (13.6%), all being CET, NOS. All tumors in the comparison cohort were negative for C19MC amplification, Lin28A and Olig2 except for 27% of ATRTs that were Lin28A positive. CONCLUSION: ETMR, C19MC-altered constitute less than 14% of CETs, with majority remaining uncharacterized as CET, NOS. Lin28A is 100% sensitive for the detection of C19MC amplification; however, its specificity is limited by its expression in ATRTs. Olig2 expression is seen only in a small subset of CET, NOS and is of limited diagnostic utility.

Confocal air-coupled ultrasonic optical coherence elastography probe for quantitative biomechanics.

We present an air-coupled ultrasonic radiation force probe co-focused with a phase-sensitive optical coherence tomography (OCT) system for quantitative wave-based elastography. A custom-made 1 MHz spherically focused piezoelectric transducer with a concentric 10 mm wide circular opening allowed for confocal micro-excitation of waves and phase-sensitive OCT imaging. Phantom studies demonstrated the capabilities of this probe to produce quasi-harmonic excitation up to 4 kHz for generation of elastic waves. Experimental results in ocular tissues showed highly detailed 2D and 3D elasticity mapping using this approach with great potential for clinical translation.

Longitudinal elastic wave imaging using nanobomb optical coherence elastography: erratum.

We present an erratum to correct an inadvertent error made during the calculations of the in-focus fluence of pulsed laser used to excite nanoparticles [Opt. Lett.44, 3162 (2019)OPLEDP0146-959210.1364/OL.44.003162] and to update the conclusion regarding laser safety limits achieved with this type of excitation.