A Spatial Interpolation Approach to Assign Magnetic Resonance Imaging-Derived Material Properties for Finite Element Models of Adeno-Associated Virus Infusion Into a Recurrent Brain Tumor.

Adeno-associated virus (AAV) is a clinically useful gene delivery vehicle for treating neurological diseases. To deliver AAV to focal targets, direct infusion into brain tissue by convection-enhanced delivery (CED) is often needed due to AAV's limited penetration across the blood-brain-barrier and its low diffusivity in tissue. In this study, computational models that predict the spatial distribution of AAV in brain tissue during CED were developed to guide future placement of infusion catheters in recurrent brain tumors following primary tumor resection. The brain was modeled as a porous medium, and material property fields that account for magnetic resonance imaging (MRI)-derived anatomical regions were interpolated and directly assigned to an unstructured finite element mesh. By eliminating the need to mesh complex surfaces between fluid regions and tissue, mesh preparation was expedited, increasing the model's clinical feasibility. The infusion model predicted preferential fluid diversion into open fluid regions such as the ventricles and subarachnoid space (SAS). Additionally, a sensitivity analysis of AAV delivery demonstrated that improved AAV distribution in the tumor was achieved at higher tumor hydraulic conductivity or lower tumor porosity. Depending on the tumor infusion site, the AAV distribution covered 3.67-70.25% of the tumor volume (using a 10% AAV concentration threshold), demonstrating the model's potential to inform the selection of infusion sites for maximal tumor coverage.

Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

For over two centuries, clinicians have been aware of various conditions affecting white matter which had come to be grouped under the umbrella term multiple sclerosis. Within the last 20 years, specific scientific advances have occurred leading to more accurate diagnosis and differentiation of several of these conditions including, neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody disease. This new understanding has been coupled with advances in disease-modifying therapies which must be accurately applied for maximum safety and efficacy.

Brain Dead and Pregnant.

The presence of pregnancy in a brain-dead woman is a rare circumstance. We present a case of a 31-year-old woman who was 22 weeks pregnant at the time of diagnosis of brain death after intracranial and subarachnoid hemorrhage. After a multidisciplinary approach, the decision was made to continue somatic support to maintain the pregnancy until optimal fetus viability. Cesarean section was performed after 11 weeks (33 weeks gestational age) of brain-death diagnosis with a successful delivery of a live infant. Management of brain-death complications during pregnancy is described.

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation.

Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient's white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.

NS-HGlio: A generalizable and repeatable HGG segmentation and volumetric measurement AI algorithm for the longitudinal MRI assessment to inform RANO in trials and clinics.

Background: Accurate and repeatable measurement of high-grade glioma (HGG) enhancing (Enh.) and T2/FLAIR hyperintensity/edema (Ed.) is required for monitoring treatment response. 3D measurements can be used to inform the modified Response Assessment in Neuro-oncology criteria. We aim to develop an HGG volumetric measurement and visualization AI algorithm that is generalizable and repeatable. Methods: A single 3D-Convoluted Neural Network, NS-HGlio, to analyze HGG on MRIs using 5-fold cross validation was developed using retrospective (557 MRIs), multicentre (38 sites) and multivendor (32 scanners) dataset divided into training (70%), validation (20%), and testing (10%). Six neuroradiologists created the ground truth (GT). Additional Internal validation (IV, three institutions) using 70 MRIs, and External validation (EV, single institution) using 40 MRIs through measuring the Dice Similarity Coefficient (DSC) of Enh., Ed. ,and Enh. + Ed. (WholeLesion/WL) tumor tissue and repeatability testing on 14 subjects from the TCIA MGH-QIN-GBM dataset using volume correlations between timepoints were performed. Results: IV Preoperative median DSC Enh. 0.89 (SD 0.11), Ed. 0.88 (0.28), WL 0.88 (0.11). EV Preoperative median DSC Enh. 0.82 (0.09), Ed. 0.83 (0.11), WL 0.86 (0.06). IV Postoperative median DSC Enh. 0.77 (SD 0.20), Ed 0.78. (SD 0.09), WL 0.78 (SD 0.11). EV Postoperative median DSC Enh. 0.75 (0.21), Ed 0.74 (0.12), WL 0.79 (0.07). Repeatability testing; Intraclass Correlation Coefficient of 0.95 Enh. and 0.92 Ed. Conclusion: NS-HGlio is accurate, repeatable, and generalizable. The output can be used for visualization, documentation, treatment response monitoring, radiation planning, intra-operative targeting, and estimation of Residual Tumor Volume among others.

Pituitary Apoplexy (PA): Delayed Diagnosis of a Rare Clinical Syndrome in a Patient With a Known Pituitary Adenoma.

Pituitary apoplexy (PA) is a rare clinical syndrome in which the pituitary gland undergoes infarction or hemorrhage, predominantly in the setting of an underlying tumor. We report on apoplexy of an expanding pituitary macroadenoma that was compressing the optic chiasm in a patient with progressively worsening neurologic deficits. Due to the patient's rapidly declining clinical status and family's goals of care, no neurosurgical intervention took place, and the patient expired a few days following discharge to hospice. This case highlights the importance of early suspicion for apoplexy in a patient with a history of pituitary adenoma and signs of neurologic deficit.

Visualization of the perivenous glymphatic efflux in human brain after laser interstitial thermal therapy.

Recent studies have revealed that there is existence of a specific waste clearance pathway in the brain, coined the glymphatic system. This case report demonstrates supportive finding of drainage of Gadolinium and waste products released after Laser Interstitial Thermal Therapy via perivenous routes and a paradural lymphatic system. These findings provide further evidence of interstitial fluid drainage along the perivenous spaces in accordance with a glymphatic system theory.

A Comparison of Pediatric- and Adult-Onset Aquaporin-4 Immunoglobulin G-Positive Neuromyelitis Optica Spectrum Disorder: A Review of Clinical and Radiographic Characteristics.

BACKGROUND: The identification of immunoglobulin G antibodies against the aquaporin-4 channel (AQP-IgG) in the majority of adult patients differentiates neuromyelitis optica as a distinct disease entity. The high specificity of AQP4-IgG for neuromyelitis optica has allowed the identification of seropositive patients with atypical presentations of this disease. Neuromyelitis optica spectrum disorder has been increasingly recognized in children who demonstrate patterns of clinical involvement beyond the traditional boundaries of the optic pathways and spinal cord. METHODS: This is a single-center, retrospective review comparing demographic, clinical/paraclinical, and laboratory features of children and adults with a serologically confirmed diagnosis of AQP4-IgG-positive neuromyelitis optica spectrum disorder. RESULTS: Of 151 reviewed patient charts, 12 pediatric-onset and 31 adult-onset patients had AQP4-IgG-positive neuromyelitis optica spectrum disorder. The mean age of pediatric-onset neuromyelitis optica spectrum disorder was 12 ± 3.58 years with a female predilection (3:1). Pediatric patients showed more frequent involvement of the brainstem (6/12 [50%]); P = .008) and diencephalon (3/12 [25%]; P = .018). A preceding infection was identifiable in only 3 of 12 (25%) pediatric-onset patients. Moreover, disability as calculated on the expanded disability status scale was less severe in pediatric-onset cases compared to adult-onset cases in their most recent assessment (0 [0-9]) vs 6.5 [0-10]; P = .005). Pediatric-onset patients were also more likely to respond to treatment of acute episodes with corticosteroids ± intravenous immunoglobulin and/or plasmapheresis (Clinical Global Impression-Change scale: 2.5 [1-4] vs 4 [1-6], P = .009). INTERPRETATION: This retrospective study was able to compare and contrast pediatric- and adult-onset neuromyelitis optica spectrum disorder. Relative to their adult counterparts, pediatric-onset neuromyelitis optica spectrum disorder patients were more likely to respond to treatment and less likely to be disabled from their disease at follow-up. Therefore, pediatric-onset disease may represent a less virulent form of neuromyelitis optica spectrum disorder.

Presumptive Diagnosis of Pallister-Hall Syndrome Using Magnetic Resonance Imaging.

Pallister-Hall syndrome (PHS) is an extremely rare genetic disorder for which the diagnosis is often overlooked. The objective of this case report is to highlight how clinical features used in conjunction with brain MRI findings can lead to an expeditious diagnosis without the need for invasive measures or genetic test results. We present the case of a three-day-old infant delivered at 34 and 4/7 weeks gestation who presented with mild respiratory distress and bilious emesis in the setting of an uncomplicated gestational course and vaginal delivery with no known teratogen exposure. A diagnosis of Pallister-Hall syndrome was made on the basis of physical exam findings, hormonal abnormalities and the identification of a hypothalamic hamartoma on brain MRI. The patient underwent multiple procedures for diagnosis and management of PHS complications, including a diverting jejunostomy for a long-segment Hirschsprung's and a laryngoscopy which identified a bifid epiglottis. The patient tolerated the interventions and did not have seizures on admission. The MRI brain detection of a hypothalamic hamartoma led to an earlier diagnosis of Pallister-Hall syndrome and thus further screening and identification of complications associated with this disorder were performed before genetic analyses or brain biopsies were obtained. Given the unique MRI features of hypothalamic hamartomas, brain MRI can be a useful tool for making an early PHS diagnosis when taken with clinical features concerning possible PHS.

Management of Cavernous Sinus Thrombosis Following Herpes Zoster Ophthalmicus.

Herpes zoster opthalmicus (HZO) is the reactivation of latent varicella zoster virus (VZV) within the ophthalmic branch of the trigeminal ganglion (V1). Common complications are postherpetic neuralgia and vasculopathy. Here, we report a rare case of a 47-year-old female presenting with HZO and aseptic cavernous sinus thrombosis (CST). Early screening for rare and deadly complications such as CST using CT cerebral venography (CTV) and magnetic resonance venography (MRV), as was done, is crucial to detection at earlier stages when intervention is most effective. Anticoagulation therapy was promptly started, and the patient's symptoms continued to improve during the hospital stay.

Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes.

Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.

Pediatric craniosynostosis computed tomography: an institutional experience in reducing radiation dose while maintaining diagnostic image quality.

BACKGROUND: Children with craniosynostosis may undergo multiple computed tomography (CT) examinations for diagnosis and post-treatment follow-up, resulting in cumulative radiation exposure. OBJECTIVE: To reduce the risks associated with radiation exposure, we evaluated the compliance, radiation dose reduction and clinical image quality of a lower-dose CT protocol for pediatric craniosynostosis implemented at our institution. MATERIALS AND METHODS: The standard of care at our institution was modified to replace pediatric head CT protocols with a lower-dose CT protocol utilizing 100 kV, 5 mAs and iterative reconstruction. Study-ordered, protocol-utilized and radiation-dose indices were collected for studies performed with routine pediatric brain protocols (n=22) and with the lower-dose CT protocol (n=135). Two pediatric neuroradiologists evaluated image quality in a subset (n=50) of the lower-dose CT studies by scoring visualization of cranial structures, confidence of diagnosis and the need for more radiation dose. RESULTS: During the 30-month period, the lower-dose CT protocol had high compliance, with 2/137 studies performed with routine brain protocols. With the lower-dose CT protocol, volume CT dose index (CTDIvol) was 1.1 mGy for all patients (0-9 years old) and effective dose ranged from 0.06 to 0.22 mSv, comparable to a 4-view skull radiography examination. CTDIvol was reduced by 98% and effective dose was reduced up to 67-fold. Confidence in diagnosing craniosynostosis was high and more radiation dose was considered unnecessary in all studies (n=50) by both radiologists. CONCLUSION: Replacing the routine pediatric brain CT protocol with a lower-dose CT craniosynostosis protocol substantially reduced radiation exposure without compromising image quality or diagnostic confidence.

Cryptococcosis Presenting as Cerebrovascular Disease.

Infection plays a complex role in cerebrovascular disease and is believed to have both direct and indirect mechanisms on stroke pathogenesis. if not diagnosed and treated promptly, this may have devastating consequences. Management of infection-related strokes focuses on the treatment of the underlying infection with appropriate antimicrobial drugs and the prevention of medical complications. This can lead to devastating neurological deficits. We present two cases of cryptococcal meningoencephalitis that presented with an atypical cerebral infarction. A 55-year-old male with a history of unknown autoimmune disease presented with acute onset cognitive changes and no stroke-like symptoms. A 35-year-old male with no history of autoimmune disease or other existing immunodeficiency presented with breakthrough seizure a long with stroke-like symptoms. Both patients developed multiple cerebral infarcts in multiple vascular territories, with histologic and radiologic findings consistent with a central nervous system cryptococcosis. They were subsequently diagnosed with cryptococcal meningoencephalitis and started on the appropriate anti-fungal regimen with amphotericin B and flucytosine. Prior to discharge to an inpatient rehabilitation facility, both patients were notably improved and near their neurologic baseline. It is important to understand the pathogenesis of cryptococcal infection in the central nervous system because it produces a wide variety of clinico-radiographic features that can be overlooked. Clinicians should keep infection-mediated cerebral infarcts in mind, regardless of risk factors, in order to expedite antimicrobial therapy and minimize adverse events.

Moyamoya Disease in a Young Female With Neurofibromatosis Type 1.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive stenosis of the terminal portions of the internal carotid arteries (ICAs) and the development of a network of abnormal collateral vessels. This case depicts a 25-year-old African American female patient with neurofibromatosis type 1 (NF-1), whose initial hospital presentation occurred in a hypertensive emergency setting. Surveillance studies with magnetic resonance imaging (MRI) revealed multiple asymptomatic right cortical strokes. Genetic testing evidenced a novel, unique pathogenic variant on the NF-1 gene. The patient underwent combined bypass surgery first and then was placed on aspirin and a blood pressure control regimen. Our case illustrates the need for clinicians to include moyamoya disease in the list of differential diagnoses when encountering a young patient, without major risk factors, presenting with ischemic stroke. It should be considered even with no known history of previously diagnosed MMD or NF-1, as these pathologies may have yet to be evaluated in subclinical cases.

Detailed imaging of abducens nerve anatomy using contrast-enhanced 3D-TOF MR angiography.

PURPOSE: Cranial nerves (CNs), particularly CN IV and VI are difficult to visualize with conventional MRI techniques, particularly within the cavernous sinus region. The aim of this study was to evaluate the capacity of high-resolution contrast enhanced 3D time-of-flight (TOF) MR angiography using new generation 3 T imaging technology to provide detailed visualization of CN VI anatomy, particularly within the cavernous sinus and petroclival regions. METHODS: Two neuroradiologists conducted bilateral evaluation of CN VI visibility in 23 patients for nerve segments located in the petroclival segment (dural cave and Dorello's canal), and three divisions of the cavernous sinus. All images were collected using contrast enhanced TOF MR angiography using a new generation 3 T machine. RESULTS: Of the CN VI segments assessed, average visibility of CN VI was best achieved in Dorello's canal. Overall visibility of CN VI within the regions inspected was best achieved in the axial view, with the exception of the dural cave, which was best assessed using the coronal view. We also identified strong agreement in assessment of nerve visibility between the two reviewers. We also identified a putative CN6 duplication and a small schwannoma, highlighting the fidelity of our approach. CONCLUSION: Contrast enhanced 3D TOF MR angiography can visualize CN VI anatomy, particularly within the petrocavernosal region and cavernous sinus with simultaneous visualization of arterial and venous structures. This cannot be easily achieved using traditional MRI techniques. This imaging technique might be used with new generation machines to evaluate CN VI anatomy and pathologies within the petrocavernosal region and cavernous sinus, especially relating to vascular pathologies.

Gadolinium in tears: Evidence for an alternative cerebrospinal fluid absorption pathway in the setting of ischemia-induced blood brain barrier disruption.

Cerebral ischemia results in disruption of the blood-brain barrier (BBB) allowing leakage of gadolinium-based contrast media (GBCM) into cerebrospinal fluid (CSF) within the craniospinal and perineural subarachnoid spaces (SAS). This phenomenon is well visualized with fluid-attenuated inversion recovery MRI techniques and allows for visualization of CSF flow dynamics. We present a case of ischemia-induced BBB disruption resulting in accumulation of GBCM in the SAS and ocular chambers as well as within the precorneal tear film and nasolacrimal duct. We present imaging evidence for a hypothetical alternate CSF absorption pathway through the ocular structures in keeping with prior experimental evidence.

Anti-MOG associated disorder-Clinical and radiological characteristics compared to AQP4-IgG+ NMOSD-A single-center experience.

BACKGROUND: The discovery of two immunoglobulin G (IgG) antibodies against aquaporin 4 (anti-AQP4) and myelin oligodendrocyte glycoprotein (anti-MOG) has led to the distinction of the disorders anti-AQP4 immunoglobulin G positive neuromyelitis spectrum disorder (AQP4-IgG+ NMOSD) and anti-MOG associated disorder (MOGAD). Different clinical and radiological features have been proposed to distinguish these two demyelinating CNS diseases. METHODS: This is a single-center retrospective review at the University of Florida (UF) including all patients with the diagnostic code ICD G36 ("other acute disseminated demyelination") from October 2015 to January 2020 (n=141) and all charts included in the clinical NMOSD database of the UF Division of Neuroimmunology (n=36). A total of 151 cases were reviewed for presence of anti-MOG and anti-AQP4 antibodies and NMOSD diagnostic criteria. Differences in MOGAD and AQP4-IgG+ NMOSD were compared. RESULTS: Of the 151 reviewed patient charts, 11 were consistent with MOGAD and 43 with AQP4-IgG+ NMOSD. Patients with MOGAD were significantly younger at symptom onset compared to patients with AQP4-IgG+ NMOSD (14 [1-33] years vs. 37 [6-82] years; p=0.005). In comparison with AQP4-IgG+ NMOSD, optic neuritis in MOGAD was more frequently associated with bilateral optic nerve involvement: (6/11 [54.5%] vs. 6/43 [13.9%]; p=0.009) and fundoscopic presence of optic disc edema (5/11 [45.5%] vs. 3/43 [7%]; p=0.006). Perineuritis was a common radiological feature in MOGAD (present in 4 cases). In case of myelitis, there was more frequent involvement of the conus medullaris in MOGAD (4/11 [36.4%] vs. 2/43 [4.7%]; p=0.012). Symptomatic cerebral syndrome with supratentorial white matter lesions was seen in MOGAD patients with pediatric onset (pediatric onset: 4/6 [66.7%] vs. adult onset: 0/5 [0%]. In MOGAD, evidence for combined central and peripheral demyelination and increased intracranial pressure was present in one patient each. A preceding inciting event (illness/postpartum) was more frequently identifiable in MOGAD (4/11 [36.4%] vs. 4/43 [7%]; p=0.045). Disability as calculated on the Expanded Disability Status Scale was less severe in MOGAD compared to AQP-IgG+ NMOSD (most severe presentation: 5 [2-7] vs. 7 [1-10]; p=0.015; most recent assessment: 2 [0-5] vs. 5 [0-10]; p=0.045) and patients were more likely to respond to treatment of acute attacks with corticosteroids and/or plasmapheresis (Clinical Global Impression-Global Change scale: 1 [1-4] vs. 3 [1-6]; p=0.001). INTERPRETATION: The study confirms that simultaneous bilateral optic neuritis, presence of optic disc edema, transverse myelitis with conus involvement and a less severe disease course are distinctive features of MOGAD.

Glioblastoma with a primitive neuroectodermal component: two cases with implications for glioblastoma cell-of-origin.

BACKGROUND: Glioblastoma (GBM) is the most common primary brain malignancy, but much remains unknown about the histogenesis of these tumors. In the great majority of cases, GBM is a purely glial tumor but in rare cases the classic-appearing high-grade glioma component is admixed with regions of small round blue cells with neuronal immunophenotype, and these tumors have been defined in the WHO 2016 Classification as "glioblastoma with a primitive neuronal component." METHODS: In this paper, we present two cases of GBM-PNC with highly divergent clinical courses, and review current theories for the GBM cell-of-origin. RESULTS AND CONCLUSIONS: GBM-PNC likely arises from a cell type competent to give rise to glial or neuronal lineages. The thesis that GBM recapitulates to some extent normal neurodevelopmental cellular pathways is supported by molecular and clinical features of our two cases of GBM-PNC, but more work is needed to determine which cellular precursor gives rise to specific cases of GBM. GBM-PNC may have a dramatically altered clinical course compared to standard GBM and may benefit from specific lines of treatment.