Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Advanced Imaging in the Diagnosis and Response Assessment of High-Grade Glioma: AJR Expert Panel Narrative Review.

This AJR Expert Panel Narrative explores the current status of advanced MRI and PET techniques for the post-therapeutic response assessment of high-grade adult-type gliomas, focusing on ongoing clinical controversies in current practice. Discussed techniques that complement conventional MRI and aid the differentiation of recurrent tumor from post-treatment effects include DWI and diffusion tensor imaging; perfusion MRI techniques including dynamic susceptibility contrast (DSC), dynamic contrast-enhanced MRI, and arterial spin labeling; MR spectroscopy including assessment of 2-hydroxyglutarate (2HG) concentration; glucose- and amino acid (AA)-based PET; and amide proton transfer imaging. Updated criteria for Response Assessment in Neuro-Oncology are presented. Given the abundant supporting clinical evidence, the panel supports a recommendation that routine response assessment after HGG treatment should include perfusion MRI, particularly given the development of a consensus recommended DSC-MRI protocol. Although published studies support 2HG MRS and AA PET, these techniques' widespread adoption will likely require increased availability (for 2HG MRS) or increased insurance funding in the United States (for AA PET). The article concludes with a series of consensus opinions from the author panel, centered on the clinical integration of the advanced imaging techniques into posttreatment surveillance protocols.

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

Validation of a highly accelerated post-contrast wave-controlled aliasing in parallel imaging (CAIPI) 3D-T1 MPRAGE compared to standard 3D-T1 MPRAGE for detection of intracranial enhancing lesions on 3-T MRI.

OBJECTIVES: High-resolution post-contrast T1-weighted imaging is a workhorse sequence in the evaluation of neurological disorders. The T1-MPRAGE sequence has been widely adopted for the visualization of enhancing pathology in the brain. However, this three-dimensional (3D) acquisition is lengthy and prone to motion artifact, which often compromises diagnostic quality. The goal of this study was to compare a highly accelerated wave-controlled aliasing in parallel imaging (CAIPI) post-contrast 3D T1-MPRAGE sequence (Wave-T1-MPRAGE) with the standard 3D T1-MPRAGE sequence for visualizing enhancing lesions in brain imaging at 3 T. METHODS: This study included 80 patients undergoing contrast-enhanced brain MRI. The participants were scanned with a standard post-contrast T1-MPRAGE sequence (acceleration factor [R] = 2 using GRAPPA parallel imaging technique, acquisition time [TA] = 5 min 18 s) and a prototype post-contrast Wave-T1-MPRAGE sequence (R = 4, TA = 2 min 32 s). Two neuroradiologists performed a head-to-head evaluation of both sequences and rated the visualization of enhancement, sharpness, noise, motion artifacts, and overall diagnostic quality. A 15% noninferiority margin was used to test whether post-contrast Wave-T1-MPRAGE was noninferior to standard T1-MPRAGE. Inter-rater and intra-rater agreement were calculated. Quantitative assessment of CNR/SNR was performed. RESULTS: Wave-T1-MPRAGE was noninferior to standard T1-MPRAGE for delineating enhancing lesions with unanimous agreement in all cases between raters. Wave-T1-MPRAGE was noninferior in the perception of noise (p < 0.001), motion artifact (p < 0.001), and overall diagnostic quality (p < 0.001). CONCLUSION: High-accelerated post-contrast Wave-T1-MPRAGE enabled a two-fold reduction in acquisition time compared to the standard sequence with comparable performance for visualization of enhancing pathology and equivalent perception of noise, motion artifacts and overall diagnostic quality without loss of clinically important information. KEY POINTS: • Post-contrast wave-controlled aliasing in parallel imaging (CAIPI) T1-MPRAGE accelerated the acquisition of three-dimensional (3D) high-resolution post-contrast images by more than two-fold. • Post-contrast Wave-T1-MPRAGE was noninferior to standard T1-MPRAGE with unanimous agreement between reviewers (100% in 80 cases) for the visualization of intracranial enhancing lesions. • Wave-T1-MPRAGE was equivalent to the standard sequence in the perception of noise in 94% (75 of 80) of cases and was preferred in 16% (13 of 80) of cases for decreased motion artifact.

Atretic cephalocele and encephalocele: A single-institution clinicopathological study.

BACKGROUND: Encephaloceles are neural tube defects characterized by herniation of meninges, neural tissue and cerebrospinal fluid, while atretic cephaloceles denote a rudimentary connection to the intracranial space with absence of herniated neural tissue and represent an infrequent dermatopathologic diagnosis. Limited reports of these entities confound the challenge in their histopathologic distinction. Accurate classification is important given associated anomalies and neurologic manifestations that impact prognosis. METHODS: We describe the clinicopathological and immunohistochemical [glial fibrillary acidic protein (GFAP), S100, epithelial membrane antigen (EMA), and somatostatin receptor subtype 2A (SSTR2A)] features in a retrospective series encountered at a single institution between 1994 and 2020. RESULTS: We identified 13 cases classified as atretic cephalocele (n = 11) and encephalocele (n = 2). Hamartomatous changes and multinucleated cells were unique to atretic cephaloceles while myxoid areas were unique to encephaloceles. At least focal staining for SSTRA was seen in all atretic cephaloceles with the majority (87.5%) staining for EMA; negative staining for GFAP and S100 confirmed absence of neural tissue. Encephaloceles were GFAP and S100 positive, and negative for SSTR2 and EMA. Atretic cephaloceles had a favorable prognosis compared to encephaloceles, with severe morbidity present in both encephalocele cases. CONCLUSION: Our study raises awareness of atretic cephalocele and encephalocele among dermatopathologists and reveals a mutually exclusive immunophenotype that facilitates their distinction for prognostication and management.

Myo-Inositol Levels Measured with MR Spectroscopy Can Help Predict Failure of Antiangiogenic Treatment in Recurrent Glioblastoma.

Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.

Optimization of magnetization transfer contrast for EPI FLAIR brain imaging.

PURPOSE: To evaluate the impact of magnetization transfer (MT) on brain tissue contrast in turbo-spin-echo (TSE) and EPI fluid-attenuated inversion recovery (FLAIR) images, and to optimize an MT-prepared EPI FLAIR pulse sequence to match the tissue contrast of a clinical reference TSE FLAIR protocol. METHODS: Five healthy volunteers underwent 3T brain MRI, including single slice TSE FLAIR, multi-slice TSE FLAIR, EPI FLAIR without MT-preparation, and MT-prepared EPI FLAIR with variations of the MT-preparation parameters, including number of preparation pulses, pulse amplitude, and resonance offset. Automated co-registration and gray matter (GM) versus white matter (WM) segmentation was performed using a T1-MPRAGE acquisition, and the GM versus WM signal intensity ratio (contrast ratio) was calculated for each FLAIR acquisition. RESULTS: Without MT preparation, EPI FLAIR showed poor tissue contrast (contrast ratio = 0.98), as did single slice TSE FLAIR. Multi-slice TSE FLAIR provided high tissue contrast (contrast ratio = 1.14). MT-prepared EPI FLAIR closely approximated the contrast of the multi-slice TSE FLAIR images for two combinations of the MT-preparation parameters (contrast ratio = 1.14). Optimized MT-prepared EPI FLAIR provided a 50% reduction in scan time compared to the reference TSE FLAIR acquisition. CONCLUSION: Optimized MT-prepared EPI FLAIR provides comparable brain tissue contrast to the multi-slice TSE FLAIR images used in clinical practice.

An artificial intelligence-accelerated 2-minute multi-shot echo planar imaging protocol for comprehensive high-quality clinical brain imaging.

PURPOSE: We introduce and validate an artificial intelligence (AI)-accelerated multi-shot echo-planar imaging (msEPI)-based method that provides T1w, T2w, T2∗ , T2-FLAIR, and DWI images with high SNR, high tissue contrast, low specific absorption rates (SAR), and minimal distortion in 2 minutes. METHODS: The rapid imaging technique combines a novel machine learning (ML) scheme to limit g-factor noise amplification and improve SNR, a magnetization transfer preparation module to provide clinically desirable contrast, and high per-shot EPI undersampling factors to reduce distortion. The ML training and image reconstruction incorporates a tunable parameter for controlling the level of denoising/smoothness. The performance of the reconstruction method is evaluated across various acceleration factors, contrasts, and SNR conditions. The 2-minute protocol is directly compared to a 10-minute clinical reference protocol through deployment in a clinical setting, where five representative cases with pathology are examined. RESULTS: Optimization of custom msEPI sequences and protocols was performed to balance acquisition efficiency and image quality compared to the five-fold longer clinical reference. Training data from 16 healthy subjects across multiple contrasts and orientations were used to produce ML networks at various acceleration levels. The flexibility of the ML reconstruction was demonstrated across SNR levels, and an optimized regularization was determined through radiological review. Network generalization toward novel pathology, unobserved during training, was illustrated in five clinical case studies with clinical reference images provided for comparison. CONCLUSION: The rapid 2-minute msEPI-based protocol with tunable ML reconstruction allows for advantageous trade-offs between acquisition speed, SNR, and tissue contrast when compared to the five-fold slower standard clinical reference exam.

Clinical validation of Wave-CAIPI susceptibility-weighted imaging for routine brain MRI at 1.5 T.

OBJECTIVES: Wave-CAIPI (Controlled Aliasing in Parallel Imaging) enables dramatic reduction in acquisition time of 3D MRI sequences such as 3D susceptibility-weighted imaging (SWI) but has not been clinically evaluated at 1.5 T. We sought to compare highly accelerated Wave-CAIPI SWI (Wave-SWI) with two alternative standard sequences, conventional three-dimensional SWI and two-dimensional T2*-weighted Gradient-Echo (T2*w-GRE), in patients undergoing routine brain MRI at 1.5 T. METHODS: In this study, 172 patients undergoing 1.5 T brain MRI were scanned with a more commonly used susceptibility sequence (standard SWI or T2*w-GRE) and a highly accelerated Wave-SWI sequence. Two radiologists blinded to the acquisition technique scored each sequence for visualization of pathology, motion and signal dropout artifacts, image noise, visualization of normal anatomy (vessels and basal ganglia mineralization), and overall diagnostic quality. Superiority testing was performed to compare Wave-SWI to T2*w-GRE, and non-inferiority testing with 15% margin was performed to compare Wave-SWI to standard SWI. RESULTS: Wave-SWI performed superior in terms of visualization of pathology, signal dropout artifacts, visualization of normal anatomy, and overall image quality when compared to T2*w-GRE (all p < 0.001). Wave-SWI was non-inferior to standard SWI for visualization of normal anatomy and pathology, signal dropout artifacts, and overall image quality (all p < 0.001). Wave-SWI was superior to standard SWI for motion artifact (p < 0.001), while both conventional susceptibility sequences were superior to Wave-SWI for image noise (p < 0.001). CONCLUSIONS: Wave-SWI can be performed in a 1.5 T clinical setting with robust performance and preservation of diagnostic quality. KEY POINTS: • Wave-SWI accelerated the acquisition of 3D high-resolution susceptibility images in 70% of the acquisition time of the conventional T2*GRE. • Wave-SWI performed superior to T2*w-GRE for visualization of pathology, signal dropout artifacts, and overall diagnostic image quality. • Wave-SWI was noninferior to standard SWI for visualization of normal anatomy and pathology, signal dropout artifacts, and overall diagnostic image quality.

Cutaneous Findings of Sporadic, Adult-Onset Neuronal Intranuclear Inclusion Disease.

ABSTRACT: Neuronal intranuclear inclusion disease is a rare, progressive neurodegenerative disease whose hallmark histopathologic finding is the presence of ubiquitin-positive hyaline intranuclear inclusions in neuronal and non-neuronal cells. We present a case of neuronal intranuclear inclusion disease in a 61-year-old Asian man with a history of repeated episodes of altered mental status, long-standing bladder dysfunction, and cerebrovascular accidents. The patient had characteristic magnetic imaging findings of high signal along the cortico-medullary junction on diffusion-weighted sequences and symmetric T2 hyperintensity in the paravermal area of the cerebellum. Skin biopsies showed characteristic histopathologic findings of ubiquitin-positive intranuclear inclusions that ultrastructurally composed of filamentous material without limiting membrane within eccrine epithelium and dermal fibroblasts. Our case highlights the utility of readily accessible skin biopsy in the diagnosis of this rare neurodegenerative disease.

Evaluation of highly accelerated wave controlled aliasing in parallel imaging (Wave-CAIPI) susceptibility-weighted imaging in the non-sedated pediatric setting: a pilot study.

BACKGROUND: Susceptibility-weighted imaging (SWI) is highly sensitive for intracranial hemorrhagic and mineralized lesions but is associated with long scan times. Wave controlled aliasing in parallel imaging (Wave-CAIPI) enables greater acceleration factors and might facilitate broader application of SWI, especially in motion-prone populations. OBJECTIVE: To compare highly accelerated Wave-CAIPI SWI to standard SWI in the non-sedated pediatric outpatient setting, with respect to the following variables: estimated scan time, image noise, artifacts, visualization of normal anatomy and visualization of pathology. MATERIALS AND METHODS: Twenty-eight children (11 girls, 17 boys; mean age ± standard deviation [SD] = 128.3±62 months) underwent 3-tesla (T) brain MRI, including standard three-dimensional (3-D) SWI sequence followed by a highly accelerated Wave-CAIPI SWI sequence for each subject. We rated all studies using a predefined 5-point scale and used the Wilcoxon signed rank test to assess the difference for each variable between sequences. RESULTS: Wave-CAIPI SWI provided a 78% and 67% reduction in estimated scan time using the 32- and 20-channel coils, respectively, corresponding to estimated scan time reductions of 3.5 min and 3 min, respectively. All 28 children were imaged without anesthesia. Inter-reader agreement ranged from fair to substantial (k=0.67 for evaluation of pathology, 0.55 for anatomical contrast, 0.3 for central noise, and 0.71 for artifacts). Image noise was rated higher in the central brain with wave SWI (P<0.01), but not in the peripheral brain. There was no significant difference in the visualization of normal anatomical structures and visualization of pathology between the standard and wave SWI sequences (P=0.77 and P=0.79, respectively). CONCLUSION: Highly accelerated Wave-CAIPI SWI of the brain can provide similar image quality to standard SWI, with estimated scan time reduction of 3-3.5 min depending on the radiofrequency coil used, with fewer motion artifacts, at a cost of mild but perceptibly increased noise in the central brain.

Intact Brain Network Function in an Unresponsive Patient with COVID-19.

Many patients with severe coronavirus disease 2019 (COVID-19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID-19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID-19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness. ANN NEUROL 2020;88:851-854.

Nelson Syndrome: Clival Invasion of Corticotroph Pituitary Adenoma Resulting in Alternating Sixth Nerve Palsies.

ABSTRACT: A 44-year-old woman presented with 2 painful and self-limited episodes of binocular horizontal diplopia within 1 year that at the beginning were thought to be secondary to microvascular insult. Her medical history was significant for Cushing syndrome status post transsphenoidal resection with bilateral adrenalectomy 4 years prior, hypertension, and diabetes mellitus. Neuro-ophthalmic evaluation was significant for left abduction deficit and incomitant esotropia consistent with left abducens nerve palsy. Of note, the patient had experienced a similar episode but on the contralateral side a few months prior. Although initially MRI of the brain demonstrated stable residual postoperative finding in the sella, upon review, an heterogenous T-1 hypointense marrow in the clivus was noted. Hypermetabolism of the clivus was also noted on computed tomography positron emission tomography of the skull base. A clival biopsy demonstrated a corticotroph adenoma with elevated proliferation index and scattered mitoses. A corticotroph pituitary adenoma after adrenalectomy, also known as Nelson syndrome, was diagnosed. Radiation therapy was offered to the patient, and resolution of symptoms was gradually observed.

Comparison of ultrafast wave-controlled aliasing in parallel imaging (CAIPI) magnetization-prepared rapid acquisition gradient echo (MP-RAGE) and standard MP-RAGE in non-sedated children: initial clinical experience.

BACKGROUND: Fast magnetic resonance imaging (MRI) sequences are advantageous in pediatric imaging as they can lessen child discomfort, decrease motion artifact and improve scanner availability. OBJECTIVE: To evaluate the feasibility of an ultrafast wave-CAIPI (controlled aliasing in parallel imaging) MP-RAGE (magnetization-prepared rapid gradient echo) sequence for brain imaging of awake pediatric patients. MATERIALS AND METHODS: Each MRI included a standard MP-RAGE sequence and an ultrafast wave-MP-RAGE sequence. Two neuroradiologists evaluated both sequences in terms of artifacts, noise, anatomical contrast and pathological contrast. A predefined 5-point scale was used by two independent pediatric neuroradiologists. A Wilcoxon signed-rank test was used to evaluate the difference between sequences for each variable. RESULTS: Twenty-four patients (14 males; mean age: 11.5±4.5 years, range: 1 month to 17.8 years) were included. Wave-CAIPI MP-RAGE provided a 77% reduction in scan time using a 32-channel coil and a 70% reduction using a 20-channel coil. Visualization of the pathology, artifacts and pathological enhancement (including parenchymal, leptomeningeal and dural enhancement) was not significantly different between standard MP-RAGE and wave-CAIPI MP-RAGE (all P>0.05). For central (P<0.001) and peripheral (P<0.001) noise, and the evaluation of the anatomical structures (P<0.001), the observers favored standard MP-RAGE over wave-CAIPI MP-RAGE. CONCLUSION: Ultrafast brain imaging with wave-CAIPI MP-RAGE is feasible in awake pediatric patients, providing a substantial reduction in scan time at a cost of subjectively increased image noise.

Magnetic resonance imaging quality control, quality assurance and quality improvement.

Quality in MR imaging is a comprehensive process that encompasses scanner performance, clinical processes for efficient scanning and reporting, as well as data-driven improvement involving measurement of key performance indicators. In this paper, the authors review this entire process. This article provides a framework for establishing a successful MR quality program. The collective experiences of the authors across a spectrum of pediatric hospitals is summarized here.