Faculty Bibliography

Purpose of the Study/UNASSIGNED:More than 50% of breast cancer survivors without a diagnosis of lymphedema suffer daily from numerous and co-occurring lymphedema symptoms. This study aimed to identify lymphedema symptom patterns and the association of such patterns with phenotypic characteristics and biomarkers using latent class analysis (LCA). A prospective, descriptive, and repeated-measure design was used to enroll 140 women and collect data. Recent Findings/UNASSIGNED:LCA identified three distinct lymphedema symptom classes at 8 weeks and 12 months post-surgery: low, moderate, and severe symptom classes and associated phenotypic characteristics. Participants were more likely to be in the severe symptom classes at 12 months post-surgery if they had lower education level, cording, an axillary syndrome at 8 weeks post-surgery, neoadjuvant chemotherapy, and radiation. Summary/UNASSIGNED:Pre-surgery level of IL1-a, IL-6, IL-8, and VEGF was associated with the severe symptom class at 8 weeks post-surgery, suggesting that such biomarkers may be used to predict risk for lymphedema symptoms.

Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. In patients who underwent seizure focus resection for treatment-resistant epilepsy, whole genome DNA methylation profiling identified 3 main clusters of which one showed strong association with receptor tyrosine kinase (RTK) genes. We identified focal copy number gains involving epidermal growth factor receptor (EGFR) and PDGFRA loci. The dysplastic neurons of cases with amplifications showed marked overexpression of EGFR and PDGFRA, while glial and endothelial cells were negative. Targeted sequencing of regulatory regions and DNA methylation analysis revealed that only enhancer regions of EGFR and gene promoter of PDGFRA were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Somatic focal copy number gains of noncoding regulatory represent a previously unrecognized genetic driver in epilepsy and a mechanism of abnormal activation of RTK genes. Upregulated RTKs provide a potential avenue for therapy in seizure disorders.

BACKGROUND AND PURPOSE/OBJECTIVE:Various patterns of leukoencephalopathy have been described in coronavirus disease 2019 (COVID-19). In this article, we aimed to describe the clinical and imaging features of acute disseminated leukoencephalopathy in critically ill patients with COVID-19 and the imaging evolution during a short-term follow-up. MATERIALS AND METHODS/METHODS:We identified and reviewed the clinical data, laboratory results, imaging findings, and outcomes for 8 critically ill patients with COVID-19 with acute disseminated leukoencephalopathy. RESULTS:All patients demonstrated multiple areas of white matter changes in both cerebral hemispheres; 87.5% (7/8) of patients had a posterior predilection. Four patients (50%) had short-term follow-up imaging within a median of 17 days after the first MR imaging; they developed brain atrophy, and their white matter lesions evolved into necrotizing cystic cavitations. All (8/8) patients had inflammatory cytokine release syndrome as demonstrated by elevated interleukin-6, D-dimer, lactate dehydrogenase, erythrocyte sedimentation rate, C-reactive protein, and ferritin levels. Most (7/8; 87.5%) patients were on prolonged ventilator support (median, 44.5 days; interquartile range, 20.5 days). These patients had poor functional outcomes (6/8 [75%] patients were discharged with mRS 5) and high mortality (2/8, 25%). CONCLUSIONS:Critically ill patients with COVID-19 can develop acute disseminated leukoencephalopathy that evolves into cystic degeneration of white matter lesions with brain atrophy during a short period, which we dubbed virus-associated necrotizing disseminated acute leukoencephalopathy. This may be the result of COVID-19-related endothelial injury, cytokine storm, or thrombotic microangiopathy.

The carotid web is a proposed stroke mechanism that may underlie cryptogenic stroke, particularly in younger patients without vascular risk factors. The web appears as a shelf-like projection into the lumen of the proximal cervical internal carotid artery without evidence of calcification. It is pathologically defined as intimal fibromuscular dysplasia. Altered haemodynamics distal to the web cause flow stagnation and remote embolisation of fibrin-based clots. It is best demonstrated and diagnosed on CT angiography (CTA) of the neck because of its ability to resolve calcium and create multiplanar reconstructions. Although they can be readily visualised on CTA, carotid webs may be missed or misinterpreted because they do not typically cause haemodynamically significant stenosis and can mimic arterial dissection, non-calcified atherosclerotic plaque and intraluminal thrombus. Options for management include antiplatelet therapy, carotid endarterectomy and carotid artery stenting. Modern management strategies for cryptogenic stroke include long-term cardiac monitoring, further investigation for structural cardiac disease and a diagnostic workup for arterial hypercoagulability, however, these strategies are not likely to capture the possibility of a carotid web. Carotid webs should be suspected in a young patient presenting with recurrent unihemispheric strokes particularly when conventional vascular risk factors are not present.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.

OBJECTIVE:The carotid web (CW) is an underrecognized source of cryptogenic, embolic stroke in patients younger than 55 years of age, with up to 37% of these patients found to have CW on angiography. Currently, there are little data detailing the best treatment practices to reduce the risk of recurrent stroke in these patients. The authors describe their institutional surgical experience with patients treated via carotid endarterectomy (CEA) for a symptomatic internal carotid artery web. METHODS:A retrospective, observational cohort study was performed including all patients presenting to the authors' institution with CW. All patients who were screened underwent either carotid artery stenting (CAS) or CEA after presentation with ischemic stroke from January 2019 to February 2020. From this sample, patients with suggestive radiological features and pathologically confirmed CW who underwent CEA were identified. Patient demographics, medical histories, radiological images, surgical results, and clinical outcomes were collected and described using descriptive statistics. RESULTS:A total of 45 patients with symptomatic carotid lesions were treated at the authors' institution during the time period. Twenty patients underwent CAS, 1 of them for a CW. Twenty-five patients were treated via CEA, and of these, 6 presented with ischemic strokes ipsilateral to CWs, including 3 patients who presented with recurrent strokes. The mean patient age was 55 ± 12.6 years and 5 of 6 were women. CT angiography or digital subtraction angiography demonstrated the presence of CWs ipsilateral to the stroke in all patients. All patients underwent resection of CWs using CEA. There were no permanent procedural complications and no patients had stroke recurrence following intervention at the latest follow-up (mean 6.1 ± 4 months). One patient developed mild tongue deviation most likely related to retraction, with complete recovery at follow-up. CONCLUSIONS:CEA is a safe and feasible treatment for symptomatic carotid webs and should be considered a viable alternative to CAS in this patient population.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients with the Coronavirus Disease of 2019 (COVID-19) are at increased risk for thrombotic events and mortality. Various anticoagulation regimens are now being considered for these patients. Anticoagulation is known to increase the risk for adverse bleeding events, of which intracranial hemorrhage (ICH) is one of the most feared. We present a retrospective study of 33 patients positive for COVID-19 with neuroimaging-documented ICH and examine anticoagulation use in this population. METHODS:Patients over the age of 18 with confirmed COVID-19 and radiographic evidence of ICH were included in this study. Evidence of hemorrhage was confirmed and categorized by a fellowship trained neuroradiologist. Electronic health records were analyzed for patient information including demographic data, medical history, hospital course, laboratory values, and medications. RESULTS:We identified 33 COVID-19 positive patients with ICH, mean age 61.6 years (range 37-83 years), 21.2% of whom were female. Parenchymal hemorrhages with mass effect and herniation occurred in 5 (15.2%) patients, with a 100% mortality rate. Of the remaining 28 patients with ICH, 7 (25%) had punctate hemorrhages, 17 (60.7%) had small- moderate size hemorrhages, and 4 (14.3%) had a large single site of hemorrhage without evidence of herniation. Almost all patients received either therapeutic dose anticoagulation (in 22 [66.7%] patients) or prophylactic dose (in 3 [9.1] patients) prior to ICH discovery. CONCLUSIONS:Anticoagulation therapy may be considered in patients with COVID-19 though the risk of ICH should be taken into account when developing a treatment regimen.

The cavernous sinus is a complex structure susceptible to a wide variety of vascular, neoplastic and inflammatory pathologies. Vascular pathologies include ICA aneurysms, carotid-cavernous fistulas, cavernous sinus thrombosis, and cavernous hemangioma. Neoplasms that involve the cavernous sinus include pituitary adenoma, meningioma, schwannoma, lymphoma, perineural tumor spread, metastases, and direct tumor invasion. Infectious and inflammatory diseases include Tolosa-Hunt syndrome, sarcoidosis, granulomatosis with polyangiitis, IgG-4 related disease and invasive fungal infections. In this article, we review the clinical and imaging findings of a number of pathologies involving the cavernous sinus, focusing on key features that can narrow the differential diagnosis and, in some cases, support a particular diagnosis.

Background/UNASSIGNED:Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown. Methods/UNASSIGNED:We used immunohistochemistry in tumor specimens and non-neoplastic cadaveric brain tissue to profile GPR133 expression in adult gliomas. Results/UNASSIGNED:We show that GPR133 expression increases as a function of WHO grade and peaks in glioblastoma, where all tumors ubiquitously express it. Importantly, GPR133 is expressed within the tumor bulk, as well as in the brain-infiltrating tumor margin. Furthermore, GPR133 is expressed in both isocitrate dehydrogenase (IDH) wild-type and mutant gliomas, albeit at higher levels in IDH wild-type tumors. Conclusion/UNASSIGNED:The fact that GPR133 is absent from non-neoplastic brain tissue but de novo expressed in glioma suggests that it may be exploited therapeutically.