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A 13-year-old male presented with a 10-day history of left eye swelling and pain. These symptoms prompted presentation to the emergency department. He had no significant past medical history and no preceding fevers or chills. He was found on examination of the eyes and the orbit to have left supraorbital erythema, edema, and pain with upward and medial gaze. Examination of the globe, fundus, and visual fields were normal. His white blood cell count was 6.2 (x1000/mm3) with an erythrocyte sedimentation rate of 4 (mm/hr). Diagnostic endoscopic biopsy was performed. Here we present this case alongside clinical reasoning and diagnostic evaluation with relevant input from respective experts. This case discussion reviews the final diagnosis, as well as the corresponding evaluation and management. Diagnostic algorithms based on literature review and clinical experience are also included.

BACKGROUND Reports of cerebrovascular ischemia and stroke occurring as predominant neurological sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), are increasingly evident within the literature. While various pathophysiological mechanisms have been postulated, including hypercoagulability, endothelial invasion, and systemic inflammation, discrete mechanisms for viral neurotropism remain unclear and controversial. OBSERVATIONS The authors present a unique case study of a 64-year-old male with acute COVID-19 infection and acute worsening of previously stable cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare heritable arteriopathy due to mutation in the Notch3 gene, which is critical for vascular development and tone. Delayed cranial neuropathies, brainstem fluid-attenuated inversion recovery signal, and enhancement of olfactory and vagus nerves on magnetic resonance neurography in this patient further support viral neurotropism via cranial nerves in addition to cerebral vasculature. LESSONS To the authors’ knowledge, this is the first case in the literature that not only demonstrates the consequences of COVID-19 infection in a patient with altered cerebrovascular autoregulation such as CADASIL but also highlights the tropism of SARS-CoV-2 for (1) cranial nerves as a mode of entry to the central nervous system and (2) vessels as a cause of cerebrovascular ischemia.

The study identifies the importance of positron emission tomographic (PET) and anatomic imaging modalities and their individual performances in detecting succinate dehydrogenase A (SDHA)-related metastatic pheochromocytoma and paraganglioma (PPGL). The detection rates of PET modalities—68Ga-DOTATATE, 18F-FDG, and 18F-FDOPA—along with the combination of computed tomography (CT) and magnetic resonance imaging (MRI) are compared in a cohort of 11 patients with metastatic PPGL in the setting of a germline SDHA mutation. The imaging detection performances were evaluated at three levels: overall lesions, anatomic regions, and a patient-by-patient basis. 68Ga-DOTATATE PET demonstrated a lesion-based detection rate of 88.6% [95% confidence interval (CI), 84.3–92.5%], while 18F-FDG, 18F-FDOPA, and CT/MRI showed detection rates of 82.9% (CI, 78.0–87.1%), 39.8% (CI, 30.2–50.2%), and 58.2% (CI, 52.0–64.1%), respectively. The study found that 68Ga-DOTATATE best detects lesions in a subset of patients with SDHA-related metastatic PPGL. However, 18F-FDG did detect more lesions in the liver, mediastinum, and abdomen/pelvis anatomic regions, showing the importance of a combined approach using both PET modalities in evaluating SDHA-related PPGL.

PURPOSE OF REVIEW: Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10–20% of metastatic PPGL patients, have inoperable disease. This has necessitated the development of noninvasive treatments (e.g., radio/chemotherapy), which, in affording disease-modification, have led to an ever-growing population of surviving patients with inoperable PPGL. These patients experience debilitating symptoms arising from discomforts related to the masses themselves (e.g., pain from osseous metastasis) and symptoms from tumoral catecholamine production and release. Unfortunately, management of these conditions is not yet well-defined. Adding further insult-to-injury, these noninvasive treatments can trigger catecholamine release, worsening catecholamine-induced symptoms. Herein, we detail these ailments and their management especially while patients receive these noninvasive treatments. RECENT FINDINGS: Improved diagnostic evaluations have allowed for earlier detection of PPGL, prolonging survival in patients with inoperable PPGLs. Accordingly, noninvasive treatment strategies have rapidly evolved alongside state-of-the-art theranostics and genetic determinants which inform ongoing management and therapeutic response. SUMMARY: While treatments afford improved survival, there must be a corresponding attention to quality-of-life. This is ensured by employing supportive management which mitigates debilitating symptoms. This is best accomplished with a multidisciplinary approach and familiarity with genetic and biochemical determinants which guide patient education and management.

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.

Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome., We discovered vascular malformations due to failure of developmental vascular regression in patients with EPAS1 gain-of-function mutation syndrome and the corresponding transgenic mouse model.

The risk factors for severe COVID-19 are diverse, yet closely resemble the clinical manifestations of catecholamine excess states (eg, hypertension, cardiovascular disease, immune dysregulation, and hyperglycaemia), suggesting a potentially common basis for disease. Unfortunately, severe illness (eg, respiratory failure, compromised cardiac function, and shock) incurred by COVID-19 hinders the direct study of catecholamines in these patients, especially among those on multiple medications or those on adrenaline or noradrenaline infusions, or both. Phaeochromocytoma and paraganglioma (PPGL) are tumours that secrete catecholamines, namely adrenaline and noradrenaline, often in excess. PPGL are well studied disease processes in which the effects of catecholamines are easily discernible and therefore their potential biochemical and physiological influences in patients with COVID-19 can be explored. Because catecholamines are expected to have a role in patients with critical illness, patients on vasopressor infusions, and patients who sustain some acute and chronic physical stresses, the challenges involved in the management of catecholamine excess states are directly relevant to the treatment of patients with COVID-19. In this Personal View, we discuss the complex interplay between catecholamines and COVID-19, and the management of catecholamine excess states, while referencing relevant insights derived from the study of PPGL.

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.