Faculty Bibliography

Vascular structures in the developing brain are thought to form via angiogenesis from preformed blood vessels in the cephalic mesenchyme. Immunohistochemical studies of developing mouse brain from E10.5-E13.5 revealed the presence of avascular blood islands of primitive erythroid cells expressing the hemangioblast markers (Flk1, Tal1/Scl1, platelet endothelial cell adhesion molecule 1 [PECAM1], vascular endothelial-cadherin [VE-cadherin] and CD34) and an endothelial marker recognized by Griffonia simplicifolia isolectin B4 (IB4) in the cephalic mesenchyme. These cells formed a perineural vascular plexus from which angiogenic sprouts originated and penetrated the neuroepithelium. In addition, avascular isolated cells expressing primitive erythroid, hemangioblast and endothelial makers were visible in the neuroepithelium where they generated vasculogenic and hemogenic foci. From E10.5-E13.5, these vasculogenic foci were a source of new blood vessel formation in the developing brain. In vitro, cultured E13.5 brain endothelial cells contained hemogenic endothelial cells capable of generating erythroid cells. Similar cells were present in primary cultures of dissociated cells from E10.5 embryonic head. Our results provide new evidence that the brain vasculature, like that of the yolk sac and the eye choriocapillaris and hyaloid vascular systems, develops at least in part via hemovasculogenesis, a process in which vasculogenesis and hematopoiesis occur simultaneously.

Background: We assessed cost-effectiveness of insertable cardiac monitors (ICMs) in a US cryptogenic stroke population. Materials & methods: We modelled lifetime costs and quality-adjusted life years for three monitoring strategies post cryptogenic stroke: ICM starting immediately, ICM starting after Holter monitoring (delayed ICM) and standard of care involving intermittent ECG and Holter monitoring. Patient characteristics and detection efficacy were based on the CRYSTAL-AF trial. AF detection altered the modelled anticoagulation therapy and subsequent stroke and bleed risks. Results & conclusion: Immediate ICM was found to be cost-effective versus standard of care and cost-saving versus delayed ICM. Results were robust to sensitivity analyses. ICMs are a cost-effective diagnostic tool for the prevention of recurrent stroke in a US cryptogenic stroke population.

Objective/UNASSIGNED:-related neurodevelopmental disorder in 33 individuals. Methods/UNASSIGNED:using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results/UNASSIGNED:-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions/UNASSIGNED:-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

OBJECTIVE:To correlate intraoperative changes of the laryngeal adductor reflex (LAR), alone or in combination with corticobulbar motor evoked potential of vocal muscles (vocal-CoMEPs), with postoperative laryngeal function after posterior fossa and brainstem surgery. METHODS:We monitored 53 patients during cerebellar-pontine angle and brainstem surgeries. Vocal-CoMEPs and LAR were recorded from an endotracheal tube with imbedded electrodes or hook-wires electrodes. A LAR significant change (LAR-SC) defined as ≥ 50% amplitude decrement or loss, was classified as either transient or permanent injury to the vagus or medullary pathways by the end of the surgery. RESULTS:All patients with permanent LAR loss (n = 5) or LAR-SC (n = 3), developed postoperative laryngeal dysfunction such as aspiration/pneumonia and permanent swallowing deficits (5.6%). Vocal-CoMEP findings refined postoperative vocal motor dysfunction. All seven patients with transient LAR-SC or loss, reverted by changing the surgical approach, did not present permanent deficits. CONCLUSIONS:Permanent LAR-SCs or loss correlated with postoperative laryngeal dysfunction and predicted motor and sensory dysfunction of the vagus nerve and reflexive medullary pathways. In contrast, a LAR-SC or loss, averted by a timely surgical adjustment, prevented irreversible damage. SIGNIFICANCE/CONCLUSIONS:Monitoring of the LAR, with vocal-CoMEPs, may enhance safety to resect complex posterior fossa and brainstem lesions.

The virtual practice has made major advances in the way that we care for patients in the modern era. The culture of virtual practice, consulting, and telemedicine, which had started several years ago, took an accelerated leap as humankind was challenged by the novel coronavirus pandemic (COVID19). The social distancing measures and lockdowns imposed in many countries left medical care providers with limited options in evaluating ambulatory patients, pushing the rapid transition to assessments via virtual platforms. In this novel arena of medical practice, which may form new norms beyond the current pandemic crisis, we found it critical to define guidelines on the recommended practice in neurotology, including remote methods in examining the vestibular and eye movement function. The proposed remote examination methods aim to reliably diagnose acute and subacute diseases of the inner-ear, brainstem, and the cerebellum. A key aim was to triage patients into those requiring urgent emergency room assessment versus non-urgent but expedited outpatient management. Physicians who had expertise in managing patients with vestibular disorders were invited to participate in the taskforce. The focus was on two topics: (1) an adequate eye movement and vestibular examination strategy using virtual platforms and (2) a decision pathway providing guidance about which patient should seek urgent medical care and which patient should have non-urgent but expedited outpatient management.

COVID-19 is a highly infectious viral disease caused by the novel coronavirus SARS-CoV-2. While it was initially regarded as a strictly respiratory illness, the impact of COVID-19 on multiple organs is increasingly recognized. The brain is among the targets of COVID-19, and it can be impacted in multiple ways, both directly and indirectly. Direct brain infection by SARS-CoV-2 may occur via axonal transport via the olfactory nerve, eventually infecting the olfactory cortex and other structures in the temporal lobe, and potentially the brain stem. A hematogenous route, which involves viral crossing of blood-brain barrier, is also possible. Secondary mechanisms involve hypoxia due to respiratory failure, as well as aberrant immune response leading to various forms of encephalopathy, white matter damage, and abnormal blood clotting resulting in stroke. Multiple neurological symptoms of COVID-19 have been described. These involve anosmia/ageusia, headaches, seizures, mental confusion and delirium, and coma. There is a growing concern that in a number of patients, long-term or perhaps even permanent cognitive impairment will persist well after the recovery from acute illness. Furthermore, COVID-19 survivors may be at increased risk for developing neurodegenerative diseases years or decades later. Since COVID-19 is a new disease, it will take months or even years to characterize the exact nature, scope, and temporal extent of its long-term neurocognitive sequelae. To that end, rigorous and systematic longitudinal follow-up will be required. For this effort to succeed, appropriate protocols and patient registries should be developed and put in place without delay now.

Caffeine, a very widely used and potent neuromodulator, easily crosses the placental barrier, but relatively little is known about the long-term impact of gestational caffeine exposure (GCE) on neurodevelopment. Here, we leverage magnetic resonance imaging (MRI) data, collected from a very large sample of 9157 children, aged 9-10 years, as part of the Adolescent Brain and Cognitive Development^sm (ABCD ®) study, to investigate brain structural outcomes at 27 major fiber tracts as a function of GCE. Significant relationships between GCE and fractional anisotropy (FA) measures in the inferior fronto-occipito fasciculus and corticospinal tract of the left hemisphere (IFOF-LH; CST-LH) were detected via mixed effects binomial regression. We further investigated the interaction between these fiber tracts, GCE, cognitive measures (working memory, task efficiency), and psychopathology measures (externalization, internalization, somatization, and neurodevelopment). GCE was associated with poorer outcomes on all measures of psychopathology but had negligible effect on cognitive measures. Higher FA values in both fiber tracts were associated with decreased neurodevelopmental problems and improved performance on both cognitive tasks. We also identified a decreased association between FA in the CST-LH and task efficiency in the GCE group. These findings suggest that GCE can lead to future neurodevelopmental complications and that this occurs, in part, through alteration of the microstructure of critical fiber tracts such as the IFOF-LH and CST-LH. These data suggest that current guidelines regarding limiting caffeine intake during pregnancy may require some recalibration.