Brainstem neuropathology in two cases of COVID-19: SARS-CoV-2 trafficking between brain and lung

Introduction SARS-CoV-2 might spread through the nervous system, reaching respiratory centers in the brainstem. Because we recently reported neurophysiological brainstem reflex abnormalities in COVID-19 patients, we here neuropathologically assessed structural brainstem damage in two COVID-19 patients. Materials and methods We assessed neuropathological features in two patients who died of COVID-19 and in two COVID-19 negative patients as controls. Neuronal damage and corpora amylacea (CA) numbers /mm2 were histopathologically assessed. Other features studied were the immunohistochemical expression of the SARS-CoV-2 nucleoprotein (NP) and the Iba-1 antigen for glial activation. Results Autopsies showed normal gross brainstem anatomy. Histopathological examination demonstrated increased neuronal and CA damage in Covid-19 patients’ medulla oblongata. Immunohistochemistry disclosed SARS-CoV-2 NP in brainstem neurons and glial cells, and in cranial nerves. Glial elements also exhibited a widespread increase in Iba-1 expression. Sars-Co-V2 was immunohistochemically detected in the vagus nerve fibers. Discussion Neuropathologic evidence showing SARS-CoV-2 in the brainstem and medullary damage in the area of respiratory centers strongly suggests that the pathophysiology of COVID-19-related respiratory failure includes a neurogenic component. Sars-Co-V2 detection in the vagus nerve, argues for viral trafficking between brainstem and lung.

Postictal brainstem hypoperfusion and risk factors for sudden unexpected death in epilepsy

ObjectiveSince the strongest risk factor for sudden unexpected death in epilepsy (SUDEP) is frequent bilateral tonic-clonic seizures (BTCS), our aim was to determine whether postictal hypoperfusion in brainstem respiratory centers (BRCs) is more common following tonic-clonic seizures.MethodsWe studied 21 patients with focal epilepsies who underwent perfusion imaging with arterial spin labeling MRI. Subtraction maps of cerebral blood flow were obtained from the postictal and baseline scans. We identified 6 regions of interest in the brainstem that contain key BRCs. Patients were considered to have postictal BRC hypoperfusion if any of the 6 regions of interest were significantly hypoperfused.ResultsAll 6 patients who experienced BTCS during the study had significant clusters of postictal hypoperfusion in BRCs compared to 7 who had focal impaired awareness seizures (7/15). The association between seizure type studied and the presence of BRC hypoperfusion was significant. Duration of epilepsy and frequency of BTCS were not associated with postictal brainstem hypoperfusion despite also being associated with risk for SUDEP.ConclusionPostictal hypoperfusion in brainstem respiratory centers occurs more often following BTCS than other seizure types, providing a possible explanation for the increased risk of SUDEP in patients who regularly experience BTCS.

Neuromuscular Respiratory Failure

Breathing is a continuous, rhythmic, to-and-fro movement that requires a close interplay between arterial PCO2, oxygen, and respiratory centers. Certain thresholds exist for respiratory drive, and these thresholds change with acute neurologic disease. Primary structural lesions to the brainstem are most common, but decreased levels of consciousness frequently trigger episodic breathing. This chapter discusses the essentials of the respiratory pacemaker and neurologic breathing patterns.

Intersektorale Konzepte zur außerklinischen Beatmung

The care of patients with extraclinical mechanical ventilation has to be improved particularly with regard to their specialist care. One care option is the empowering of clinicians at the respiratory centers to enable ambulant care of patients and home visits. An intersectoral linkage in the form of transfer management is the basis for competent coordination. Aim is to ensure the necessary multidisciplinary collaboration in the outpatient care of multimorbid chronically ill patients. For the optimal care of chronically ill patients, sectoral limits should become more permeable.

Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, PiO2 = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly ( P < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia.NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti-inflammatory properties, also blocks astrocyte activation in respiratory centers during chronic hypoxia and ventilatory acclimatization. However, minocycline cannot reverse ventilatory acclimatization after it is established. Hence, glial cells may provide signals that initiate but do not sustain ventilatory acclimatization.