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Microvascular Injury of Brain, Olfactory Bulbs Seen in COVID-19

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Multifocal microvascular injury in the brain and olfactory bulbs is another possible adverse outcome from COVID-19, new research suggests.

Postmortem MRI brain scans of 13 patients who died from COVID-19 showed abnormalities in 10 of the participants.

Of these, 9 showed punctate hyperintensities, “which represented areas of microvascular injury and fibrinogen leakage,” the investigators report. Immunostaining also showed a thinning of the basal lamina in 5 of these patients.

Further analyses showed punctate hypointensities linked to congested blood vessels in 10 patients. These areas were “interpreted as microhemorrhages,” the researchers note.

Interestingly, there was no evidence of viral infection, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“These findings may inform the interpretation of changes observed on [MRI] of punctate hyperintensities and linear hypointensities in patients with COVID-19,” write Myoung-Hwa Lee, PhD, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, and colleagues.

The findings were published online December 30 in a “correspondence” piece in the New England Journal of Medicine.

Interpret With Caution

The investigators examined brains from a convenience sample of 19 patients (mean age, 50 years), all of whom died from COVID-19 between March and July 2020.

An 11.7-Tesla scanner was used to obtain magnetic resonance microscopy images for 13 of the patients. In order to scan the olfactory bulb, the scanner was set at a resolution of 25 µm; for the brain, it was set at 100 µm.

Chromogenic immunostaining was used to assess brain abnormalities found in 10 of the patients. Multiplex fluorescence imaging was also used for some of the patients.

For 18 study participants, a histopathological brain examination was performed. In the patients who also had medical histories available to the researchers:

The punctate hyperintensities found on magnetic resonance microscopy were also found on histopathological exam. Collagen IV immunostaining showed a thinning in the basal lamina of endothelial cells in these areas.

In addition to congested blood vessels, punctate hypointensities were linked to areas of fibrinogen leakage — but also to “relatively intact vasculature,” the investigators report.

“There was minimal perivascular inflammation in the specimens examined, but there was no vascular occlusion,” they add.

SARS-CoV-2 was also not found in any of the participants. “It is possible that the virus was cleared by the time of death or that viral copy numbers were below the level of detection by our assays,” the researchers note.

In 13 of the patients, hypertrophic astrocytes, macrophage infiltrates, and perivascular-activated microglia were found. Eight patients showed CD3+ and CD8+ T cells in spaces and lumens next to endothelial cells.

Finally, five patients showed activated microglia next to neurons. This is “suggestive of neuronophagia in the olfactory bulb, substantial nigra, dorsal motor nucleus of the vagal nerve, and the pre-Bötzinger complex in the medulla, which is involved in the generation of spontaneous rhythmic breathing,” write the investigators.

In summary, vascular pathology was found in 10 cases, perivascular infiltrates were present in 13 cases, acute ischemic hypoxic neurons were present in 6 cases, and changes suggestive of neuronophagia were present in 5 cases.

The researchers note that although the study findings may be helpful when interpreting brain changes on MRI scan in this patient population, availability of clinical information for the participants was limited.

Therefore, “no conclusions can be drawn in relation to neurologic features of COVID-19,” they write.

The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS). Lee and all but one of the other investigators report no relevant financial relationships. Marco Hefti, MD, University of Iowa, Iowa City, reports having received grants from NINDS during the conduct of this study.

N Engl J Med. Published online December 30, 2020. Full text

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