By Alexander E. Merkler, MD, MS
Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College, and Assistant Attending Neurologist, New York-Presbyterian Hospital
SYNOPSIS: In an autopsy study of 41 patients who died from COVID-19 in a single medical center in New York City, most of the brain pathology was the result of hypoxic-ischemic injury, infarction, and hemorrhage, with microglial activation and neuronophagia caused by inflammation. Studies for the presence of viral proteins were negative, and very low levels of viral ribonucleic acid were detected.
SOURCE: Thakur KT, Miller EH, Glendinning MD, et al. COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain 2021;144:2696-2708.
COVID-19 is the most impactful pandemic of our lifetime and at present has affected more than 247 million people and led to 5 million deaths worldwide.1 Neurological manifestations of COVID-19 are common and include olfactory and gustatory dysfunction, cerebrovascular disease, encephalopathy, seizures, and neuropathy. Whether these neurological disorders are all a result of systemic medical illness caused by COVID-19 or may be a consequence of direct nervous tissue invasion of SARS-CoV-2 remains uncertain. Furthermore, long-term neuropsychiatric sequelae of COVID-19 are relatively common and yet we continue to lack a clear understanding of its pathophysiology.
In the current study, Thakur et al described the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infection who died and underwent autopsy at a tertiary care academic medical center in New York City during the early surge in Spring 2020. Among these 41 patients, 24 (59%) were admitted to the intensive care unit, eight (20%) had deep vein thrombosis/pulmonary embolism, seven (17%) had acute kidney injury requiring dialysis, and 10 (24%) had positive blood cultures during admission. Eight (20%) died within 24 hours of hospital admission and 11 (27%) died more than four weeks after hospital admission.
Evidence of cerebrovascular disease was common. Head computed tomography was performed on 11 (27%) patients and two (5%) also underwent brain magnetic resonance imaging (MRI). Intracerebral hemorrhages were found in three patients and multiple subacute ischemic strokes were found in one patient. Five patients had imaging evidence of diffuse cerebral edema and hypoxic-ischemic injury, three of whom had concurrent prior hemorrhages. Nine brains (22%) were imaged post-mortem; five had evidence of intracerebral hemorrhage and one had an acute cerebral infarct. At autopsy, all brains had evidence of hypoxic damage; 18 (44%) had evidence of ischemic stroke (acute, subacute, or chronic) and eight (19%) had intracranial hemorrhage, the majority of which seemed to represent hemorrhagic transformation of an ischemic stroke.
Among 28 patients studied, polymerase chain reaction analysis revealed low to very low detectable levels of SARS-CoV-2 ribonucleic acid (RNA) within brain tissue. In addition, RNAscope and immunocytochemistry failed to detect SARS-CoV-2 messenger RNA or SARS-CoV-2 viral proteins in the brains. Microglial activation with microglial nodules was present in 81% of patients and was most prominent in the brainstem. Perivascular lymphocytic inflammation and infiltration into the brain parenchyma was sparse. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases — not a surprise, since the mean age of the group was 74 years. Based on these findings, the authors concluded that direct brain tissue invasion of SARS-CoV-2 is an unlikely explanation for the identified neuropathological findings. Instead, the neuropathological findings likely are the result of systemic medical illness, coagulation disorders, and inflammation.
Limitations of this study include the fact that all patients were from New York City at a single academic medical center, many had significant preexisting medical comorbidities, and the majority of patients were of Hispanic ethnicity.
COMMENTARY
Overall, this study adds to our growing understanding of the effects of COVID-19 on the central nervous system. Cerebrovascular manifestations of COVID-19 are common and appear to be the result of systemic effects of COVID-19 on the coagulation system rather than direct SARS-CoV-2 invasion of the brain.
The authors also opined that the distribution of microglial activation potentially may help explain the long-term neuropsychiatric effects of survivors of COVID-19. Microglial activation was found throughout the brain, but particularly in the brainstem. Although intriguing, patients with long-term neuropsychiatric effects of COVID-19 do not appear to have symptoms of brainstem pathology, such as cranial nerve dysfunction. Neuroimaging, including MRI, on patients who have recovered has not revealed any pathology other than ischemic stroke.
In conclusion, patients with COVID-19 have evidence of significant neuropathology that likely is a result of systemic medical illness, coagulation disorders, and inflammation and is not related to direct SARS-CoV-2 infection of brain tissue.
REFERENCE
- World Health Organization. WHO coronavirus (COVID-19) dashboard. https://covid19.who.int/
