In Reply to the Letter to the Editor Regarding “Neurological Impact of Coronavirus Disease (COVID-19): Practical Considerations for the Neuroscience Community”

We thank Mishra et al.¹ for their comments regarding our report, which discussed the multifactorial nature of severe coronavirus disease 2019 (COVID-19) secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and raised several comments regarding the pathogenesis of injury in patients with central nervous system (CNS) involvement.2, 3, 4, 5 The authors noted that severe disease has been observed in association with an uncontrolled immune response, which exacerbates the injury, as evident by the reported elevations in a wide range of acute phase reactants (APRs),⁵ a characteristic relatively atypical for viral disease.2, 3, 4, 5, 6 They then remarked that a temporal association between CNS injury and APR trends has not been shown.7, 8 We agree that this is an interesting area of future study; however, we would caution that difficulties could arise in that the systemic marker levels might not necessarily correlate with the presence or severity of neuroinflammation,⁶ could be confounded by the presence of systemic severe disease,⁶ and that COVID-19–associated encephalopathy could, at times, have a noninflammatory etiology.9, 10

D-dimer elevations, an APR associated with hypercoagulability, were later discussed by Mishra et al.¹ as a pathway of ischemic CNS injury without direct viral involvement. As they stated, D-dimer elevations have been documented to be correlated with severe COVID-19 and multiple associated thrombotic complications, including ischemic stroke.6, 8 The ischemic insult in such patients has been presumed to be secondary to intracranial large vessel occlusion (LVO), which has been shown in viral-associated pulmonary embolism and deep venous thrombosis.⁹ However, multiple reports, including one recently conducted to analyze the neurological manifestations in patients with critical COVID-19 at our own facility in New Orleans, Louisiana, have shown a high proportion of large territory anterior circulation infarcts with no evidence of LVO and the presence of segmental nonocclusive stenosis.9, 10 These findings suggest an alternative pathway of direct viral-associated vasculopathy, which has also been observed and reported with human immunodeficiency virus 1 and 2 and human herpes virus 3 infections.¹⁰ The reported cases of COVID-19–associated vasculopathy and secondary acute ischemic stroke have often occurred in the context of therapeutic anticoagulation, making thrombosis less likely.¹¹ Although an interesting topic of active discussion concerning COVID-19–associated cerebrovascular disease, coagulopathy would not account for the other CNS manifestations, including electrographic and radiographic encephalopathy.10, 11, 12 Interestingly, Mishra also raised the possibility of hypoxia as a cause of CNS damage. Hypoxic injury, in addition to the many other consequences of severe multisystem disease, could very well be a contributor to CNS involvement, and imaging characteristic of hypoxic-anoxic injury have been reported.¹⁰ We postulate that both mechanisms of hypoxia and coagulopathy are 2 of the several pathways of indirect and direct CNS injury secondary to SARS-CoV-2 infection.

Mishra et al.¹ also stated that no pathology reports from autopsy studies have confirmed the presence of SARS-CoV-2 in the CNS. We agree that neuropathology examination using brain cutting and relevant stains would be of vital interest in further disease characterization. The lack of findings of SARS-CoV-2 in the CNS has likely been because SARS-CoV-2 is regarded by pathologists as a hazardous organism, and autopsies have been conducted conservatively to limit exposure.13, 14 Despite this, the accumulating data documenting neurologic involvement in patients with COVID-1911, 12, 13 have fueled an increasing interest in the neuropathological research of postmortem tissue.¹⁵ As we discussed, SARS-CoV-2 genetic material has been isolated from cerebrospinal fluid, even in cases in which oropharyngeal swab testing was negative for the virus.¹⁶

Mishra et al.¹ reported that the comorbidities appear to be associated with severe COVID-19 and with cerebrovascular accidents associated with severe disease. We very much agree that evolving evidence concerning critically hospitalized patients with confirmed COVID-19 has strongly linked the comorbidities of diabetes mellitus type 2, hypertension, chronic obstructive pulmonary disease, chronic kidney disease, obesity, and cardiovascular disease with an increased risk of more severe disease course and multisystem effects.17, 18 Presumably, increasing age predicts for the presence of medical comorbidities, and most of those linked with more severe COVID-19 effects will result in increased strain on the cardiopulmonary system. Therefore, it would be intuitive that patients with multisystemic disease at baseline would be more likely to experience a more severe clinical course in the event of an infectious insult, especially if their immune system or innate inflammatory cascade has been in any way deregulated.

Concerning the final comments on the prevalence of cerebrovascular disease in the context of multisystem involvement and severe COVID-19, the increased prevalence of acute cerebrovascular disease in patients with severe infection has been thought to be related to elevated D-dimer levels. Increased D-dimer levels have been previously shown to correlate with unfavorable outcomes in patients with stroke,10, 19 although not always as a result of LVO.¹⁰ It is likely that thrombosis secondary to severe infection and a hypercoagulable state represents a subset of patients with neurological involvement; however, for those with therapeutic anticoagulation at clinical deterioration, D-dimer elevations have been suspected to be correlative and not causative.

Cerebrovascular disease is a known predisposing factor for the development of acute respiratory distress syndrome in a neurocritical care setting,¹⁹ It is, therefore, challenging to interpret what could be a confounding variable in a novel disease with a heterogeneous clinical presentation likely consequent to multiple parallel and synergistic pathways. Recent reports have attempted to clarify the specific disease patterns of CNS injury,¹⁰ and we agree that further study is necessary. Although no specific guidelines are available concerning preexisting stroke or elevated D-dimers in the setting of COVID-19, it seems likely that these patients would have an increased risk of progressing to severe disease and would warrant increased vigilance in monitoring the disease course.