Reply to: Neurological, Cognitive and Behavioral Disorders During COVID-19: The Nitric Oxide Track.

To the Editor: We read with great interest the letter of Annweiler et al. They propose an intriguing mechanism for cognitive impairment related to coronavirus disease 2019 (COVID‐19). We would like to clarify a couple of points related to our case. First, although we wanted to exclude COVID‐19 encephalitis as a possibility, this was not possible without cerebrospinal fluid analysis and magnetic resonance imaging, which was refused by our patient. Our patient fulfilled the Confusion Assessment Method criteria for delirium on admission, which was our working diagnosis. In fact, the rapid improvement in his cognitive function might argue against COVID‐19 encephalitis. Second, our patientʼs usual medication included lisinopril, an angiotensin‐converting enzyme 2 inhibitor, for treatment of hypertension in the context of diabetes mellitus, type II. Possibly, the mechanism proposed by Annweiler et al pertaining to the nitric oxide track could explain the rapid improvement in our patient’s cognition following just a brief period of supportive management.

It is important to emphasize that delirium is a heterogeneous entity caused by multiple causative factors and complex underlying pathogenesis. , , In fact, nitric oxide has long been implicated in the pathogenesis of delirium and cognitive impairment. , Whether the nitric oxide track will prove to have a central role in the acute manifestations of COVID‐19–related cognitive impairment remains to be seen. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection could activate multiple downstream molecular pathways affecting each individual distinctly. We propose that the underlying mechanism of COVID‐19 central nervous system manifestation or delirium depends on the interaction between SARS‐CoV‐2 activated molecular pathways and the individual related factors, including age, COVID‐19 severity, individualʼs underlying genetic susceptibility, vascular risk factors, premorbid cognitive function, use of certain medication, and comorbidities.

Several other mechanisms have been linked to COVID‐19 neurological and cognitive manifestations. , However, the retrospective design of the study by Mao et al limits our ability to infer the causal mechanism of cognitive decline in COVID‐19 patients. We propose possible mechanisms of COVID‐19–related cognitive dysfunction (Table 1), which could help researchers in studying the specific pathways associated with each possible mechanism. Finally, the core message of our study is for clinicians to proactively screen for delirium in hospitalized older adults. Once delirium is identified, a comprehensive individualized assessment should be pursued, including COVID‐19 testing during this pandemic.

Table 1

Possible mechanisms of COVID‐19–related cognitive dysfunction

Indirect CNS involvement through inflammatory or immune response

Viral encephalitis due to direct CNS invasion

COVID‐19–related organ failure (lung, heart, kidney, or vasculature) and metabolic dysfunction

COVID‐19 ICU‐related delirium

Large‐vessel stroke or lacunar stroke syndrome

Exacerbation or unmasking of underlying cognitive impairment or neurodegenerative process

Medication‐related adverse reaction

Other unknown mechanism

Abbreviations: CNS, central nervous system; COVID‐19, coronavirus disease 2019; ICU, intensive care unit.