Beyond delirium: The neuropsychiatric dimensions of COVID-19

Beyond delirium: The neuropsychiatric dimensions of COVID-19
By Mark Oldham, MD

The data are clear and, sadly, just as clearly predictable.1,2 COVID-19 has caused delirium—lots of it in fact. Twenty to 30% of older adults with COVID-19 develop delirium, with older adults at higher risk of delirium than younger adults.3 Older adults with COVID-19 commonly have delirium without traditional case-defining COVID-19 symptoms: this is true in more than a third of cases.4,5 COVID-19 disease severity is also positively correlated with delirium risk, with each 1 mg/L increase in CRP significantly associated with a 1% increased delirium risk, and delirium in COVID-19 has been associated with more than twice the odds of mortality.6 Further complicating matters, the COVID-19 literature is mired in imprecise terminology, with the terms confusion, dysexecutive syndrome, altered mental status, altered consciousness, and encephalopathy7 often used indiscriminately. Unfortunately, terminological chaos is par for the course.8

The neuropsychiatric disorders due to COVID-19 are broader than delirium alone,9,10 that is, defining “neuropsychiatric” as demonstrable neural substrate abnormalities and salient psychiatric symptoms (analogous to the DSM-5 definition of “neurocognitive”11). However, it remains unclear to what extent presentations of acute psychosis, mood alterations, or suicide attempts in patients with COVID-19 are attributable to psychosocial factors vs neuropathogenesis, as occurring in encephalitis, CNS demyelination, or other CNS-specific disease.12

Adding to its impact, COVID often affects patients well after the acute phase illness. Long-COVID—a heterogeneous constellation of persisting systemic symptoms—is very common.13 In fact, reports have described more than 50 long-term effects attributable to COVID-19, with 80% of patients experiencing at least one persisting symptom.14 The most common post-COVID symptom reported is fatigue, affecting 3 out of every 5 patients, followed by headache (44%) and attentional difficulties (27%). Given the relatively limited longitudinal data available thus far, it’s not yet known how long such symptoms may ultimately persist.

Not that the pandemic has spared those without infection. Seclusion—whether due to community-wide lockdowns, enforced quarantine, or personal decisions for protection—has inflicted its own brand of suffering.15 The pandemic has imposed especially steep costs on persons with dementia subjected to isolation.16 The psychophysiological stress of loneliness and impoverishment of social interactions has led to a host of psychiatric symptoms including apathy, anxiety, and agitation among cognitively vulnerable older adults.17 And similar to how COVID-19 is communicable, the heightened distress brought about by COVID-19 has been communicated to caregivers of people with dementia, causing caregiver depression and anxiety.18

Foresight bias

That a severe disease like COVID-19 would cause delirium or that delirium in COVID-19 would be associated with a variety of sobering outcomes, as harrowing as this has been for all affected, is not especially surprising.7 On the one hand, the predictability of these findings adds its own invisible but unmistakable sting. On the other, the fact that conversations about the psychiatric and cognitive wellbeing of patients have been a consistent theme throughout the pandemic is an encouraging sign, and people are listening. Personally, though, the issue of foreseeability strikes me as prosaic because I have difficulty finding poetry in watching a train wreck in motion that was both anticipated but, for all our best efforts, seemingly unavoidable.

Now is a time for taking inventory and reflection, and whatever else it might be it is decidedly not a time to disengage. More than this, the fact of the pandemic’s high neuropsychiatric and other mental health costs is certainly not a valid reason for resignation. Our goal remains, to protect and to improve the lives of patients with frailty, cognitive vulnerability, and functional impairments. We need to consider the events that have transpired with a gimlet gaze, not cynical or despairing, but with a tireless sense of possibility. We need to keep pens in hand, writing the future until it arrives, and once it does to continue writing.

We should also humbly consider that we as healthcare professionals, like our patients, are human,19 which means that we have had our own fears and struggles. Front-line clinicians the world over deserve admiration for their personal devotion, for leaning in, and for embracing their calling during bleak days. And yet, despite the truly aspirational kind of service that clinicians have given, we practice in a biomedical culture steeped in responsivity rather than proactivity. It rallies to address the needs of patients, often even heroically so, with the unprecedented pace of vaccine development for SARS-CoV-2 as case-in-point. To be fair, preparing for all possibilities is neither feasible nor reasonable, but, for my tastes, I think we could do with a fair deal more proactivity.20

We must never become pessimists about advocacy. We have had loud voices and small sticks by comparison (for one, a lack of efficacious treatments for delirium), but we need to enlarge both. Awareness is good, but action is better (Table 1). At the risk of tautology, vulnerable patients are vulnerable, but this is precisely why and where action is needed. The pandemic has laid bare not only the vulnerability of large swaths of patients but also the vulnerability of our interventions, as when we’ve been unable to provide personal support to patients with or at risk for delirium because of infection control precautions. Our experiences have also shown us in unprecedented ways the profound power of human touch, physical presence, and personal connection.

It is a painful reality that mental health is routinely secondary among clinical considerations. But I might suggest that what we’ve encountered with COVID-19 is a case of ontogeny recapitulating phylogeny. For instance, mental health needs didn’t become a widespread interest to practitioners in critical care until ICU survival was commonplace. But, if this interpretation is correct, then we may now have a great wind at our backs. At this very moment—with efficacious vaccines and COVID-19 treatments available—we might justifiably anticipate an imminent inflection point of interest in cognitive and mental health. Advocacy in action may now have its greatest impact and reach yet. There’s only one way to find out, and I say we try it.

Table 1: Next steps for engaging the burden of neuropsychiatric and psychiatric costs of COVID-19
  1. In the spirit of NIDUS, we need a unified message, shared goals, and a blueprint for action.21,22
  2. We need terminological clarity, especially a harmonized approach to delirium and acute encephalopathy.23
  3. Clinical care and research are team sports that require inter-disciplinary and inter-professional collaboration..24
  4. Ongoing advocacy for humanism in medicine. After all, up to 40% of delirium is preventable with person-centered, non-pharmacological interventions.25
  5. Effective strategies (e.g., Hospital Elder Life Program26 and the A-to-F bundle27) are only as good as implementation, though they may require extra doses of creativity at times.28
  6. The principles of trauma-informed care should be integral to our response to patients affected, in various ways and to varying degrees, by COVID-19.15
  7. Although COVID-19 is associated with a host of neuropsychiatric effects, no neuropsychiatric syndromes have been attributed thus far due to SARS-CoV-2 vaccines.29 Immunization campaigns are the single most important ingredient to seeing the pandemic to a close.


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  5. Kennedy M, Helfand BKI, Gou RY, et al. Delirium in Older Patients With COVID-19 Presenting to the Emergency Department. JAMA Netw Open 2020;3:e2029540.
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  8. Slooter AJC, Otte WM, Devlin JW, et al. Updated nomenclature of delirium and acute encephalopathy: statement of ten Societies. Intensive Care Med 2020;46:1020-2.
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  13. Cabrera Martimbianco AL, Pacheco RL, Bagattini AM, Riera R. Frequency, signs and symptoms, and criteria adopted for long COVID-19: A systematic review. Int J Clin Pract 2021:e14357.
  14. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 Long-term effects of COVID-19: A systematic review and meta-analysis. medRxiv 2021.
  15. Oldham MA, Hitchins A, Nickels MW. Mental Health, COVID-19, and the Invisible Pandemic on the Horizon. Mayo Clin Proc 2021;96:287-90.
  16. Manca R, De Marco M, Venneri A. The Impact of COVID-19 Infection and Enforced Prolonged Social Isolation on Neuropsychiatric Symptoms in Older Adults With and Without Dementia: A Review. Front Psychiatry 2020;11:585540.
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  20. Oldham MA, Desan PH, Lee HB, et al. Proactive Consultation-Liaison Psychiatry: American Psychiatric Association Resource Document. J Acad Consult Liaison Psychiatry 2021;62:169-85.
  21. Khachaturian AS, Hayden KM, Devlin JW, et al. International drive to illuminate delirium: A developing public health blueprint for action. Alzheimers Dement 2020;16:711-25.
  22. Oh ES, Akeju O, Avidan MS, et al. A roadmap to advance delirium research: Recommendations from the NIDUS Scientific Think Tank. Alzheimers Dement 2020;16:726-33.
  23. Oldham MA, Holloway RG. Delirium disorder: Integrating delirium and acute encephalopathy. Neurology 2020;95:173-8.
  24. Khan A, Boukrina O, Oh-Park M, Flanagan NA, Singh M, Oldham M. Preventing Delirium Takes a Village: Systematic Review and Meta-Analysis of Delirium Preventive Models of Care. J Hosp Med 2019;14:E1-E7.
  25. Burton JK, Craig LE, Yong SQ, et al. Non-pharmacological interventions for preventing delirium in hospitalised non-ICU patients. Cochrane Database Syst Rev 2021;7:CD013307.
  26. Hshieh TT, Yang T, Gartaganis SL, Yue J, Inouye SK. Hospital Elder Life Program: Systematic Review and Meta-analysis of Effectiveness. Am J Geriatr Psychiatry 2018;26:1015-33.
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  28. Kotfis K, Williams Roberson S, Wilson JE, Dabrowski W, Pun BT, Ely EW. COVID-19: ICU delirium management during SARS-CoV-2 pandemic. Crit Care 2020;24:176.
  29. Butler M, Tamborska a, Wood GK, et al. Defining causality in neurological & neuropsychiatric complications of SARS-CoV-2 vaccines. SSRN Preprint 2021.
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