COVID-19: a novel risk factor for perioperative neurocognitive disorders

Editor—Older patients with current or previous SARS-CoV-2 infection (COVID-19) have been undergoing surgical interventions at an increasing rate during the COVID-19 pandemic and face a high risk of postoperative complications. Most older patients are expected to recover from acute postoperative complications, including most pulmonary and renal complications and delirium. Recently, a national database study on hip fracture characteristics and outcomes during the COVID-19 pandemic in the USA showed that older patients with hip fracture and concomitant COVID-19 experienced significantly higher rates of acute postoperative complications, especially pulmonary complications (22.9%).¹ However, long-term neurological sequelae, such as perioperative neurocognitive disorders (PNDs), commonly occurring in older patients after major noncardiac surgery (incidence as high as 40%),^{2 , 3} have received relatively little attention.

PNDs that encompass acute postoperative delirium and longer-lasting postoperative cognitive dysfunction are age-related neurological disorders and are associated with dementia.⁴ Older patients with a PND have a significantly increased mortality 3 months after surgery and are at risk for a higher rate of disability, leading to loss of employment, which may lead to a greater reliance on social security.⁵ Interestingly, the enhanced expression of angiotensin-converting enzyme-2 (ACE-2) receptors in the CNS of patients with dementia may make them more susceptible to COVID-19 (Fig. 1 ).^{6 , 7} Clinical studies have identified advanced age, major surgery, low educational level, history of alcohol or opioid use, anticholinergic medication, and pre-existing cognitive impairment as important risk factors for PND.^{3 , 8} The COVID-19 pandemic has significantly affected the epidemiological characteristics of many diseases, and COVID-19 must be considered a potential risk factor for acute or chronic neurological complications because the causative virus, SARS-CoV-2, is more invasive in the CNS than other coronaviruses.^{9 , 10} Acute neurological symptoms associated with COVID-19, including confusion, headache, hypogeusia, hyposmia, and seizures, provide evidence of direct invasion by SARS-CoV-2 into the CNS. Most patients with COVID-19 fully resolve from these acute symptoms after clinical recovery.⁷ However, a small observational study showed that 33% of patients with severe COVID-19 experienced cognitive and motor dysfunction, including inattention, disorientation, and poorly organised movements in response to command, even after hospital discharge.¹¹ Long-term neurological disorders have been observed in non-critical patients with COVID-19 as well, although results are yet to be completed.¹² Moreover, COVID-19 may promote the initiation and progression of age-related progressive neurodegenerative conditions, such as Alzheimer's disease (AD). Preliminary observations have revealed that COVID-19 causes worsening of behavioural symptoms and potential gradual aggravation of the underlying AD neuropathologies and related dementia, which may take months or years to detect.13, 14, 15 Support for a relationship between age-related neurodegenerative conditions and COVID-19 has yet to be reported because of the recent origin of the pandemic.

Fig 1.

Mechanism of neuroinvasion by SARS-CoV-2 and the potential association between SARS-CoV-2 infection, anaesthesia and surgery, and PND in cognitive impairment. Neuroinvasion by SARS-CoV-2 occurs through retrograde axonal transport along the olfactory bulb or disrupted blood–brain barrier. SARS-CoV-2 infection combined with anaesthesia and surgery may lead to significant neuroinflammation, excess mtROS, and amyloid-beta accumulation that can cause hippocampus injury. Furthermore, PND may lead to enhanced ACE-2 expression in the hippocampus, making it more susceptible to SARS-CoV-2 infection. ACE-2, angiotensin-converting enzyme-2; IL-1β, interleukin-1β; IL-6, interleukin-6; mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive oxygen species; PND, perioperative neurocognitive disorder; TNF-α, tumour necrosis factor-α.

Anaesthesia and surgery can disrupt the integrity of the blood–brain barrier (BBB) and facilitate migration of peripheral innate immune molecules into the hippocampus, and SARS-CoV-2 infection may accelerate this process.^{16 , 17} Neurotoxicity via ACE-2 receptors in the hippocampus can be caused by SARS-CoV-2 via its access to the CNS through retrograde axonal transport along the olfactory bulb or disrupted BBB (Fig. 1).^{7 , 9} SARS-CoV-2-mediated immune responses can also play a critical role in cognitive impairment through indirect CNS involvement. Furthermore, the molecular mechanisms, including significant neuroinflammation, mitochondrial oxidative stress, and accumulation of amyloid beta (Aβ), of SARS-CoV-2-induced cognitive disorders are similar to those of PNDs (Fig. 1).^{7 , 8} Surgical trauma can trigger complement signalling activation in the CNS and subsequently activate microglia via CD11b signalling, which further increases SARS-CoV-2-mediated neuroinflammation.^{9 , 18} A recent editorial suggested a correlation between PND and cognitive disorders associated with SARS-CoV-2 because of their overlapping inflammatory response to injury.¹² The authors stated that it may be beneficial to alleviate long-term neurological consequences of COVID-19 by implementing preventive interventions or treatments before surgery and anaesthesia, which could improve pre-existing poor cognitive and functional outcomes for patients with COVID-19.

Increasing evidence suggests that mitochondrial dysfunction is involved in both PND and COVID-19.^{8 , 19} SARS-CoV-2 can enter cells via the ACE-2 receptor and affect mitochondria, causing increased fusion and excess production of reactive oxygen species, thereby damaging mitochondrial DNA and accelerating CNS oxidative stress.¹⁹ Additionally, reports have suggested a critical role of Aβ accumulation in the brain in PND.²⁰ SARS-CoV-2 neuroinvasion could promote endothelial dysfunction and loss of pericytes (disrupted BBB), which can impair Aβ clearance and lead to excess Aβ generation in the hippocampus.^{7 , 16} SARS-CoV-2 infection could directly induce Aβ generation in the CNS as part of the immune response; however, this hypothesis needs to be tested further.⁷

Taken together, COVID-19 may potentially lead to an accelerated cognitive decline associated with anaesthesia and surgical stress through independent and synergistic mechanisms. COVID-19 soon could be recognised as a long-term risk factor for accelerated onset or deterioration of PND in the ageing population undergoing surgery. Future clinical research needs to consider COVID-19 as a potential risk factor for PND in the post-COVID-19 era. Long-term prospective longitudinal studies in older patients undergoing surgery and anaesthesia with concomitant or previous COVID-19 diagnosis should be designed to determine the effect of COVID-19 on the pathological progression of PND and other age-related dementias.

Declarations of interest

The authors declare that they have no conflicts of interest.

Funding

Natural Science Foundation of Shandong Province (ZR2020QH291 and ZR2020MH126); Key Research and Development Plan of Shandong Province (2019GSF108228); Qingdao Key Health Discipline Development Fund (2019); Qingdao Outstanding Health Professional Development Fund (2019); Scientific Research Foundation of Qilu Hospital of Shandong University (Qingdao), China (QDKY2018QN12 and QDKY2019YC06).