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Discussion

Various adverse neurological and psychiatric outcomes occurring after COVID-19 have been predicted and

www.thelancet.com/psychiatry Vol 8 May 2021

………..The data presented in this study, from a large electronic health records network, support these predictions and provide estimates of the incidence and risk of these outcomes in patients who had COVID-19 compared with matched cohorts of patients with other health conditions occurring contemporaneously with the COVID-19 pandemic .

The severity of COVID-19 had a clear effect on subsequent neurological diagnoses . Overall, COVID-19 was associated with increased risk of neurological and psychiatric outcomes, but the incidences and HRs of these were greater in patients who had required hospitalisation, and markedly so in those who had required ITU admission or had developed encephalopathy, even after extensive propensity score matching for other factors (eg, age or previous cerebrovascular disease). Potential mechanisms for this association include viral invasion of the CNS, hypercoagulable states and neural effects of the immune response. However, the incidence and relative risk of neurological and psychiatric diagnoses were also increased even in patients with COVID-19 who did not require hospitalisation.

Some specific neurological diagnoses merit individual mention. Consistent with several other reports, the risk of cerebrovascular events (ischaemic stroke and intracranial haemorrhage) was elevated after COVID-19, with the incidence of ischaemic stroke rising to almost one in ten (or three in 100 for a first stroke) in patients with encephalopathy. A similarly increased risk of stroke in patients who had COVID-19 compared with those who had influenza has been reported. Our previous study reported preliminary evidence for an association between COVID-19 and dementia. The data in this study support this association. Although the estimated incidence was modest in the whole COVID-19 cohort , 2·66% of patients older than 65 years and 4·72% who had encephalopathy , received a first diagnosis of dementia within 6 months of having COVID-19. The associations between COVID-19 and cerebrovascular and neurodegenerative diagnoses are concerning, and information about the severity and subsequent course of these diseases is required.

Whether COVID-19 is associated with Guillain-Barré syndrome remains unclear;26 our data were also equivocal, with HRs increased with COVID-19 compared with other respiratory tract infections but not with influenza , and increased compared with three of the four other index health events . Concerns have also been raised about post-COVID-19 parkinsonian syndromes, driven by the encephalitis lethargica epidemic that followed the 1918 influenza pandemic.27 Our data provide some support for this possibility, although the incidence was low and not all HRs were significant. Parkinsonism might be a delayed outcome, in which case a clearer signal might emerge with a longer follow-up.

The findings regarding anxiety and mood disorders were broadly consistent with 3-month outcome data from a study done in a smaller number of cases than our cohort, using the same network,14 and showed that the HR remained elevated, although decreasing, at the 6-month period. Unlike the earlier study, and in line with previous suggestions, we also observed a significantly increased risk of psychotic disorders, probably reflecting the larger sample size and longer duration of follow-up reported here. Substance use disorders and insomnia were also more common in COVID-19 survivors than in those who had influenza or other respiratory tract infections (except for the incidence of a first diagnosis of substance use disorder after COVID-19 compared with other respiratory tract infections). Therefore, as with the neurological outcomes, the psychiatric sequelae of COVID-19 appear widespread and to persist up to, and probably beyond, 6 months. Compared with neurological disorders, common psychiatric disorders (mood and anxiety disorders) showed a weaker relationship with the markers of COVID-19 severity in terms of incidence or HRs . This might indicate that their occurrence reflects, at least partly, the psychological and other implications of a COVID-19 diagnosis rather than being a direct manifestation of the illness.

HRs for most neurological outcomes were constant, and hence the risks associated with COVID-19 persisted up to the 6-month timepoint. Longer-term studies are needed to ascertain the duration of risk and the trajectory for individual diagnoses.

Our findings are robust given the sample size, the propensity score matching, and the results of the sensitivity and secondary analyses. Nevertheless, they have weaknesses inherent to an electronic health records study, such as the unknown completeness of records, no validation of diagnoses, and sparse information on socioeconomic and lifestyle factors. These issues primarily affect the incidence estimates, but the choice of cohorts against which to compare COVID-19 outcomes influenced the magnitude of the HRs . The analyses regarding encephalopathy (delirium and related conditions) deserve a note of caution. Even among patients who were hospitalised, only about 11% received this diagnosis, whereas much higher rates would be expected. Under-recording of delirium during acute illness is well known and probably means that the diagnosed cases had prominent or sustained features; as such, results for this group should not be generalised to all patients with COVID-19 who experience delirium. We also note that encephalopathy is not just a severity marker but a diagnosis in itself, which might predispose to, or be an early sign of, other neuropsychiatric or neurodegenerative outcomes observed during follow- up. The timing of index events was such that most infections with influenza and many of the other respiratory tract infections occurred earlier on during the pandemic, whereas the incidence of COVID-19 diagnoses increased over time The effect of these timing differences on observed rates of sequelae is unclear but, if anything, they are likely to make the HRs an underestimate because COVID-19 cases were diagnosed at a time when all other diagnoses were made at a lower rate in the population Some patients in the comparison cohorts are likely to have had undiagnosed COVID-19; this would also tend to make our HRs an underestimate. Finally, a study of this kind can only show associations; efforts to identify mechanisms and assess causality will require prospective cohort studies and additional study designs.

In summary, the present data show that COVID-19 is followed by significant rates of neurological and psy- chiatric diagnoses over the subsequent 6 months. Services need to be configured, and resourced, to deal with this anticipated need.

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