Though the COVID-19 virus primarily affects pulmonary and cardiorenal functions, a large amount of neurological involvement has also been presented. As per the study published in The Lancet using electronic health records of more than two lakh COVID positive patients, 34%  were diagnosed with a neurological or psychiatric condition within six months of infection.

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Neurological complications in COVID-19

The researchers from the University of Oxford and TriNetX (USA) found that anxiety (17%) and mood disorders (14%) were the most common. The researchers added, “Neurological diagnoses such as stroke and dementia were rarer, but not uncommon in those who had been seriously ill during COVID-19 infection. For example, of those who had been admitted to intensive care, 7% had a stroke and almost 2% were diagnosed with dementia”.

Ever since the COVID-19 pandemic began on March 11, 2020, there has been concern that survivors might be at an increased risk of neurological disorders. This concern, initially based on findings from other coronaviruses, was soon followed by case series, emerging evidence of COVID-19 Central Nervous System (CNS) involvement, and the identification of mechanisms by which this could occur. There was also some evidence that showed that COVID-19 survivors were at increased risk of mood and anxiety disorders in the 3 months after infection.

The researchers realised that they need large scale, robust, and longer-term data to properly identify and quantify the consequences of the COVID-19 pandemic on brain health.

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The study

The researchers used data from the TriNetX electronic health records network (with over 81 million patients) for the present study. TriNetX is a company set up on “an idea that incorporating real-world data results in better clinical trial design, improves the site selection and patient recruitment process and generates real-world evidence (RWE) to advance the collective understanding of human health".

They identified a primary cohort of 236,379 patients who had a COVID-19 diagnosis, one matched control cohort of 105,579 patients diagnosed with influenza, and another matched control cohort of 236,038 patients diagnosed with any respiratory tract infection including influenza in the same period.

The cohorts included patients older than 10 years who had an index event on or after Jan 20, 2020, and who were still alive on Dec 13, 2020. The researchers estimated the incidence of 14 neurological and psychiatric outcomes in the 6 months after a confirmed diagnosis of COVID-19 including intracranial haemorrhage; ischaemic stroke; Parkinsonism; Guillain-Barré syndrome etc.

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Findings from the study

Among the 236,379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33.62%. Most of the 14 diagnostic categories were more common in patients who had COVID-19 than in those who had influenza with a hazard ratio [HR] 1.44. As with incidences, HRs were higher in patients who had more severe COVID-19. The most common diagnoses after COVID-19 were anxiety disorders (occurring in 17% of patients), mood disorders (14%), substance misuse disorders (7%), and insomnia (5%). The incidence of neurological outcomes was lower, including 0.6% for brain haemorrhage, 2.1% for ischaemic stroke, and 0.7% for dementia.

“Our study provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection. Risks were greatest in, but not limited to, patients who had severe COVID-19. This information could help in service planning and identification of research priorities”. The researchers reported.

Professor Paul Harrison, lead author of the study, from the University of Oxford, UK, clarified that these are real-world data from a large number of patients. They confirm the high rates of psychiatric diagnoses after COVID-19 and show that serious disorders affecting the nervous system (such as stroke and dementia) occur too. While the latter is much rarer, they are significant, especially in those who had severe COVID-19.

Professor Paul Harrison said in the press release from the journal, “Although the individual risks for most disorders are small, the effect across the whole population may be substantial for health and social care systems due to the scale of the pandemic and that many of these conditions are chronic. As a result, health care systems need to be resourced to deal with the anticipated need, both within primary and secondary care services”.

Risks of a neurological or psychiatric diagnosis were greatest in, but not limited to, patients who had severe COVID-19. Compared to the overall 34% incidence, a neurological or psychiatric diagnosis occurred in 38% of those who had been admitted to hospital, 46% of those in intensive care, and 62% in those who had delirium (encephalopathy) during their COVID-19 infection. This gradient of risk applied to individual disorders too. For example, 2.7% of people needing intensive care and 3.6% of people with encephalopathy had a brain haemorrhage (compared to 0.3% in people without hospitalisation); 6.9% and 9.4% had an ischaemic stroke (compared to 1.3% without hospitalisation); 1.7% and 4.7% developed dementia (0.4% without hospitalisation), and 2.8% and 7% were diagnosed with a psychotic disorder (0.9% without hospitalisation).

The authors also looked at people who experienced flu and other respiratory tract infections over the same time frame to help understand whether these neurological and mental health complications were linked specifically to COVID-19. After taking into account age, sex, ethnicity, and existing health conditions, there was overall a 44% greater risk of neurological and mental health diagnoses after COVID-19 than after flu and a 16% greater risk after COVID-19 than with respiratory tract infections. As a result, the authors say that COVID-19 does lead to a greater risk of neurological and psychiatric disorders than these other health conditions. However, this was not seen for all conditions; there was no clear evidence that COVID-19 led to an increased risk of Parkinsonism or and Guillain-Barré syndrome.

While accepting that their results indicate that brain diseases and psychiatric disorders are more common after COVID-19 than after flu or other respiratory infections, even when patients are matched for other risk factors, Dr Max Taquet, a co-author of the study, from the University of Oxford, UK, said that they now need to see what happens beyond six months. “The study cannot reveal the mechanisms involved but does point to the need for urgent research to identify these, with a view to preventing or treating them”, he added in the Lancet press release.

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Limitations of the study

1. Firstly, the completeness and accuracy of the electronic health records are not known.
2. Secondly, many people with COVID-19 have mild or no symptoms and do not present for health care, therefore, the people studied here are likely to have been more severely affected than in the general population.
3. Thirdly, the severity and course of the neurological and psychiatric disorders are not known.

The Lancet press release quoted from a linked comment article by Dr Jonathan Rogers, who was not involved in the study, from University College London (UCL), UK, thus: “[this] study points us towards the future, both in its methods and implications. Researchers need to be able to observe and anticipate the neurological and psychiatric outcomes of future emerging health threats by the use of massive, international, real-world clinical data. Selection biases will remain an issue, not necessarily mitigated by sample size, and thus the onus should be on countries with public health-care systems to enable truly comprehensive national data to be available for research. Sadly, many of the disorders identified in this study tend to be chronic or recurrent, so we can anticipate that the impact of COVID-19 could be with us for many years”.

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Experts’ comments

COVID-19 affects both the brain and mind

Prof Sir Simon Wessely, Regius Chair of Psychiatry, King’s College London stated that this is a very important paper. “It confirms beyond any reasonable doubt that COVID-19 affects both brain and mind in equal measure. Some were already known – for example, increased rates of stroke and also anxiety disorders. Others less so – dementia and psychosis for example. What is very new is the comparisons with all respiratory viruses or influenza, which suggests that these increases are specifically related to COVID-19, and not a general impact of viral infection,” he clarified.

Carefully controlled and considered study

Prof Dame Til Wykes, Vice Dean of Psychology and Systems Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London stated that this is a carefully controlled and considered study looking back on 2020 COVID-19 cases mostly in the USA over six months. But it also has some limitations not least the dependence on US data, looking back not forwards, and the potential for treatments developed in 2020 to change the types and incidence of problems”, she cautioned.

She noted that the study confirms the suspicions that a COVID-19 diagnosis is not just related to respiratory symptoms; it is also related to psychiatric and neurological problems. “Looking over 6 months after diagnosis has demonstrated that the “after-effects” can appear much later than expected – something that is no surprise to those suffering from Long-COVID. Although as expected the outcomes are more serious in those admitted to hospital, the study does point out that serious effects are also evident in those who had not been admitted to hospital,” she clarified.

She disclosed that there is little good news from these data except that the anxiety and depression rates were decreasing compared to data collected 3 months after diagnosis, but this is balanced by the increase in more serious psychotic illnesses.

Robust piece of work in a large cohort

Dr Musa Sami, Clinical Associate Professor in Psychiatry, University of Nottingham, characterised this as a robust piece of work in a large cohort demonstrating the association between COVID-19 and psychiatric and neurological complications. This is a very important topic as there has been considerable consternation regarding COVID-19 as a ‘brain disease’.

“We need accurate data and estimates of the size of this association before we can draw this conclusion“, he cautioned. He conceded that this work has several strengths: a very large sample size, adjusting for a variety of confounders, and appropriate control samples. All together around 1 in 3 patients who develop COVID-19 will have a neurological or psychiatric disorder at six months, and 1 in 9 patients of those who develop COVID-19 will receive a new diagnosis of neurological or psychiatric disorder.

“We would expect individuals with influenza and other respiratory illnesses to also present with some of these illnesses, and they do. What this paper show is that COVID-19 makes the presentation of these illnesses more likely in the order of around 44% for influenza and 16% for other respiratory illnesses. What we do not fully understand at the moment is the mechanism by which COVID-19 has this effect: psychological stress longer stays in hospital and characteristics of the illness itself may play a part", he added.

“This data provides very important information for services and policymakers to estimate the burden of neurological and psychiatric disease from COVID-19. What is important for the public to remember is that most patients who develop COVID-19 will not develop these complications. The severity of COVID-19 appears to be associated with an increased likelihood of developing these complications in those admitted to ITU or those diagnosed with encephalopathy and delirium. Those experiencing psychological or neurological symptoms should seek medical attention and remember that effective treatments are available for many of these conditions”.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.