Traces of Covid-19 remain in the body months after shaking off the virus and the risk of developing a psychiatric or neurological condition, such as psychotic episodes, dementia, brain fog or epilepsy, continues for up to two years, according to a new study published in The Lancet. However, this does not apply to all associated mental conditions. According to the study, the risk of suffering from anxiety and mood disorders, for example, is no greater for those who have had Covid-19 than any other respiratory infection.
There are still questions that remain unanswered regarding the eventual impact of Covid-19 in the short, medium and long term. We know that long Covid produces heterogeneous clinical cases with more than 200 different sequelae, but why these arise, who they affect and for how long remains a mystery. The most in-depth study to date estimates that one in eight Covid-19 patients suffer symptoms long after getting over the virus, but why, who and to what degree is yet to be established.
Now new research, carried out by scientists at Oxford University reopens the investigation on long Covid with a focus on neuropsychiatric issues. Though the scientific community has been aware since the start of the pandemic that Covid-19 raises the risk of developing certain psychiatric and neurological diseases, the Oxford researchers have tried to address when and if these elevated risks return to the normal baseline, whether they target certain demographics, and whether the risk profiles change according to the different Covid-19 variants.
The research was based on clinical information from databases containing statistics on 1.28 million people with Covid-19, mostly from the United States, but also from Spain, India, Australia, Bulgaria, Taiwan and Malaysia. They then cross-referenced this information with that of a control cohort consisting of an equal number of patients suffering from other respiratory infections. “To our knowledge, this is the first study with a comparator cohort that assesses the risks of a range of neurological and psychiatric outcomes of Covid-19 up to 2 years after the index SARS-CoV-2 infection,” the researchers’ report states. “We found that the risks of post-Covid neurological and psychiatric outcomes follow different trajectories.”
Some conditions are going to be two to three times more common after coping with Covid than other respiratory infectionsPaul Harrison, Oxford University
Paul Harrison, a professor of Psychiatry at Oxford University and lead author of the study, has said that these risks are not dramatic and differ substantially according to age. “I think the worst odds ratio is two to three: some things are going to be two to three times more common after coping with Covid than other [respiratory] infections. But the things that are relatively more common also tend to be generally rare,” he said during a press conference.
The research has revealed that the risks of common psychiatric disorders, such as anxiety or depression, disappear within two months. “Good news,” says Max Taquet, a researcher in psychiatry at the National Institute for Health and Care Research and co-author of the study. “The excess risk of some disorders, in particular anxiety disorders, disappeared within three months without a general excess of cases within two years. What that means is that two years after infection, the number of people that had a diagnosis of depression or an anxiety disorder post-Covid was in the same range as the number of people who had another respiratory tract infection. And that’s very reassuring.”
The same cannot be said, however, for other conditions among the 14 analyzed. The risks of suffering from cognitive conditions such as brain fog, dementia, psychotic disorders, epilepsy and seizures were still comparatively high up to two years after diagnosis. “From the risk perspective, if no anxiety disorder has been diagnosed within two months of a Covid diagnosis, the patient can be confident that his or her risk is no longer higher than after another respiratory infection,” the research states. “If a patient had an ischemic stroke within two months of Covid diagnosis, it is plausible that the Covid diagnosis contributed, either directly or indirectly, but beyond two months, other causes should be actively considered.”
The researchers have pointed out that their results do not indicate “a tsunami” of dementia cases and that the increase in psychotic disorders may not be chronic, but rather one-off episodes occurring at a specific time. However, they stress that the potential increase in diagnoses should not be neglected either.
One of the limitations of the study, as the researchers themselves acknowledge, is that they do not know “the severity or course of each disorder after diagnosis, or whether or not they are similar after Covid compared to other respiratory infections.”
The fact is that these risk trajectories are useful for devising public health policies and serve as a guide for patients and healthcare professionals, flagging up the need to be “on the look out” for possible “late sequelae.” In terms of health planning, Harrison adds: “The results have important implications for patients and health services, as they suggest that new neurological conditions related to Covid are likely to occur a considerable time after the pandemic has subsided. Our work also highlights the need for more research into why this happens after Covid and what can be done to prevent or treat these conditions.”
Higher risk of seizures in children
The researchers also found that the profiles and trajectories of the risk of developing some neuropsychiatric conditions changed according to age. On the one hand, adults younger than 64 were at higher risk of developing brain fog or muscle issues compared to those in the same age bracket who suffered from other respiratory infections. Meanwhile, among the oldest demographic, a higher incidence of brain fog, dementia and psychotic disorder was noted compared to the control group.
The risk of neuropsychiatric diagnoses was lower in children than in adults, but they were more likely to suffer a psychotic episode or seizures in the two years following Covid than the control group. “Children are three times at risk of developing psychotic disorders and twice of epilepsy or seizures,” explained Taquet. Even so, he explained that the absolute risk was very low because the incidence of these ailments in the pediatric population is tiny: for example, for psychotic disorders, the incidence was 0.18% after two years of Covid compared to 0.063% in the control group who had other respiratory infections.
As for anxiety and mood disorders, the children were not at increased risk at any stage after Covid compared to children with other respiratory infections. Brain fog, Taquet added, was also “transient” and the risks of developing it were not higher post-Covid.
While the research delves into the risks of developing certain ailments, it also leaves other questions unresolved. For example, why it happens. Regarding children, the theory is: “Sequelae might in part be driven by a post-infectious immune-mediated mechanism such as acute disseminated encephalomyelitis (ADEM), as has been suggested in a prospective study of 52 children hospitalised with Covid-19. This is consistent with our observations of an increased risk of encephalitis in children only, and a higher rate of post-Covid epilepsy or seizures in children.”
In terms of the persistent risk of cognitive deficits, dementia, psychotic disorder, epilepsy and seizures over the long term in all age brackets, the research “suggests that any underlying mechanism must have continued activity long after acute infection.” The researchers also argue that the short-term disappearance or non-existence of the added risk of anxiety in children may be because Covid “precipitates mood and anxiety disorders in individuals with an underlying predisposition, via a short-lived stress-related pathogenesis to which children are less susceptible.”
The influence of variants
The researchers also found that risk patterns for these diseases differ according to the evolution of the major Covid variants: just after the appearance of the delta variant, they saw a higher risk of ischemic stroke, epilepsy and seizures, cognitive deficits, insomnia, and anxiety disorders than previously, all compounded by a higher mortality rate. While there was a lower mortality rate prior to the emergence of the Omicron variant, the risks of neuropsychiatric outcomes remained the same. “The comparable risks seen after the emergence of Omicron indicate that the neurological and psychiatric burden of Covid-19 might continue even with variants that lead to otherwise less severe disease.,” the research states.
According to Josep Maria Tormos, head of research at the Guttman Institute, which specializes in neurorehabilitation, the research is “groundbreaking” and highlights what they already suspected: “an increase in psychiatric and neurological conditions” post-Covid. “We now know that some degenerative diseases and psychotic disorders are affected by inflammatory components,” says Tormos. “We would therefore be looking at the secondary effects of having been exposed to systemic inflammatory levels and how this influences the development or unmasking of conditions that may have already existed in a dormant state.”
However, Ana Rodríguez, a neurologist at the Hospital del Mar in Barcelona, urges caution with the new data: “One limitation is that it is based on electronic health records and the information may be biased. For example, with cognitive deterioration – cases of dementia –the question is whether the sufferer already had incipient cognitive deterioration. The fact that a person is not diagnosed does not mean that he or she does not have the condition.” The neurologist also points out that “it cannot be said that it is exactly related to Covid. It is an association, not a consequence. The authors of the study themselves say that further research should be carried out.”
Acknowledging the limitations of the study, the researchers point out that the Covid cohort may under-represent asymptomatic Covid cases. Only those infected at the beginning of the pandemic have two-year follow-up data, and variants were not genotyped individually. Nevertheless, the results are “relevant,” as far as they relate to preparing and anticipating health policy: “The persistent increased risk of cognitive deficits, dementia, psychotic disorders, and post-covid epilepsy or seizures two years after the index infection means better provision of services are needed to diagnose and manage these sequelae as is research to understand the mechanisms,” according to The Lancet article.
Tormos agrees, above all, on the need to have a healthcare system with the capacity to respond to all the conditions resulting from the virus. “What is striking is that if you subject the population to a pandemic, there is one acute impact [Covid] and another medium-term semi-acute one which unmasks other diseases. We have to develop strategies to shore up the general population’s health to avoid this secondary impact.”