New research by UCL adds to growing concerns over neurological symptoms, in both the short and long term. What are these sometimes strange symptoms and how dangerous are they?
Writer: Eva Lymberopoulos
Editor: Altay Shaw
Artist: Lauren Troy
Probably the best known symptoms of COVID-19 are cough and fever, as well as some neurological symptoms such as fatigue, headaches and the loss of taste and smell. But, more severe neurological abnormalities lurk in the background. “Delirium and confusion are the most common complications I saw”, says Dr Nik Sharma, a consultant neurologist and UCL researcher who worked on the COVID-19 ward in the National Hospital for Neurology and Neurosurgery (NHNN) during the peak of infections. In even more serious cases, seizures, stroke, or aphasia (a loss of language abilities) can occur, often despite mild respiratory symptoms. More and more research is shedding light on the extent, etiology, and progression of neurological complications. One such report by UCL clinicians and academics has gained significant publicity.
UCL clinicians at the forefront
The study, published in Brain, is a collaborative effort from a multidisciplinary and multi-institutional group of neurologists, radiologists, virologists, and infectious disease experts. Since March, they have held weekly meetings at NHNN to discuss relevant cases. The 43 patients included in the study varied in age, COVID-19 severity and ethnic background. Some patients showed neurological symptoms even before classic COVID-19 symptoms, and others several weeks after their recovery.
What were the common symptoms?
The authors identified four disease groups, spanning the entire nervous system. The most common disease group had inflammatory brain disorders, mainly acute disseminated encephalomyelitis (ADEM). This disease, rare in adults and often triggered by viral infection, involves the progressive destruction of the myelin sheath that insulates nerves, leading to symptoms of multiple sclerosis. Alarmingly, the number of ADEM cases observed in the 5-week study would normally be seen over a span of 5 months. Additionally, many of these patients experienced bleeds in the brain, including one fatality.
The second biggest group included encephalopathies. Patients showed confusion, delirium, seizures, and psychosis. For example, a day after being discharged from hospital, one patient described seeing lions and monkeys in her home, and experienced auditory hallucinations and complex delusions. Another disease group included peripheral nerve damage, with patients showing weakness or damage to nerves caused by an immune system attack. Finally, and perhaps most concerningly, there was a large number of stroke patients. Some patients experienced multiple strokes and many had so-called microbleeds (bleeding from the small vessels in the brain). Notably, everyone showed extremely high blood clotting markers which had previously been associated with COVID-19. “This marker is non-specific, so we see increases in many disorders”, says Dr Sharma, “but it is strange that they are so far off the normal range”.
Why do these problems happen?
There is a lot of discussion about the possible mechanisms of these symptoms. One likely explanation is hyperinflammation, where the innate immune system overreacts and floods the body with a ‘cytokine storm’. It is also likely that after the infection, the immune system builds antibodies to brain structures in a post-infectious autoimmune reaction.
Direct infection of the brain with the virus, as had been observed for the SARS virus, is a hotly contested option and could help to explain the increased number of strokes. Brain tissues express high levels of the receptor through which the SARS-CoV-2 virus enters cells. For example, some case studies have detected the virus in endothelial cells, which line the inside of the brain’s blood vessels, or the cerebrospinal fluid of patients. However, this evidence is sparse and indeed, the current study did not observe this.
What can we conclude from this study?
The report and its proposed mechanisms support an emerging consensus that COVID-19 is not just a respiratory, but a vascular disease. As mentioned, it has been shown that the virus infects the inside of blood vessels, and so can affect all well-vascularised structures, such as the lungs, kidneys, gut and brain, and cause clotting there. This conceptualisation can thus explain the multi-organ symptoms of COVID-19, and even the strange lesioning and rashes on fingers and toes.
However, the report does not allow for inferences about causality since it only describes what clinicians observed. Despite this, it is an important piece of work, says Dr Sharma of his colleagues’ report: “This kind of detailed phenotyping is what the Institute of Neurology is very good at. And it is necessary for taking good care of patients – if we don’t know what to look for, we can’t detect it.”
Another limitation to keep in mind is the bias toward hospitalised patients which have more severe disease than much of the general population. However, the prevalence of neurological symptoms might also be higher than suggested, as they are difficult to diagnose in very ill patients – an MRI scan is often required but hard to obtain. COVID-19 patients need more sedatives than other patients, which could mean symptoms such as seizures might be missed. Additionally, patients presenting primarily with neurological symptoms might not be tested for COVID-19.
How dangerous are neurological complications of COVID-19?
It is clear that the neurological symptoms of COVID-19 are not to be underestimated. For example, brain damage is much harder to recover from than damage to other organs, which can often be aided by machines. Additionally ‒ and against what has become common sense ‒ it is evident from this and other studies that not just the elderly and those with comorbidities are affected. Even children are vulnerable: very recently, an infant who was infected with COVID-19 in the womb showed white matter injury. There is also a possibility for long-term neurological symptoms such as fatigue, depression, vision problems, and memory loss, months after the infection has ceased. The coronaviruses SARS and MERS had similar consequences. Other viruses have also shown strange long-term neuropsychiatric problems, such as the “sleeping sickness” associated with the Spanish Flu, or depression after the 1957 influenza pandemic. Some even speak of the potential for a “second hidden pandemic” of neurological symptoms, but how big is this issue?
“We definitely need to closely follow-up COVID patients for neurological symptoms”, Dr Sharma stresses. “However, we shouldn’t let this distract us from more common diseases that need treatment”. Indeed, an estimated 2,000 cases of cancer go undiagnosed each week; similarly, many stroke cases are missed. These disorders are common and early detection and fast treatment is a matter of life or death. On the other hand, neurological sequelae of COVID-19 are relatively rare and often resolve spontaneously, without many deaths. It thus seems that while COVID-19 is a serious disease with many potentially fatal complications that we are just beginning to uncover, it is crucial to find a balanced and sustainable response that doesn’t neglect other parts of the healthcare system which could lead to more deaths than the pandemic itself.
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