The first widespread reports that SARS-CoV-2 might be affecting our nervous system were quite innocuous. Back in March, doctors noted that many patients who were otherwise asymptomatic lost their sense of smell and taste before testing positive for COVID-19. Whilst an obvious inconvenience (it’s particularly cruel to be denied the sensory relief that a tub of ice cream has brought to many during this crisis), these symptoms appeared quite mild as compared to the crippling effects on the respiratory system that were – at the time – the main hallmark of acute COVID-19 infection.
But over the following months, reports of far more severe neurological side effects emerged. Dr Rachel Brown, a clinical research training fellow in the Faculty of Medical Sciences at University College London, recently co-authored a review examining COVID-19 effects on the brain. Brown, speaking to Technology Networks, says that neurological signs of the infection are varied. “We were able to identify different patterns of neurology occurring in relation to COVID-19 illness, including temporary brain dysfunction, inflammation in the brain, stroke and inflammation of the nerves,” Brown explained.
Loss of smell in COVID-19: The tell-tale nose
The initial hint that COVID-19 might be impacting the nervous system came from the tell-tale anosmia that neurologists began to record in unusually high frequencies. As the pandemic reached its peak, a joint statement from Claire Hopkins and Nirmal Kumar, presidents of the British Rhinological Society and ENT UK, respectively, noted they had seen four patients, all under 40, who had reported sudden anosmia in the preceding week. This compared to a normal incidence of less than one case per month.
Anosmia, says Brown, is a sign that something is affecting the brain’s olfactory pathways. “Neurologists take an interest in anosmia; frequently causes are non-neurological, such as coryzal illness or head injury, however it can be associated with a range of neurological diseases. For example, the gradual loss of smell can be an early sign of neurodegenerative disease such as Parkinson’s disease, but there are usually other additional clues pointing towards these disorders and in these cases, anosmia is a more persistent or permanent,” says Brown. “This is therefore very different to anosmia associated with COVID-19, which seems to start abruptly, and mostly improve over days or weeks or in some cases months.” How and why Covid-19 causes anosmia is the subject of investigation by a range of specialists including those in ear, nose and throat medicine, infectious diseases, and neurology.
More severe symptoms emerge
This relatively benign symptom wasn’t the focus of the weekly multidisciplinary meetings at the London-based National Hospital for Neurology and Neurosurgery that became the basis of Brown’s paper, which was published in Brain in July. Instead, the team discussed more severe, isolated cases of neurological dysfunction. Some of these signs are caused by a diverse range of conditions, but others, says Brown, are much rarer encounters.
Guillain-Barré syndrome, a severe but rare neurological syndrome caused by the body’s immune system attacking nerve cells outside the brain, has been noted repeatedly in COVID-19 patients. This is no small matter – symptoms include burning sensations in patients’ limbs and, in some cases, temporary paralysis and weakness. Guillain-Barré, says Brown, typically appears after bacterial or viral infection. The condition’s onset has been noted after cases of Zika virus or even influenza.
Other symptoms that severe COVID-19 shares with other conditions include psychiatric symptoms such as delirium, which Brown points out “is common in the context of fever or acute illness, particularly with increasing age.” When patients are put into intensive care and separated from their families in the height of a novel worldwide pandemic, it’s perhaps unsurprising that patients manifest confusion and fear.
But other symptoms are more unique to COVID-19 infection. “A number of things seemed more unusual,” says Brown. “We reported nine patients with acute disseminated encephalomyelitis (ADEM)-like illness over a short study period. We would not usually expect to see this disorder so frequently – in our paper we note that we would usually expect to see this number of patients over five months – suggesting that there may be an increased incidence of this in patients with COVID--19 infection.”
ADEM is an inflammatory disorder affecting the brain. A rush of immune cells into the central nervous system can lead to symptoms such as fever, fatigue, nausea and headache. But this incredibly rare condition is appearing in complex and damaging variants in some very ill COVID-19 patients. One case study from Brown’s paper, of a 47-year-old woman, detailed symptoms of acute hemorrhagic leukoencephalitis, a form of ADEM that involves bleeding and cell death within the brain. To treat this case, the team had to conduct a hemicraniectomy, where a flap of the skull is removed to relieve pressure on the swollen and inflamed brain. The patient, says the case study, thankfully continued to improve clinically after this procedure, but ADEM is no minor affliction.
Other more severe, COVID-specific symptoms, Brown says, relate to bleeding in the brain, something she says has been reported by multiple groups. Other patients entered a prothrombotic state, where their blood becomes much more likely to clot, leading to a higher risk of stroke. Some patients also had blood clots in their lungs simultaneously.
What’s the role of the immune system?
These symptoms are, unquestionably, rare. Nevertheless, their incidence, especially when an immune component is involved, raises the question of whether COVID-19 is causing damage by itself, or whether the body’s immune response to the virus is the bigger culprit – the “cytokine storm” experienced by some patients is an example of this effect in action.
Brown says it’s been unclear so far what is driving these symptoms. If the virus is causing them directly, it would have to have breached the blood-brain barrier. This, says Brown, is possible, but there’s limited evidence of SARS-CoV-2 infiltrating the brain, although more investigation is needed.
Instead, says Brown, “it seems likely that a combination of mechanisms are responsible for the different presentations. Possibilities include the body’s own immune or inflammatory response, the effects of low body oxygen level, blood vessel changes, changes in the stickiness of the blood, and the effects of severe illness.”