Brain Wave

153 severe Covid-19 patients reveal how the disease affects the brain

"Now we have a handle on the scale of the problem."

We've lived with novel coronavirus for six months – an eternity in quarantine time.

Even now, Covid-19 continues to surprise scientists, who have recently added brain complications to a list of consequences that include respiratory problems, GI discomfort, and effects on the kidney, liver, and heart.

Between April 2 and April 26, scientists in the United Kingdom identified 153 Covid-19 patients who had neurological symptoms. Those symptoms included cerebrovascular events (like a stroke), altered mental status (a change in personality, behavior, or consciousness), or issues with peripheral parts of the nervous system (like nerves outside the brain). The study was published Thursday in the The Lancet.

Importantly, these symptoms were only seen in severe Covid-19 patients. And at this point, scientists are unsure of how many patients, on a population level, might actually experience these complications.

This study follows months of smaller case studies suggesting that Covid-19 may have neurological effects. Early reports from Wuhan noted neurological symptoms in 78 of 214 severe Covid-19 patients. In March, doctors reported that woman in her 50s with a severe case of coronavirus had unexpected swelling and inflammation in her brain.

163 severe coronavirus patients in England showed signs of neurological symptoms according to a report in The Lancet. Ross D Franklin/AP/Shutterstock

Benedict Michael is a senior clinician scientist at the University of Liverpool and the study's lead author. He tells Inverse that the report helps solidify the fact that neurological symptoms are a part of Covid-19's story.

"Now we've got a handle on the scale of the problem," Michael tells Inverse.

What exactly are these neurological symptoms? – The scientists were able to collect complete data for 125 of those patients. Of that 125, 77 had suffered cerebrovascular complications. The most common, seen in 57 people, was an ischemic stroke – the most common kind of stroke that occurs when a clot blocks a blood vessel supplying blood to the brain.

The second most common symptom was an altered mental status. That can mean confusion or delirium.

"In our study, we identified 153 of these patients in three weeks."

Altered mental status was seen in 39 patients. Of those, seven showed evidence of encephalitis or swelling in the brain that could be behind the behavior.

The remaining patients showed behavior that fit better with psychiatric diagnoses. Ten were diagnosed with psychosis — the feeling of being disconnected from reality. Six showed dementia-like symptoms. The rest fell into different categories that ranged from catatonia, an inability to move normally, to mania, an elevated mood state associated with bipolar disorder.

How common are these symptoms? – Michael explains that we don't know how common these symptoms are. They're "hopefully rare," he says, but due to the sheer size of the Covid-19 pandemic that means that significant amounts of people might experience them, even so.

"Even if the number of patients is small the denominator is so large because so many people have been infected," Michael says. "We're seeing large numbers of these rare complications. In our study, we identified 153 of these patients in three weeks."

Within this sample of patients, cerebrovascular issues were more common among older patients (old, in this study, is defined as over 60). But as for altered mental status, the split was relatively even between old and young: 18 patients with an altered mental status were younger than 60, while 19 were older.

"But within the neurological and psychiatric complications of an altered mental status we had one of our largest groupings in patients in their twenties, thirties, and forties," Michael says.

There's a chance that the clustering of altered mental state symptoms in younger patients is simply a reporting issue with the data. Altered mental status in older patients can sometimes be erroneously written off as a consequence of age. If those symptoms show up in a young person, they're more likely to be referred to a psychiatrist for evaluation.

At this point, however, the study helps solidify that doctors should be on the lookout for these symptoms in both young and old patients. And as more data flows in, scientists will be able to see clearer patterns.

What is causing brain complications in Covid-19 patients?

The fact that a virus can actually cause effects on the brain isn't unique to Covid-19's virus, SARS-CoV-2. The Mayo Clinic notes that viral infection is the most common cause of brain inflammation, also called encephalitis.

The confusing part about the coronavirus and these neurological symptoms is that it appears to be linked to more than just inflammation. Symptoms range from blood clots to inflammation to an unexplained, yet altered, mental state.

Early reports suggested that Covid-19's virus might actually cross the blood-brain barrier: SARS-CoV-2 has been detected in cerebrospinal fluid in a 56-year-old patient from China, for example.

But detecting viruses in cerebrospinal fluid is not very common, Michael explains. He thinks Covid-19's effect on the brain could come down to the body's immune system, which is triggered in response to the virus "spilling over" into the central nervous system.

We've already seen evidence that Covid-19 can evoke an extremely strong immune response, which is called a cytokine storm. During a cytokine storm, the body overproduces immune cells and proteins to the point where they can attack tissues, leading to blood clots and organ failure in some cases.

More research is needed to see if responses like the cytokine storm can actually explain these neurological symptoms, Michael adds.

At this point, there's so little data on these patients that these explanations are only ideas. But if six more months of coronavirus unfold, scientists will keep looking for answers.

Background: Concerns regarding potential neurological complications of COVID-19 are being increasingly reported, primarily in small series. Larger studies have been limited by both geography and specialty. Comprehensive characterization of clinical syndromes is crucial to allow rational selection and evaluation of potential therapies. The aim of this study was to investigate the breadth of complications of COVID-19 across the UK that affected the brain.
Methods: During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals across the spectrum of major UK neuroscience bodies, comprising the Association of British Neurologists (ABN), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), and representing neurology, stroke, psychiatry, and intensive care. Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischemic, hemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behavior, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Physicians were encouraged to report cases prospectively and we permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by UK Government public health bodies.
Findings: The ABN portal was launched on April 2, 2020, the BASP portal on April 3, 2020, and the RCPsych portal on April 21, 2020. Data lock for this report was on April 26, 2020. During this period, the platforms received notification of 153 unique cases that met the clinical case definitions by clinicians in the UK, with an exponential growth in reported cases that was similar to overall COVID-19 data from UK Government public health bodies. Median patient age was 71 years (range 23–94; IQR 58–79). Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischemic stroke, nine (12%) an intra-cerebral hemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years.
Interpretation: To our knowledge, this is the first nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19. Altered mental status was the second most common presentation, comprising encephalopathy or encephalitis and primary psychiatric diagnoses, often occurring in younger patients. This study provides valuable and timely data that are urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy.
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