Covid-19 brain: How the virus can wreak havoc on the nervous system

While Covid-19 does wage war on the lungs, growing evidence suggests the virus can cause a cascade of other problems in the body, including heart attacks, GI symptoms, and inflammation.

In a new study, the first to break down the clinical presentation of neurological symptoms, scientists highlight the nervous system as another part of the body that the coronavirus harms.

Research suggests that Covid-19 can spur delirium, brain inflammation, seizures, strokes, nerve damage, and a rare inflammatory condition called ADEM.

Covid-19 doesn't seem to attack the brain directly. Instead, it sets off a firestorm of harmful side effects across the nervous, vascular, and immune systems. These effects, in turn, jeopardize brain health.

"These are serious complications, as the effects of brain damage can be everlasting or fatal," study co-author Hadi Manji, a neurologist at the University College London Hospital, tells Inverse. "We need to develop the best treatments for inflammation and stroke."

The findings, published Tuesday in the journal Brain, offer a stark reminder that Covid-19 is not strictly a respiratory illness. The research follows other studies and case reports suggesting there may be potentially devastating acute and long-lasting brain-related side effects that can cause death or linger after a patient survives Covid-19.

"Although the focus to date has been on the respiratory system, the brain, spinal cord and nerves can be affected in patients who have had Covid-19 infection," Manji says. "In fact, the neurological problems may be the presenting symptom and respiratory symptoms become apparent later."

Between April 9 and May 15, 2020, Manji and his team fastidiously documented the neurological symptoms of 43 people between ages 16 to 85 with either confirmed or suspected Covid-19. All the study participants were treated at the National Hospital for Neurology and Neurosurgery, UCLH in London.

Doctors observed a wide range of nervous system effects including neuroinflammatory diseases and stroke. These effects emerged over a range of time, from six days before to up to 27 days after the onset of their Covid-19 symptoms.

Ten patients experienced transient encephalopathies, or temporary brain dysfunction, along with delirium. This group of patients were, on average, over 50 years old and presented with disorientation and confusion to their doctors.

One patient in this group experienced visual hallucinations and reported seeing lions and monkeys in her house three days after she was discharged from the hospital.

She developed ongoing auditory hallucinations, delusions that she was being persecuted, a Capgras delusion (where someone believes a friend, spouse, parent, or other close family member has been replaced by an identical impostor), and complex systematized delusional misperceptions, the study reports. She also displayed intermittently aggressive behavior with hospital staff and her family.

Twelve other patients in the group experienced brain inflammation including encephalitis and seizures. Nine of these 12 patients with brain inflammation were subsequently diagnosed with acute disseminated encephalomyelitis (ADEM), a rare brain condition typically seen in children. ADEM can be triggered by viral infections. Manji and his team normally diagnose ADEM at this rate over the course of five months in the hospital, not five weeks.

Among the 43 patients, there were eight cases of strokes and eight others with nerve damage, mainly Guillain-Barré syndrome. This disorder typically occurs after a respiratory or gastrointestinal infection.

Some of these complications have also been linked to other coronavirus epidemics, like the 2003 SARS and 2012 MERS outbreaks, but relatively speaking, the numbers of infected individuals in those outbreaks were small — less than 11,000 people.

"With [over] 10,000,000 cases worldwide it is likely that a lot of people will be left with neurological complications of this virus and also because of the effects of being unwell in the ICU for a long period," Manji says. "These will be neurological and neuropsychological."

While brain inflammation and strokes are "clearly very serious and damaging," Manji adds, patients who have had Covid-19 — but not bad enough to go to the hospital — can still experience other harmful neurological effects. These include fatigue, cognitive problems, muscle pain, loss of smell and taste, and headache.

"All patients who have suffered from Covid-19 will need to be followed up to detect any long term complications," Manji advises.

Why can Covid-19 damage the brain? — The underlying mechanisms driving Covid-19's dangerous effects on the nervous system are not yet understood.

Based on current evidence, it does not appear that SARS-CoV-2, the Covid-19 virus, is directly attacking or infecting the brain. Manji explains that there have only been a few cases where there was evidence for the virus in the cerebrospinal fluid (CSF) surrounding the brain — an indication of an attack.

When Manji's team tested patients, they didn't find evidence for the virus in CSF. However, Manji notes that this research is in its "early days" and techniques for detection of the virus may not be great.

He speculates that a multitude of factors may be driving Covid-19's neurological symptoms:

• Sepsis and low levels of oxygen linked to respiratory symptoms.
• Increased stickiness of the blood due to the systemic viral infection and the virus invading cells lining the blood vessels. This seems to be especially important when it comes to strokes and Covid-19.
• Overstimulation of the immune system. This may be causing inflammatory problems in the brain and spinal cord like ADEM and myelitis.
• Cytokine storms: The immune overreactions which have been linked to Covid-19 patients' sudden crash, may be involved in this immune hyperstimulation. As of now, "this is just a theory," Manji says. "We need more research by measuring cytokine levels in the brain and spinal fluid to see if that hypothesis is correct."
• "Molecular mimicry:" A virus may trigger the immune and antibody systems and cause the cases of nerve inflammation or Guillain Barre syndrome. These are similar to cases seen after other infections such as campylobacter jejuni, mycoplasma, HIV, and Zika.

Ultimately, we are just beginning to unwind how Covid-19 influences the nervous system. What must happen now, Manji says, is that physicians become aware of these risks.

Abstract: Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi- disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro- thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms, which will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.