How COVID-19 affects your brain

'There are different reasons for brain involvement depending on how the virus has entered the body.'
'If the virus enters the brain from the nose, the impairment will be different as opposed to if the virus impairs other organs which in turn impair the brain.'
'If it affects the lungs or heart, there can still be brain changes from secondary effects of reduction in oxygen delivery, or reduction in blood supply to the brain.'

Patient A

A 71-year-old man, a COVID-19 patient with a history of recent liver transplantation was hospitalised after an episode of feeling lightheaded, insomnia and confusion.

After admission, he developed fevers and respiratory distress. He was intubated and EEG monitoring was begun.

He developed agitation and eye twitching, rhythmic movements of the head, mouth, and neck that were concerning for seizure-like activity.

Neuroimaging (CAT scans, MRIs) revealed periventricular white matter hypodensities. [Also called White matter disease which is responsible for about a fifth of all strokes worldwide and is a contributing factor in up to 45 per cent of dementias.]

Continuous EEG monitoring was repeated 32 days later for right face twitching and revealed multiple independent bilateral fronto-temporal focal electrographic seizures.

He developed fibrotic lung changes and had persistent respiratory acidosis.

The patient died after cardiac arrest.

[Edited for clarity]
-- A study by the University of Pittsburgh Comprehensive Epilepsy Center, Department of Neurology, University of Pittsburgh Medical Center, USA.

Patient A, above, was part of one, a single study, of the Electroencephalogram (EEG) of a COVID-19 patient.

The study looked at a total of eight patients. It was carried out by the university to add to a small body of evidence of neurological findings of COVID-19 patients.

Neurological manifestations of coronavirus disease had been reported, but had never been analysed and summarised.

Till October 2020.

Dr Zulfi Haneef, assistant professor, neurology-neurophysiology, Baylor College of Medicine, and Arun Raj Antony, associate professor, department of neurology, University of Pittsburgh Medical Center, collaborated to analyse and review 84 studies of EEGs of COVID-19 patients with neurological symptoms.

It is the first published review of EEGs of COVID-19 patients and helps both our understanding of the SARS-Cov-2 virus and enhances our ability to treat patients.

The review, published in,Seizure: European Journal of Epilepsy, underlines that EEG should be considered a diagnostic tool to evaluate COVID-19 patients with altered mental status and seizures.

"Mortality rates in patients with COVID have fallen and we believe that they can go back to a normal life, but these findings tell us that there might be long-term issues.

"Scientists have suspected that for long now, but our findings give evidence to back that up," Dr Haneef told Rediff.com's Swarupa Dutt over an e-mail interview.

You have analysed 84 studies on COVID-19 patients with neurological symptoms. How many patients does that comprise?

There were 614 patients in the studies, so basically our analysis was based on studies on these patients.

You have called your study a 'systemic review'. Explain.

Systematic reviews are invaluable to scientific activities. The rationale for such reviews is to provide the healthcare sector, researchers, and policy makers, who are inundated with unmanageable amounts of information, cogent data to enable decision making.

Systematic reviews establish whether scientific findings are consistent and can be generalised across populations, settings, and treatment variations.

So, as I said, our systematic review is based on EEG data of COVID-19 patients treated by the authors of the individual studies, mostly in hospitals.

[EEG is a test used to evaluate the electrical activity in the brain. Brain cells communicate with each other through electrical impulses. An EEG can be used to help detect potential problems associated with this activity.]

Why did you consider doing a systemic review?

The current literature on EEGs of COVID-19 patients is incomplete and suffers from low patient volumes.

Larger numbers enable you to find patterns that are otherwise not apparent, and also to get more data for the study.

We concluded our study in around four months.

Have any other systemic reviews been done on EEGs of COVID-19 patients?

No. Ours is the only published systematic review

We have 84 studies in our systematic review, more have been done since we published our review.

This and other research is always in evolution. Bigger and better studies happen all the time, which is how scientific knowledge advances.

What are the top five findings of your review?

Broadly speaking, they are:

1) Brain involvement is not uncommon in COVID-19 patients. When EEGs were done continuously, 98 per cent of the patients showed abnormality.

2) Brain involvement seems to be more common in the frontal lobes of the brain.

3) When EEGs were done it was observed that seizures occur in 1 in 20 patients.

4) We found that 2/3rds of the patients showing symptoms of brain impairment were male, with an average age of 61 years.

5) Children can also be affected with brain involvement and seizures.

Is the virus primarily responsible for causing the abnormal EEG readings in the brain in the studies you analysed? Alterations in oxygen intake, heart problems etc are all Covid-induced, am I right?

Yes, if the virus directly enters the brain it can cause abnormal EEG findings.

On the other hand, if it affects the lungs or heart, there can still be brain changes from secondary effects of reduction in oxygen delivery, or reduction in blood supply to the brain.

What would be the percentile of the COVID-19 patients who showed brain impairment in your study?

When EEG was done continuously, it can run for days, 98 per cent of the patients showed abnormal graphs.

When done routinely, usually 20 minutes, 69 per cent were abnormal.

However, this is not to be confused with the percentage of COVID-19 patients who will have brain abnormalities.

Our studies were on patients with suspected brain involvement who were asked to get an EEG test for confirmation.

A previous study on all COVID patients showed 4/5 had some neurologic involvement (although even headache and muscle pain were included in this count), and 1/3 of those had brain involvement, which is a more accurate representation.

We found abnormalities in more than 600. Before, when we saw this in small groups we weren't sure if this was just a coincidence, but now we can confidently say there is a connection between brain impairment and COVID-19.

How does brain impairment in a COVID-19 patient show up?

Well, largely altered mental state (confusion) was the most common reason the patient went in for an EEG in our series.

Seizures also occurred in some patients. Going by our findings, the most common red flag is an altered mental state.

Which means, the patient is unnaturally drowsy, not very responsive, or frankly confused.

What is 'not very responsive'?

The patient is not responsive to external stimuli (calling out to the patient, not responsive to touching, shaking etc).

The patient may also be inattentive and disorientated.

Or/and somebody who is very drowsy, or frankly obtunded.

[Obtundation is a state similar to lethargy in which the patient has a lessened interest in the environment, slowed responses to stimulation, and tends to sleep more than normal with drowsiness in between sleep states.]

But brain impairment does not manifest in all COVID patients. Why?

There are different reasons for brain involvement depending on how the virus has entered the body.

If the virus enters the brain from the nose, the impairment will be different as opposed to if the virus impairs other organs which in turn impair the brain.

A study in the Lancet Psychiatry found brain complications in 125 seriously ill coronavirus patients in UK hospitals. Nearly half had suffered a stroke due to a blood clot while others had brain inflammation, psychosis, or dementia-like symptoms. This was in June 2020. What more do we know now?

We did not look at brain strokes in our study. This was a study on patients who had EEG testing done (which looks at brain wave activity or how the brain functions).

EEG is usually done to look for seizures. In our study, 5 per cent of the patients in our study had seizures.

Going by your study, it is truly frightening to note that the damage to the brain is irreversible. Which means the recovery battle has just begun for COVID survivors?

Although most of our studies had brain involvement to some extent, it is important to note that we looked at patients who had an EEG to begin with, or brain involvement was suspected.

I would not say that most patients with COVID have impaired brain activity, but it would be true to say that in those COVID patients who had an EEG done, many had brain involvement.

Many of these may not be irreversible. Some may be irreversible.

A long term follow up would be needed to say what the chance is for irreversible brain damage, something our study was not designed to answer.

Also, this was not a study that we did on our patients. It is a systematic review which looked at 84 different studies.

In stroke patients, while the part destroyed by the stroke does not repair itself, synapses build new contact points to neurons, bypassing the affected area of the brain, which brings back some normalcy to the patient. Why do we not see this in a COVID patient with brain impairment?

Brain plasticity as you describe it, is certainly possible in this group of patients too.

As noted above, we do not have an answer the likelihood of permanent brain damage.

But if the extent of damage is minor the patient is likely to recover; may be not if the brain damage is excessive.

More major involvement like seizures (seen in 5 per cent of this group, again of those suspected to have brain involvement) may indicate possible long-term consequences.

Is it possible that a recovered COVID patient who does not exhibit any brain impairment, has a normal EEG, at the time of discharge, suddenly develop clots or a heart attack as a result of the infection?

It is certainly possible. What the chances are would be speculative.

I'm not sure if somebody else has looked at this particular aspect.

Your study establishes a connection between the entry point of the virus (the nose) and the part of the brain that is located directly above the nose (the frontal lobe). Can you elaborate?

COVID-19 attaches to ACE (angiotensin converting enzyme) receptors which are present in the nasopharynx (the area behind the nose in the throat).

The frontal lobe of the brain is directly above the nasopharynx and has direct connections between them via olfactory nerves -- the nerves that help you smell.

There is a theory that this is the mechanism of viral entry to the brain.

What we found is this: 50 per cent of our patient group had impairment in the frontal lobe and 1/3rd of all seizures were frontal in origin.

We need to try EEG on a wider range of patients, as well as other types of brain imaging, such as MRI or CT scans, that will give us a closer look at the frontal lobe.

Why is it that not all the patients developed the same impairments in the frontal lobe?

The studies we analysed, quite often, said frontal lobe impairment was involved. That got us interested and we explored the reason.

There are different reasons for brain involvement/impairment.

The brain could be affected because of the COVID-19 virus entering through the nose (the nasopharynx) and therefore affecting the frontal lobe of the brain is impaired.

If the brain involvement/impairment is because of low oxygen or blood supply because the virus has affected the lung or heart, then a more general brain impairment is seen in any of the other lobes of the brain -- temporal, parietal, or occipital.

Your study says that brain involvement in COVID-19 could be more common in older males. Why? Why not in older females? There are studies that have found microthrombi in patients in their thirties.

These are the numbers we found in our group. The reason for this age/sex distribution is unclear.

I think this goes along the general trend of the COVID-19 virus causing more symptoms in the elderly, particularly in males.

There have been studies done on that aspect.

It will be nearly a year since the virus made landing, why is it still such a work- in-progress? Why are there studies that completely negate the findings of other studies? Why are scientists still unsure about the extent of damage the virus causes, its virulence, prevalence of antibodies etc?

Less common findings like brain involvement and therefore impairment take time to show up as a common pattern.

Although reports of brain involvement have been popping up since earlier in the year, most reports are on a single patient or less than 40 patients.

For instance, there were only two large-ish studies in our review -- one on 53 patients and one on 111 patients -- which provide wider data to base a systemic review.

This motivated us to put together these studies and derive a larger number of patients (617 in our compilation) to give more reliable results.

Thereon, there will be still more reports, on larger groups, by other scientists, and that is just the way medical knowledge advances.

How well is India fighting the pandemic? We will soon have over a crore (10 million) Covid cases. What did we do right and what did we do wrong?

I don't think there is a right or wrong answer yet. The final word is still to be written. The pandemic is not over.

Countries which seemed to have made early gains have shown rebounds.

I think this is a question for the future when all is said and done -- we can look back and see who did the right things and who did the wrong things!

India and the US have large numbers of patients. But we don't know yet if this is necessarily the worst possibility among all options.

And finally, when will we be able to go back to living our pre-Covid lives?

I'm honoured you thought I could answer that question! I don't think anybody knows.

If I were to guess, I'll say 4-5 years. But my guess is as good as anybody else's.

• The War Against Coronavirus