Brainstem Dysfunction in Long Covid?

Long-COVID is a post-viral illness that can affect survivors of COVID-19 regardless of initial disease severity or age. The symptoms of long-COVID include fatigue, shortness of breath, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and more. The current theories to the possible causes of long-COVID include:

  • long-term tissue damage

  • viral persistence

  • chronic inflammation

In the last week there have been two pre-papers * that have added another theory to the mix - Brainstem Dysfunction.

The first if these is Shin Jie Yong et al in their paper "Persistent Brainstem Dysfunction in Long-Covid: a Hypothesis”.

What is the Brainstem? The brainstem lies between the base of the brain and the top of the spinal cord.

It is the structure that connects the cerebrum of the brain to the spinal cord and cerebellum.

It is composed of 3 sections - the midbrain, pons, and medulla oblongata from top to bottom.

It is responsible for many vital functions of life, such as breathing, consciousness, blood pressure, heart rate, and sleep.

The brainstem contains many critical collections of white and grey matter and has three broad functions:

  1. Serves as a conduit for the ascending and descending pathways connecting the spinal cord to the different parts of the higher centres in the forebrain.

  2. Contains important reflex centres associated with the control of respiration, the cardiovascular system, consciousness and autonomic functions such as digestion, salivation, perspiration, dilation or contraction of the pupils, urination, etc.

  3. Contains the nuclei of Cranial Nerves III to XII

In summary the brainstem is the most evolutionarily ancient part of our brain, but is still very complex and important.

  • it carries all of the information to and from those areas we do associate with higher intelligence.

  • It ensures the vital functions necessary to support those areas continue uninterrupted

So Yong et al split their "Persisting Brain Dysfunction Hypothesis" into two parts:

1. Brainstem tropism and damage

The brainstem has a relatively high expression of ACE2 receptors compared with other brain regions. We already know that the SARS-CoV-2 virus uses these receptors to enter the cells so it can use the machinery there to replicate. The researchers here are saying that the virus will be drawn towards the brainstem - in scientific terms “tropism”

"Viral tropism can be defined by the ability of different viral strains to infect different cell types and to induce acute or chronic infectious virus production as a result of infection"

Autopsy studies have found SARS-CoV-2 RNA and it's proteins in the brainstem. The brainstem is highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases.

2. Long Covid Symptoms and the functions of the brainstem

The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to Long COVID.

" As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and therefore IS long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome"

Guedj's paper entitled "18F-FDG brain PET hypometabolism in patients with long COVID" in the European Journal of Nuclear Medicine and Molecular Imaging Jan 2021

They looked at PET scans of 35 patients with long COVID (tested positive on PCR) and compared them to 44 healthy subjects controlled for age and sex. Patients were scanned at more than 3 weeks after initial acute symptoms in those who had persisting ongoing symptoms. All were scanned at the same medical centre.

They found that, in comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism.

Bilateral - meaning both sides of the brain

Hypometabolism - characterized by decreased glucose consumption in the cells. A simpler way to look at it is a decrease in the brain activity.

They found this feature in:

  • The olfactory bulb - this is a rounded mass of tissue that contains several types of nerve cells that are involved in the sense of smell. The olfactory bulbs receive information about smells from the nose and send it to the brain by way of the olfactory tracts.

  • The limbic/paralimbic area - this is the part of the brain involved in our behavioural and emotional responses, especially when it comes to behaviours we need for survival: feeding, reproduction and caring for our young, and fight or flight responses.

  • The brainstem - autonomic functions such as heart rate, digestion, respiratory rate, pupillary response, sleep, urination, and sexual arousal.

  • The cerebellum - coordination, precision and timing of movements, balance.

These hypometabolic clusters were highly discriminant to Long Covid sufferers. To explain this another way one could look at a PET scan with the above features and know that that patient would definitely have Long Covid, and you would be right 100% of the time!

These clusters of hypometabolism were significantly associated with those who had more functional complaints (brainstem and cerebellar clusters), and ALL associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia).

In a preliminary analysis the researchers found that those with olfactory symptoms had worse metabolism if they were treated with ACE drugs for high blood pressure and better in the 3 patients that had used nasal decongestant spray at the infectious stage. They suggest, as does Yong, that the ACE receptors are an olfactory gateway for viral tropism.

The researchers felt that these hypometabolisms were closely associated with the patients’ symptoms and so doctors would be able, through the use of PET scans, to identify these patients and potentially follow them up.

Some long haulers with persisting neurological symptoms or cognitive dysfunction are having a MRI scan of the brain which are reported as normal. As PET scans can determine between normal controls and those with long Covid with 100% accuracy, and can highlight areas of the brainstem which are not functioning causing a myriad of diverse symptoms, I am hoping that these two papers will attract more scientific interest and research in a currently neglected area of Long Covid.

* not yet peer reviewed and published

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