Neurological Signs, Symptoms and Diseases following COVID-19

Part I – Anosmia (loss of smell) and Parosmia (distorted smell)

(see end for a summary of key take-aways)

To all the followers of my blog, I am sorry that it has been so long since I last posted. I am going to pick up again in the series of blog posts on the long-term health consequences of COVID-19, and this current blog piece begins a look at neurological health effects resulting from COVID-19.

Part of my hiatus was due to time deadlines that had to be met for the book Dr. Epperly and I have written and will soon be released in April by Johns Hopkins University Press. For those of you interested in learning more about our book, or potentially wanting to pre-order a copy, you can read more at https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak. Our book is entitled, “Preparing for the Next Global Outbreak” and it will be released on April 18, 2023. If you scroll down the page, you will find a description and a chapter outline, and if you scroll all the way down, you will find reviews and endorsements of the book by faculty members of the Harvard and Yale schools of public health, by a world-renown epidemiologist who served on the White House Transition Team related to the national COVID-19 response, a vaccinologist who led the team that developed a COVID-19 vaccine for use in middle and lower income countries, a critical care physician who also serves as a national medical correspondent for a number of networks, and a microbiology faculty member from our own College of Western Idaho.

Back to the long-term health consequences of COVID-19. We are learning a lot. For the rest of this blog series, we will focus on different parts or functions of the body. This blog post will begin to look at what we are learning about the neurological health consequences of COVID-19. Before we begin, it is important to make sure we understand the limitations of what I will present.

1. The science is still evolving. We know a lot more today than at any prior point in the pandemic, but we will no doubt learn much more over time. Keep in mind, we often don’t develop a comprehensive understanding of viruses like SARS-CoV-2 for years, if not decades.
2. While we are discussing “long-term” health consequences, keep in mind that many of the studies conducted are based on months or at most two years of follow-up. Therefore, it is difficult to know at this point whether someone who develops neurological symptoms will eventually improve or whether the symptoms are likely to persist or even progress over time.
3. It is important to remember that studies of predominantly adults may not necessarily apply to children, that studies involving men may not necessarily apply to women, that animal studies may not completely represent what happens in humans, that the findings from autopsy studies may not represent the pathology that exists in persons who survive COVID-19, and that studies based upon small numbers of patients may not hold up when studies of large numbers of people are done in the future.
4. Keep at the top of your mind that there are many factors that may determine whether someone develops any of the health consequences we are going to highlight over the remainder of this blog series, such as their age and gender, their medical history, their prior infection history, their vaccination history, the timing of whether infected or vaccinated first, which variant they were infected with, the viral load associated with their infection, what therapies they received, the severity of their illness, their genetic make-up, and the status of their immune system before and after the infection.
5. We also must consider the possibility that different underlying pathophysiological processes may be at work in different people who appear to have the same long-term health condition. For example, perhaps persistence of the virus may be causative of a condition in one person, whereas the same condition in another patient is due to autoantibodies generated by the infection. Further, we must also consider that multiple pathophysiological processes can be occurring in one or even all patients with the post-COVID condition, e.g., perhaps there is both virus persistence as well as antibodies.

I will provide a lot of information, and I will also provide footnotes with links to the studies from which I base the review in case you want to look at any of these studies in more detail. Also, refer back to my earlier blog posts in this series if you need to review the virology, immunology or pathophysiology that is the basis for much of our discussion. Further, remember to review the blog post on interpreting clinical studies. In addition, at the end of each blog piece, I will summarize the learnings for you.

Anosmia – Loss of Smell

One of the most common questions I get from people concerning neurological sequelae from COVID-19 relates to anosmia – the loss of the sense of smell. Why do some people lose their sense of smell, what does it signify and will it resolve?

It has been reported that somewhere between 30 – 70% of patients following COVID-19 experience loss of smell, a decrease in their sense of smell or a distorted sense of smell, though the frequency has varied over the pandemic and perhaps the rate is different with different variants of concern. To those with their sense of smell intact, this might seem nothing more than an annoyance, but in fact, it is often quite distressing to patients and in severe cases can lead to life-threatening weight loss due to the accompanying loss of sense of taste and enjoyment of food. In most people, their sense of smell returns within a month, but in others it may persist.

There have been various hypotheses as to how SARS-CoV-2 induces loss of smell. These include indirect effects of the viral infection causing inflammation, swelling and potentially loss of olfactory epithelial cells (these are the cells lining the olfactory tissues); inflammation and loss of axonal neurons (these are the nerves involved in transmitting signals from the nose to the brain); inflammation and disruption of the microvasculature (small blood vessels) (specifically endothelial cell dysfunction, endothelial cell injury, endotheliitis [inflammation of the cells lining small blood vessels], and resultant disrupted microcirculation) that supplies the olfactory nerves and tissues given our knowledge that SARS-CoV-2 attacks cells that line these blood vessels; or direct viral invasion and resulting damage to the olfactory tissues, nerves or even portions of the brain associated with processing smells. Given the ability of the body to repair many of these tissues over time and the potential for some nerves to regenerate over time, it is expected that many patients will recover their sense of smell, but it is less clear whether the loss could be permanent in others.

A study published in JAMA Neurology on April 11, 2022 sheds some light on some of these questions.[1] In this cohort study, the investigators examined 23 deceased patients with COVID-19 and 14 matched controls between April 7, 2020 and September 11, 2021 (this time period would mostly have involved the original virus, Alpha and Delta). The olfactory bulb and tract (the olfactory sensory nerves that run from the nasal passages up to bulb in the front part of the brain at the base of the skull just above the nasal passages and then connect to portions of the temporal lobe (where we become consciously aware of smells), the hippocampus (where we form memories of smells), the amygdala (that triggers emotional responses to smells), the hypothalamus (in the center of the brain where multiple senses are routed and connected to our autonomic nervous system) and the reticular formation (where certain smells can elicit visceral responses, e.g., some smells triggering nausea or vomiting) in the back of the brain) was dissected, collected and evaluated by histologic exam (examination of stained tissues under the microscope); electron microscopy (a microscope so powerful that you can see the components of individual cells, including viruses; droplet digital polymerase chain reaction (this allows for the detection of nucleic acids that make up the SARS-CoV-2); immunofluorescence and immunohistochemistry (these methods allow one to look for specific proteins or other targets by using antibodies against those targets, and in the case of immunofluorescence, the binding of antibodies to a component of the virus causes the antibodies to light up vividly under the microscope). The investigators noted severe nerve damage, as well as disease of the small blood vessels involving the brain’s olfactory tissues in the deceased patients with COVID-19 compared to the controls, and these findings were more severe in the patients who died with COVID-19 who had complained of loss or disturbance of smell prior to death. In some cases, the degree of nerve damage was so severe that it would be expected, had the person survived, that the loss of smell or disturbance of smell would likely be permanent.

One hypothesis as to why anosmia may occur is direct invasion of the olfactory tissues by the virus. However, in this study, SARS-CoV-2 was detected in olfactory tissue only in 3 patients using droplet digital PCR or immunofluorescence, suggesting that olfactory pathology in most persons is not mediated by direct infection or injury to the nerve by the virus.

Endothelial cell (cells that line blood vessel walls) injury and dysfunction is common and well-documented in patients with COVID-19.

This study suggests that SARS-CoV-2 infection can damage the nerves that make up the olfactory bulb and tracts and damage the small blood vessels that are critical to the health and perfusion of these nerves without direct viral invasion.

Another study[2], also published in April of 2022, attempted to answer the question about what causes anosmia and the time course of recovery. Unlike the prior study in which the olfactory tissues can be examined post-mortem, obviously, this cannot be done in surviving humans. Therefore, the investigators used Syrian golden hamsters as an animal model, given that it is known that in many respects COVID-19 has similar manifestations in these hamsters as in humans.

The hamsters were inoculated with SARS-CoV-2 through their nasal passages at 6-weeks of age and samples were collected at several time points. Using immunofluorescence (antibodies against the virus that light up under the microscope when attached to the virus material), the investigators detected a significant number of SARS-CoV-2-positive regions throughout the olfactory epithelium (the cells that line the nasal passages) at 2 days post-infection (dpi), but not at 8 dpi (signifying that the hamsters were able to clear the virus from their nasal passages similar to humans and roughly on the same timeline). Interestingly, SARS-CoV-2-infected cells were observed not only superficially but also deep within portions of the nasal passages. The SARS-CoV-2 antigen was not observed in mature olfactory sensory neurons (OSNs) (these are the nerves that detect smells and transmit the signal from the nasal passages up towards the brain but in cells around the OSNs, mostly supporting cells (SCs). There are two types of SCs, but the ones of most concern for our purposes are the sustentacular cells that serve to provide metabolic and structural support to the olfactory epithelium and nerves. SCs are known to express the ACE-2 receptors that allow SARS-CoV-2 to bind to the cell membrane and enter (infect) the cells.

The numbers of SCs significantly decreased in the two of the four areas of the nasal passages and could not be determined in the one area due to the complete loss of the olfactory epithelium at 5 dpi, although the damage was recovered almost completely in all regions by 21 dpi. Interestingly, no SARS-CoV-2 antigen was detected within slices of the whole brain, including the olfactory bulb (OB) (this is the beginning of the main olfactory nerves – one on each side – that connects to the brain. It sits at the base of the brain, inside the skull, just above the nasal passages, with tiny branches (olfactory sensory nerves) that extend into the nasal cavity) and hippocampus.

The data from this study suggest that SARS-CoV-2 did not infect the brain parenchyma or that the level of infection was below detection limit, although some previous research has detected SARS-CoV-2 RNA and viral antigen in the brain.

Moreover, the researchers found that the olfactory epithelium thickness transiently decreased at 5 dpi but recovered fully by 21 dpi, as was the case for the SC numbers. Nevertheless, the density of mature olfactory sensory nerves did not completely recover up to 42 dpi, suggesting that the maturation of olfactory sensory nerves may be delayed and/or incomplete.

Such uneven damages to the olfactory epithelium may induce the unusual pattern of odor-induced activity in the olfactory bulb and contribute to development of parosmia (abnormal/distorted smells) during the recovery process.

These trends were also observed in the olfactory bulb, in which olfactory sensory nerves connect to clusters of nerves (called glomeruli) that all detect similar kinds of smells.

In the olfactory bulb, the density of the olfactory sensory nerve axon terminal of each glomerulus was significantly decreased within regions that contained cells with a certain enzyme. Interestingly, the size of the glomeruli themselves decreased not only in those regions, but also regions with cells that did not have that enzyme, suggesting that the multiple mechanisms may be in play that impacts olfactory bulb damage. These data indicate that SARS-CoV-2 infection impacts odor information processing within the whole olfactory bulb, but especially prominent in regions with cells containing this particular enzyme.

The researchers also examined the impact of SARS-CoV-2 on higher brain areas, including the piriform cortex (PC) and the hippocampus. Their findings indicate that SARS-CoV-2 infection in the nostril triggered the activation of microglia and astrocytes (these are structural cells in the brain that promote connections between nerve cells in neural circuits and that assist in the remodeling and repair of these circuits) even in the hippocampus, and that the impacts are significantly different in each layer of these structures. Thus, an interesting question could be posed as to whether the activated microglia and astrocytes could induce any changes in the neuronal circuits?

There are many reports that reveal glial cells induce synaptic modulation, synaptic loss, synaptic plasticity, and change of synaptic density. These changes may be associated with dementia. Therefore, the researchers did further examination of tissue from the hippocampus. Their findings may be associated with the prolonged activation of microglial cells, most notably significant at 42 dpi. These results suggest that intranasal inoculation of SARS-CoV-2 induces glial cell activation and changes dendritic spine density within the higher brain regions, including the hippocampus. These may underlie long-lasting sequelae of SARS-CoV-2 infection including depression, memory impairments, and brain fog, although more evidences to show synaptic dysfunction is needed.

Finally, let’s look at one more study[3]. This study was published as a pre-print on August 31, 2022. This study attempts to address the question as to whether different variants are more or less likely to cause the neuropathology that results in anosmia, again by using Syrian golden hamsters. To do so, they infected hamsters with different forms of SARS-CoV-2 – the original SARS-CoV-2, its ORF7-deleted mutant (ORF is open reading frame – a segment of genetic material that is part of the virus, but not its spike protein), and three variants: Gamma, Delta and Omicron/BA.1.

The investigators identified that SARS-CoV-2 Wuhan and the variants Gamma, Delta and Omicron/BA.1 are all capable of invading the brain of Syrian hamsters and of eliciting a tissue-specific inflammatory response. They were also able to demonstrate that SARS-CoV2 infects the olfactory bulbs, but the clinical profile, including the olfactory performance, is highly dependent on the variant. Fascinatingly, 62.5% of SARS-CoV-2 Wuhan-infected animals (compared to only 25% of the hamsters infected with the recombinant Wuhan strain with the ORF7 deletion) presented loss of olfaction; only 12.5% of Gamma-infected animals lost olfaction completely with 62.5% presenting an impaired olfactory performance (i.e., longer time to find the hidden cereals). In contrast, none of the Delta or Omicron/BA.1-infected animals presented signs of olfactory impairment.  

Remarkably, even if the olfactory performance differed according to the variant, positive viral titers were detected in the olfactory bulbs of animals from all infected groups, with Gamma-infected animals presenting the highest titer at 4 days post infection. These findings were corroborated by the detection of genomic viral RNA in the olfactory bulbs of animals from all infected groups as well.

When the animals were sacrificed and the brain was examined for presence of virus, the olfactory bulbs were the major infected structure in the brain.

Further, deletion of the ORF7ab sequence in the ancestral virus reduces the incidence of olfaction loss without affecting the clinical picture nor the neuro-invasiveness.

The authors conclude that the olfactory pathway is the main entry route by SARS-CoV-2 into the brain and corroborates the neurotropic potential of SARS-CoV-2 variants. Neuro-invasion and anosmia are therefore independent phenomena resulting from SARS-CoV-2 infection.

Key Take-aways:

1. Anosmia (loss of the sense of smell) is a frequent symptom with SARS-CoV-2 infection, and it can be a long-term consequence of COVID-19. While it appears that the majority of persons infected will regain their sense of smell within a month, some people do suffer from persistent anosmia, and it is possible, though not certain, that this could be permanent in a minority of persons.
2. It appears from human population studies and animal models that the frequency with which anosmia occurs may vary with different variants, and may be highly dependent upon the presence or absence of particular genetic sequences known as ORF7a and ORF7b.
3. Autopsies of persons who have died with COVID-19 demonstrate that infection can cause significant damage to olfactory epithelial cells (cells that line the nasal passages); can cause indirect damage to the olfactory sensory nerves (i.e., damage from inflammation associated with infection rather than from direct viral infection of the nerves themselves); can cause direct viral invasion and at least a temporary reduction of the sustentacular cells, which are supporting cells for the olfactory epithelium and olfactory sensory nerves; and disruption to the small blood vessels in proximity to these olfactory nerve cells. At this time, it would appear that damage to the olfactory epithelial cells and mucosal lining of the nasal cavity may be the most important of these in determining whether a patient will experience anosmia.
4. While SARS-CoV-2 appears able to directly infect olfactory sensory nerves and the olfactory bulb, this does not appear to be the main way in which anosmia results from COVID-19. In most cases, the damage appears to be indirect and perhaps due to the immune response mounted against SARS-CoV-2.
5. The damage to olfactory epithelial cells (those that line our nasal passages) and animal studies that show variable damage to glomeruli within the olfactory bulb may help explain why some people develop parosmia (distorted sense of smell).
6. There have been reports that persons who develop anosmia with COVID-19 may be more likely to have other neurological signs, symptoms and sequelae than those who don’t. It has been postulated that the anosmia is indicative that the virus has gained entry to the brain tissues through ascension up the sustentacular cells and other olfactory tissues. Though this appears possible in some individuals, this does not appear to be the dominant pathophysiologic explanation for other long-term neurological manifestations of COVID-19, because both human autopsy and animal studies suggest that only a minority of subjects have laboratory evidence of direct viral invasion in neural tissues.
7. On the other hand, animal studies suggest that SARS-CoV-2 infection in the nasal cavity triggers immune, and possibly other, mechanisms of reaction in the brain that may be deleterious, particularly activation of microglial cells and astrocytes and damage to some dendritic cells. It is postulated, but remains unproven, that these changes may contribute to long-lasting sequelae of SARS-CoV-2 infection, including depression, memory impairments, and brain fog, possibly due to disruption of neuronal circuits in the brain, and that this may even play a role in the apparent increased risk for dementia following COVID-19 (more on this in a subsequent blog post).
8. There remains much to be learned about the neuro-invasiveness of SARS-CoV-2. While there is mounting evidence to support the capability of SARS-CoV-2 to be neuro-invasive in humans, animal studies suggest that the degree of neuro-invasiveness may be highly variant-dependent. However, these same animal studies suggest that neuro-invasiveness and impairment of smell do not result from the same process.
9. Although it remains uncertain, circumstantial evidence is mounting that reducing the viral dose (amount of infecting virus one is exposed to) may lesson the likelihood of developing anosmia, and by extension, perhaps lesson the likelihood of other neurological sequelae of COVID-19. The ways to reduce viral dose are effective masking and enhancements to ventilation and filtration of air indoors.

As I conclude part I, keep in mind

1. I may have missed some other studies out there that may be relevant to this discussion. Although I read clinical studies many hours each day, I know that I can’t possibly identify or read every study out there. If I have missed an important article, please bring this to my attention.
2. I have done my best to summarize what I think we know to date. I am not an ENT specialist or neurologist. I may not have gotten every detail correct. I do feel that I have captured the big picture, but I welcome being corrected if I screwed up a detail. Further, no doubt we will learn much more over the coming months and years. That new information may further elucidate what is happening, or it may show that something I stated above is no longer correct. I will bring these new studies to your attention the best that I can, and certainly will point out clearly if anything I wrote above is no longer correct.

Part II of this series of neurological signs, symptoms and disorders associated with COVID-19 will be forthcoming next week. When we complete the review of neurological problems, I will move on to cardiovascular signs, symptoms and disorders associated with COVID-19. Until then, be safe!

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[1] https://jamanetwork.com/journals/jamaneurology/fullarticle/2790735.

[2] https://www.nature.com/articles/s41598-022-09731-7#:~:text=The%20impact%20of%20SARS%2DCoV,dendritic%20spines%20within%20the%20hippocampus.

[3] https://www.biorxiv.org/content/10.1101/2022.08.31.505985v1.