It was following her third visit to the pulmonologist, and a neurological examination, that Mrs S came to the Long Covid Clinic at Groote Schuur Hospital for neuropsychological assessment. It was clear that she was in great distress. She described feeling foggy and unable to concentrate, very unlike her usual self.

Her memory was patchy and she was terribly tired all the time. She struggled to keep track of conversations and had gradually begun avoiding social interaction. She was experiencing heart palpitations and breathlessness after minor exertions, and most of the time these episodes were accompanied by a ringing in her ears.

Unable to work as a result of these symptoms, she was on indefinite sick leave, filled with anxiety about her precarious employment status. Some days were better than others, but ever since her mild bout of Covid-19 eight months ago, Mrs S had forgotten what it felt like to be herself.

Cases such as that of Mrs S — where an initial viral infection appears to trigger another prolonged period of illness — are not unprecedented. Readers of writer-neurologist Oliver Sacks will be reminded of the encephalitis lethargica epidemic he describes in his book Awakenings, and the strange post-viral syndrome it left in its wake.

Between 1915 and 1926, encephalitis lethargica spread swiftly across the world, killing half a million people before vanishing almost overnight. Apparently caused by an enterovirus (a type of RNA virus that usually lives in the gastrointestinal tract), encephalitis lethargica was described by Sacks as a “hydra with a thousand heads” on account of the unpredictable and complex ways in which it would manifest.

Its distinctive mark was a kind of sleeping sickness, interrupted in some by agitation and insomnia. Most disturbing, however, was the post-viral syndrome associated with this disease. After a period of recovery — brief in some patients, years-long in others — symptoms would suddenly return. Often these were the same symptoms that had originally presented, but sometimes a severe and unusual form of Parkinson’s disease emerged instead, as was the case for Margaret A, whose story Sacks tells.

Margaret A was one of the last recorded individuals to contract encephalitis lethargica. Sacks describes her as a young woman born to an Irish immigrant family in New York, who until her 17th birthday lived a decidedly average, but for the most part active and contented life. In 1925, at the age of 17, she took ill and could only be roused from a deep slumber for meals or a bath, and during these moments she was overcome by intense psychological anguish and depression.

First ascribed to the shock of her father’s death, Margaret A’s illness was eventually diagnosed as encephalitis lethargica. She remained acutely ill for 10 weeks, after which time she appeared to make a gradual, but full recovery. For the next three years, Margaret enjoyed a normal life, returning to sport, social engagements and her work as a bookkeeper. Everything changed around 1929, however, when she began showing signs of Parkinson’s. She developed a tremor in both hands and lost her sense of balance. Her emotions were similarly affected, now seemingly unhinged and out of her control. Her body’s internal clock flip-flopped; daytime was marked by drowsiness, and at night she stayed awake, often consumed by an insatiable hunger. 

Not all encephalitis lethargica victims were as unlucky as Margaret A. Some recovered fully and stayed so. But the vast majority shared Margaret A’s fate, descending into psychiatric and neurologic disorder. Why encephalitis lethargica led to these extreme forms of post-encephalitic syndrome is a mystery that has never been solved. Doctors were unable to detect any sign of lingering infection in sufferers and their ordeal remains medically unexplained even today.

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Not long after the first wave of infections in the Covid-19 pandemic, many people recovering from the virus started to report hard-to-place symptoms, even up to six months after infection. They called themselves Covid “long-haulers” and the now widely accepted term “Long Covid” was born.

Generally speaking, Long Covid is the post-viral syndrome associated with Covid-19. Individual experiences of Long Covid vary widely, however. In some cases, Covid symptoms persist long after a negative test. In others, an entirely new symptom profile emerges, either immediately following the initial acute phase of the illness, or after a variable window of time. In all cases, though, the SARS-CoV2 virus does not show up in diagnostic tests. The original infection is no longer present.

While the parallels between this post-viral syndrome and the one associated with encephalitis lethargica may seem alarming, there is little evidence to suggest that Long Covid sufferers are in for the grim ride of post-encephalitis Parkinsonism that Margaret A and others endured. Parkinson’s in particular is a disorder of the central nervous system (CNS), and we’re not seeing many signs of CNS disturbance in Long Covid. Rather, Long Covid symptoms have a more diffuse nature. They generally include fatigue, headache, brain fog, breathlessness, loss of smell or taste and depression. Heart palpitations, anxiety, dizziness upon standing, sleep disturbances and pins-and-needles are also frequently reported. Symptom profiles differ from patient to patient, but almost all patients report fatigue.

Fatigue symptoms and syndromes following infections are not especially rare. In addition to the post-encephalitis syndrome already described, syndromes have emerged following infection with Epstein-Barr virus, the Ebola virus, the human herpesvirus, the West Nile virus and Dengue virus, among many other viruses. It’s hard to know why these syndromes occur in some individuals, but not others. A recent large-scale study on Long Covid found that, during the acute stage of Covid-19, five symptoms, in particular, are predictive of whether one develops the post-viral syndrome: fatigue, headache, breathlessness, hoarse voice and muscle pain. A great deal more research into the phenomenon is needed before any real conclusions can be drawn.

One fact that is becoming increasingly clear, though, is that Long Covid is showing up in much higher proportions in women compared to men. That depression and anxiety are high on the list of Long Covid symptoms are particularly problematic for women. Especially in the early days of the pandemic, disillusionment grew quickly among Long Covid patients, who were told, more often than not, that their symptoms were probably a result of anxiety and were therefore psychogenic in nature. Given the long history of gender bias in the medical profession, one cannot help but wonder whether this low-hanging fruit would have been the go-to diagnosis had most of these patients been male.

As the work of Dr Kate Young and other public health researchers has shown, doctors have filled their knowledge gaps about women’s health with hysteria narratives. Since at least as far back as the 5th century BCE, women suffering from endometriosis, for example, have been labelled immoral, rebellious, or just plain crazy. Today, endometriosis is recognised as a debilitatingly painful disease of the female reproductive system that affects about one in 10 women — but it can still take up to 10 years for women to receive a diagnosis and proper treatment, because their symptoms are not taken seriously.

Chronic fatigue syndrome (CFS), formally known as myalgic encephalomyelitis, is another well-known case in point, with even a Wikipedia page dedicated to: “Controversies related to chronic fatigue syndrome”, evidence of the debate that has engulfed this complex illness for decades. There is a lot surrounding myalgic encephalomyelitis that remains unknown: symptoms tend to spread beyond the borders of a single medical speciality and they also tend to not fit with any established medical category. Until only recently, this ambiguity led to the suspicion that symptoms were purely psychiatric in nature. The mind, it seems, can be a murky, nebulous place, one that all too often houses the doubts and insecurities of medicine.

In the end, despite evidence to suggest that CFS may be linked to autoimmune processes or to brainstem changes, there is a strong camp that still maintains that it is little more than hysteria.

There is something about fatigue — perhaps its wholly subjective nature, perhaps its higher prevalence in women — that goes against the societal norms of efficiency and productivity and that ruffles the feathers. In the case of CFS, this blind spot has radically stifled research into the condition’s underlying causes and prevented millions of people from being adequately cared for. How do we avoid this fate for Covid long-haulers?

A good starting point is understanding two simple ideas about our neuropsychology. The first is that sickness is just as much an emotional process as a physical one. The second is that the immune system works differently in male and female bodies. If we accept these ideas, we might be able to arrive at a scientific explanation for why anxiety and depression appear in post-viral syndromes such as Long Covid, and in higher rates among women, without us having to cast these syndromes and their sufferers to the denigrated wards of psychosomatic illness. Let’s explore these concepts in more detail.

No one really knows why post-viral syndromes occur, but what they all have in common is that they begin with an infection — with a period of sickness, in other words. What happens in the body during periods of sickness, and how is this experience both a physical and an emotional one?  

We need only think back to the last time we were ill ourselves to understand the way illness hijacks our body and mind. When we are ill we feel drained of energy, our body aches, and our desire to socialise diminishes. We feel woozy and sluggish. Passions of all varieties fade. We lose our appetite and usually retreat, forlorn, to a warm, safe spot.

Scientists coined the phrase “sickness behaviour” in the 1980s to refer to the dampened motivational state that accompanies infection. It is believed to be orchestrated, at the neural level, by inflammatory cytokines that turn down the activity of several neurotransmitters — including dopamine and serotonin — while at the same time increasing the turnover of hormones in the central stress pathway, which spans the hypothalamus, the pituitary gland and the adrenal glands. These mechanisms have one shared purpose: combating the infection.

Technically, our body could fight this internal battle without us being the least aware of it. But sickness doesn’t work like that, and for good reason. We experience sickness consciously because the feeling of being sick has a function. Feelings are the workhorses of the mind. They make us do what needs to be done to support the body, which in the case of illness is not very much at all. In the academic literature, sickness is widely accepted as an evolved strategy for overhauling motivational priorities to redirect energy resources towards the fight against infection. In other words, you are meant to feel tired and listless; this feeling ensures that you don’t expend unnecessary energy. The body is commanding you to stop and rest.

Since inflammation in the body is closely intertwined with dopamine, serotonin and other neurotransmitters that regulate mood, motivation, and emotion, it should not surprise us that physical illness so often co-occurs with anxiety and depression. If anxiety and depression are present, that should not preclude the presence of a real underlying physical ailment — on the contrary, it should precisely signal to us that the body needs help.

What could be happening with Long Covid and other post-viral syndromes is that, even though the body is no longer infected with the virus, the immune system is still switched on, in battle mode. The body remains inflamed, mood and emotion remain off-kilter and intense fatigue continues to govern daily life.  

For clues as to why women are more prone to Long Covid than men, we can look to the physiological differences between the male and female immune systems, linked in turn to the different male and female reproductive systems. For instance, we know that testosterone, found in much higher concentrations in male bodies, dampens down the activity of the immune system. This might be why men tend to have a more severe course of illness in response to viral infections. It would also explain why there are fewer incidences of autoimmune diseases in men, (diseases in which the immune system attacks the cells of one’s own body).

Indeed, estrogen, found in much higher concentrations in female bodies, plays a key role in switching on the various genes that orchestrate an immune reaction. This gives female bodies greater acuity in detecting and responding to a pathogen. On the other hand, female bodies must work harder not to classify a developing fetus as a parasite.

Progesterone, a hormone involved in the menstrual cycle that also helps to maintain a healthy pregnancy, partly achieves this task by suppressing T-cells, a type of white blood immune cell, when necessary. Immune activation and regulation are clearly far more nuanced and complex in female bodies, introducing more room for error — and also introducing the possibility of the immune system remaining switched on or out of whack long after the threat itself has left the body. Any one of these factors might explain why Covid itself is more prevalent in men, while Long Covid is more prevalent in women. 

In the case of Mrs S, we puzzled over what to make of her performance on our neuropsychological tests. On most of them, she did surprisingly well given our expectations. But there were some red flags. When faced with a complex problem to solve in her head, she seemed to meet with a blank. The expected flurry of thoughts and ideas that usually arises during problem-solving appeared to have flatlined. We could see evidence for this flatlining in her test scores, but there were inconsistencies, making the results inconclusive.

Medically unexplained conditions, which are far more common than we might think, ask of physicians that they embrace a simpler, much lower-tech, more relational role in their care of patients. These patients will remember a time in their lives when they were healthy, when they were whole. As a first step, doctors seeing these patients can try to get to grips with the pain of this loss by empathising with their patients. It needn’t be psychotherapy. Perhaps what most people will be looking for from the healthcare system is the sense that someone is listening to them and taking them seriously — that not only will their treatment be prioritised, but their humanity too, so that even when there seems to be no clear treatment available, we do not dismiss people’s painful symptoms.

If there is a message in any of this, it is that we will fall short of finding an acceptable explanation for Long Covid if we seek out only the mechanical facts and ignore the emotional, social and cultural world of the body, which defines what it is like to be inside a particular body, and which makes every person unique.

Tales like those from Sacks and others remind us that even disease is personal. Just as the post-viral syndrome that followed encephalitis lethargica was described as an “individual creation of the greatest complexity, determined not simply by a primary disease-process, but by a vast host of personal traits and social circumstances”, so too is it likely to be the case with Long Covid. Sickness is not just a physical response. It is fundamentally also an emotional process, and we cannot expect to completely separate the two.

Our work with Long Covid patients at Groote Schuur Hospital has shown us that, before we can even begin to untangle the possible causes of the syndrome, it will be important to properly classify the spectrum of complaints that we are seeing from patients. This will involve a lot of careful listening.

Scientific reports on Long Covid are being churned out on an impressive scale, and while this should be reassuring, it is somehow not. The research lacks nuance and tends to capture symptom profiles with broad brush strokes. The feeling of fatigue is indicative. Fatigue is similar to tiredness, but it is not just tiredness. It can feel like drowsiness or weakness or boredom, but it’s much more than any of those things. It can engulf you post-feast, post-nap or at random.

Fatigue can be felt in the body or in the mind, or in both places at once. If we want to be particular about who is most vulnerable to fatigue, and why, then we should also get specific about what we really mean by this term. And we need to listen to our patients for that.

Similar problems crop up when one talks about “brain fog” or “cognitive dysfunction”. These are frightening terms, but they are also not very meaningful in and of themselves. It might be possible to eradicate the fear in an intimidating phrase like cognitive dysfunction if we knew, for instance, that it could be explained almost entirely by its co-occurrence with fatigue. These are the sorts of questions our research is hoping to unravel.

If you have had Covid-19 or think you are suffering from Long Covid and would like to participate in our research, contact us at the following email address: [email protected] DM

The views expressed in this article represent the opinions of the authors and not those of their affiliated institutions.

Donné Minné is a postdoctoral fellow from the Applied Microbial and Health Biotechnology Institute at Cape Peninsula University of Technology in Cape Town. She is a registered clinical neuropsychologist with the Health Professions Council of South Africa and holds a PhD in Psychology from the University of Cape Town with specialisation in social neuroscience and neuropsychology. Her current research focuses on the neurocognitive and neuropsychiatric outcomes in Covid-19, and the role of psychosocial stress, inflammation and oxidative stress in neurodegenerative disorders like Alzheimer’s Disease.

Altay Yüce Turan is a neuropsychology master’s candidate at the University of Cape Town. His research focuses on characterising the mental aspects of Long Covid fatigue and is supervised by Professor Mark Solms and Dr Donné Minne. This ties into his broader research interests in understanding the mind and body in ways that help us better understand and help one another. His Twitter handle is  @AltayPsyGuy