Ask an Expert – Professor Ric Arseneau, MD, FRCP, MA(ed)

Dysautonomia is DYS-function of the AUTONOMIC nervous system (i.e., fight or flight / adrenaline). There are different medical conditions that cause dysautonomia or are associated with dysautonomia. We will focus on the dysautonomia associated with ME/CFS and CSS (central sensitivity syndrome).

Autonomic Manifestations are part of the diagnostic criteria of ME/CFS and include:

• Orthostatic intolerance – lightheadedness or feeling like you’re going to faint on standing
• Postural Orthostatic Tachycardia Syndrome (POTS)
• Hypotension – low blood pressure 
• Extreme pallor, nausea, and IBS
• Urinary frequency and bladder dysfunction 
• Palpitations 
• Shortness of breath or feeling like you can’t get enough air in

Symptoms of dysautonomia are also associated with other CSS: (e.g., fibromyalgia (FM), myofascial pain syndrome (MPS), POTS).

Interestingly, POTS is a separate CSS but is also used as part of the diagnostic criteria for diangosing ME/CFS. POTS can be thought of as a type of dysautonomia or a symptom of dysautonomia.

POTS is one of the common post-viral syndrome that we see with Long COVID. A study suggests that the POTS associated with Long COVID may be different in that it can be associated with low blood pressure. However, this study did not compare POTS in Long COVID with POTS in ME/CFS (unrelated to COVID). Low blood pressure is commonly seen in patients with ME/CFS who have POTS.

POTS is a disease of gravity. When patients go from lying to standing, the heart rate increases to compensate for gravity and ensure enough blood gets to the brain. However, the faster the heart beats, the less blood is pumped so rather than helping the patient gets lightheaded and may even faint. The classic manifestations of POTS are a heart rate that increases by 30 beats per minute or more from lying to standing WITHOUT a significant drop in blood pressure. Because low blood pressure can be seen with the POTS associated with Long COVID and ME/CFS, some physicians mistakenly think that the patient does not fulfil diagnostic criteria for POTS.

Luckily, POTS is one of the post-viral syndromes associated with Long COVID that responds well to treatment. Many patients only require salt supplementation to improve the blood flow to the brain (i.e., 9 g per day). Otherwise, POTS also responds well to medication’s (e.g., beta blockers, Ivabradine, Mestinon) and other non-mediation options (e.g.,compression garments). Many patients find that their POTS symptoms improve with time and management of Long COVID.

Low iron is not associated with ME/CFS or related CSS. Therefore, individuals with low iron (most commonly young women who menstruate) need to be evaluated for the cause of the low iron. Low iron itself (ferritin below 50) is associated with fatigue. Getting the ferritin above 50 can help with some of the fatigue but is not the cause of the ME/CFS.

If you are sick, you need to make sure to get plenty of rest and maintain your salt and fluid intake

The above is for other types of dysautonomia and I would not include it.

The diagnosis of dysautonomia in these conditions is based on symptoms without the need for special testing. However, dysautonomia can also be associated with other serious conditions (e.g., Parkinson’s disease) that may require special testing. The diagnosis of POTS itself is relatively straightforward. Many physicians mistakenly believe that patients require tilt-table testing to make a diagnosis. However, the NASA Lean Test Is more sensitive and more specific. The Canadian Cardiovascular Society Position Statement on POTS recommends against routinely performing tilt table testing.

The NASA Lean Test can be performed at home. Patient measure their heart rate before getting out of bed and for 10 minutes while leaning against a wall (there should be a spotter in case you feel faint). If the heart rate increases by 30 beats or more this is diagnostic of POTS. We recommend that the test be repeated on a separate day while measuring blood pressure to identify those patients who have a significant drop in blood pressure (or those whose blood pressure increases).

Gastroparesis (delayed gastric emptying), IBS with constipation, and constipation due to delayed transit time in the colon, can be associated with Long COVID and ME/CFS with or without POTS. We do not know the long-term history of these conditions due to the lack of research. However, the symptoms often respond to Mestinon. Small fibre neuropathy is commonly associated with ME/CFS, FM, and Long COVID. Again, we have a little data on the long-term prognosis. The symptoms, however, respond relatively well to the usual medication we use for neuropathic symptoms

Long COVID is associated with low serotonin levels. Therefore many patients with Long COVID report some improvement with SSRIs (for those with associated pain we recommend SNRIs instead). However, the role of these medications in POTS remains unclear. Some studies suggest that it can help while others suggest that it makes symptoms worse. Therefore, SSRIs and SNRIs or not usually part of the usual treatment options for POTS. However, we commonly use these medication’s for other reasons in this patient population.

Before we answer this question, we need to make a distinction between Post Covid Conditions (PCC) and Long COVID which is a post-viral syndrome. Although a naming convention has not been agreed upon, we use the one by the Mayo Clinic in Rochester, Minnesota. They suggest that we think of PCC as anything that can happen after COVID which they organize into three groups:

1. Tissue damage (e.g., lung scarring, heart damage, loss of taste or smell) and metabolic consequences (e.g., blood clots, high blood pressure, diabetes, high cholesterol)
2. Psychiatric/psychological manifestations (e.g., depression, anxiety, PTSD)
3. Post-viral syndrome – LONG COVID

Like the Mayo Clinic, we reserve the term Long COVID for those a post-viral syndrome in the absence of tissue damage. Many doctors and organizations do not make a distinction between PCC and Long COVID which is confusing and makes a lot of the medical literature difficult to interpret. Patients with post-viral syndrome of Long COVID tend to have completely normal bloodwork and investigations. However, special testing, which is not routinely available, does show many abnormalities.

The common post-viral syndrome associated with Long COVID include:

• ME/CFS 
• FM
• POTS
• MCAS (mast cell activation syndrome)

Studies show that vaccination against COVID reduces the chances of “Long COVID” by 50% (this likely includes PCC). We can therefore assume  that patients with pre-existing Long COVID are 50% less likely to experience significant worsening of their Long COVID symptoms. We encourage our patients to get vaccinated (except those who have had vaccine injury). A similar argument can be made for the use of Paxlovid and metformin during an acute bout of COVID in Long COVID patients

Brain fog is a very imprecise term but one that has made it way into our vocabulary.  Many people with Long Covid use it and it refers to things like problems attending, focusing, processing.  There are a huge array of potential contributors to brain fog which means that there is probably no single intervention that will completely alter or “fix” it.  Physiologically, many experts think inflammation at at the heart of the matter but, again, there is no “one” cause.

There is a vigorous debate going on pertaining how to best “sharpen” your brain.  In general, experts believe that challenging your brain through moderately difficult activities – often things that are unusual or new and are reasonably demanding – is beneficial as it can help accelerate the process of neuroplasticity that is at work.  In some cases, this can mean playing sudoku, in other cases, learning a language, or playing an instrument, and – perhaps – even engaging in some of the commercially available brain training programs which may help improve neuropsychological functioning.  

I’m curious if there is a pattern of Long COVID mental health characteristics aligning very closely with PTSD, but more specifically the primary and secondary traits of PTS

There is no “one” way to best manage these difficult emotions except to say – don’t do it alone.  Consider finding a mental health provider, a social worker, a member of the clergy or, really, anyone who can walk through deep water with you.  You’ll be glad you did.   

This experience – having a moment or two where your mind goes “blank” is a really terrifying phenomenon.  This is a fairly common among people with mild cognitive impairments of various kinds and while it is distressing is is probably not proof of any more severe problem, though it does generate a great deal of anxiety which, ironically, usually makes this pattern even worse.  

Experts continue to debate how to best facilitate healing of injured brains.  The key – as with almost everything – is to find a balance between engaging in activities and being exposed to stimuli that are too challenging and not engaging in activities at all.  I think the most appropriate course of action – if at all possible – is to consult with a speech and language pathologist (SLP) – SLPs are the content experts who are the best guides and authorities on brain injury recovery – you can find one in any moderate or large city.

Regarding PTSD, this is a syndrome that is very common in people with  Long Covid – it may differ slightly than more typical PTSD in its’ presentation but, in general, it is very similar.  In particular, people with Long Covid who have PTSD especially struggle with what is called medical avoidance – this is a concern because it leads them to miss appointments, avoid going to the ER or the hospital etc even when it medically called for. Treatments exist for PTSD, whatever the cause, and are highly effective – please considering  seeking out a qualified  provider who can help support you.  

Answers:

• Skin changes are noted in some people with post-exertional malaise, including as a potential early warning sign. While no specific mechanism for changes in skin color has been show in the scientific literature, one possible explanation for this skin color change may be dysautonomia resulting in shunting of blood away from capillaries near the skin. Relatedly, small fiber neuropathy sometimes can result in a white or mottled red-white appearance.
• It’s so hard to help children pace when they’re feeling good and having fun, because it doesn’t feel like “help” for anyone involved. For ideas on pacing in children to prevent PEM crashes, I recommend the blog posts by Long Covid Kids on Cautious Tortoise and Pacing Penguins.

Answer:

It’s clear immune dysfunction is a part of PEM. However, any hypothesis explaining PEM must also explain the proximate cause of observed deficiencies in energy metabolism and consequent disablement. It’s perhaps more feasible that dysfunctional cellular energy production and utilization causes the characteristic immune dysfunction of PEM than the other way around. The fact that various studies have identified abnormal oxidative metabolism in various immune cells provides some support to this idea. A couple of models have been proposed to link metabolic and immune dysfunction, including the metabolic trap and itaconate shunt hypotheses. I look forward to more definitive data on these potential pathophysiological relationships that have relevance to treatment.

Answer:

Cognitive stressors are known precipitants of PEM crashes. However, neurocognitive pacing is such a huge challenge, especially for people whose jobs require significant brain usage; who enjoy reading, puzzles, and games; or who cultivate a vibrant internal world. Establishing time limits for reading, puzzles, and games and enforcing those limits with timers may help. Some people find meditation helpful to help turn down their thinking. Yoga nidra is a form of meditation that is accessible to people with PEM, because it is done while laying down in a “conscious sleep.” It’s also important to remember that different triggers are cumulative and may result in a crash. This means some people also find success with pacing activities that do not seem cognitive to build a reserve of capacity that can be used for cognitive activities. Pacing triggers such as physical activities and exposure to environmental stimulation also may help build a reserve that improves your cognitive symptoms and signs.

Answer:

• Pacing always involves balancing activities with rest. Even people without PEM pace their exercising! Early in managing PEM, the balance swings in favor of resting to manage symptoms and signs. Some people with Long Covid are able to return to some kind of physical activity without causing a PEM crash. Staying under the line of “just enough” and “too much” is particularly important for someone living with PEM, even if it is improving to the point that some exercise has become possible again, because future crashes are still possible.
• You are not going to exercise your way out of PEM by exercising more or harder. For someone with PEM, it’s still always better to do “a little too little” than “a little too much” physical activity. So, how can you find that line?
  • Focus on short term activities: Short intervals minimizing time spent above your anaerobic threshold heart rate with complete rest are a good place to start. Starting with activities done laying down (like breathing, stretching, and limb movements) will reduce the work of the heart, improving preload and reducing orthostatic intolerance.
  • Pay attention to how you feel: If you notice more PEM signs and symptoms after an exercise session, wait until they completely resolve for at least a couple of weeks before beginning again at a lower level.
  • Watch your biometric data: An increasing resting heart rate and lowering heart rate variability at rest may suggest a crash in the near future, even if you’re feeling good.
• Maybe the hardest part of being able to do a little exercise is wanting to do more exercise. Remember: less is still more, be careful with yourself, and to keep up with what got you to this point.

Answer:

• This is an excellent question that gets my standard, universally unsatisfying response: maybe. Of course, my response isn’t to make light of a difficult conversation, but rather to highlight the uncertainty of this issue.
• Historically, most people with PEM related to ME/CFS have needed to pace over the long-term, because of a recovery rate of around 4-8% or less. Recovery is tricky to define and identify, because remissions may be temporary.
• Recovery rates for people with PEM related to Long Covid appear more promising, which suggests that at least some people are able to return to exercising in some form.
• We clinicians and researchers are still inaccurate at predicting who may improve, and recovery is non-linear when it happens. So, it is important to pace carefully while experiencing symptoms and signs of PEM, even if the capacity and desire for some more physical activity may be starting to come about.

Answer:

• Dietary supplements are a mainstay of PEM self-management. A recent systematic review and meta-analysis did not yield promising results from neutraceutical treatments for PEM related to ME/CFS. There are a number of challenges in studying neutraceutical treatments, including patient selection, potency and quality, adequate masking/placebo controls.
• While there is no widely accepted regimen, many people find neutraceutical treatments helpful that may reduce inflammation and support mitochondrial, immune, cognitive, circulatory, and digestive functioning.
• In this online lecture, Dr. Jeannette Brown goes through common over-the-counter dietary supplements and their potential uses for people with Long Covid. It is oriented more toward primary care practitioners, but there may be some information to which you can point your own medical team.
• Dr. Martha Eckey, and pharmacist living with Long Covid, has done the most extensive survey work to date regarding the use of neutraceutical treatments in Long Covid and ME/CFS. Her results may serve as a starting point to understand, on average, how often various treatments may or may not help.
• Before starting any new medication or dietary supplement, make sure to consult a physician or pharmacist who is knowledgeable about potential interactions between drugs and supplements to avoid side effects and toxicity.

Answer:

• I always recommend making sure aching legs aren’t associated with circulatory problems that are treatable, so make sure to check in with your medical team.
• Aching legs may be a sign of immediate or short-term PEM. While prevention is the best “medicine,” some people have success with self-treatments like elevation and gentle recovery compression.

Answer:

• The diagnosis of PEM is usually made using basic information from asking questions and doing some basic medical tests. A digestible overview for identifying and evaluating potential PEM may be found in the paper by Grach et al. 2023. Perhaps the fullest case definition of PEM is the International Consensus Criteria for Myalgic Encephalomyelitis (ICC-ME), which was published in 2011 by Carruthers et al. In this case definition, you will find they don’t use the term PEM, but rather identify this phenomenon as post-exertional neuroimmune exhaustion, or PENE. The things I like about the ICC-ME are that it defines the post-exertional signs and symptoms comprehensively, distinguishes ME from atypical ME or idiopathic chronic fatigue, and comments on severity.
• Some people seek cardiopulmonary exercise testing (CPET) as part of the differential diagnosis of PEM and to document disability associated with it. People with PEM often have reduced aerobic capacity and workload at submaximal levels of exertion that are in line with the work of daily activities, which is worsened on the second day of a two-day CPET.

Answer: While who gets and who does not get Long COVID seems like the outcome of the lottery there are certain baseline characteristics that impact a person’s risk of getting Long COVID. While certain characteristics such as being hospitalized, female sex, higher body mass index, smoking, preexisting comorbidities, not receiving early antiviral therapy, and not being vaccinated are associated with an increased risk of Long COVID, sequelae of COVID-19 are seen in all populations are varying incidence levels.

EXPERT: Dr Daniel Griffin, MD PhD CTropMed CTH

Credentials:
Chief, Division of Infectious Disease and Travel Medicine | Optum / Tristate
Infectious Disease Specialist / Clinical Instructor of Medicine

Columbia University Vagelos College of Physicians and Surgeons
Department of Medicine-Division of Infectious Diseases
President –Parasites Without Borders

Answer:

While avoiding COVID-19 in the first place is the best way to prevent Long COVID, behavior modifications, masking, and improved ventilation can reduce the risk of exposure. Vaccines decrease the risk of developing Long-Term COVID-19 in adults, adolescents, and children. There has been some excitement about the possible impact of early use of metformin on the risk of developing Long COVID, but this requires a challenging regimen in the published trial and has not been repeated. 

There is also uncertainty whether early treatment with an effective antiviral such as nirmatrelvir or molnupiravir may reduce the risk of all post covid conditions in people who are vaccinated, unvaccinated, boosted, and with primary and SARS-CoV-2 reinfection. Multiple studies have demonstrated that treatment of acute COVID-19 with nirmatrelvir-ritonavir can reduce the incidence of major adverse cardiac events (MACEs) (cardiovascular death, myocardial infarction, stroke, new-onset heart failure or heart failure hospitalization or ventricular arrhythmia). 

Early treatment with nirmatrelvir-ritonavir during the first 5 days after symptoms onset is associated with not only major (reduction) in cardiac events and acute events such as hospitalization and death, but also a reduction in post-acute incidence of congestive heart failure, atrial fibrillation, coronary artery disease, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, and end-stage renal disease.

Despite compelling data that monoclonal antibody therapy can have dramatic impacts on acute COVID-19 outcomes, our investigations looking at the ability of early monoclonal antibody therapy to prevent Long COVID have not been encouraging. While studies of the administration of monoclonal antibody therapy have not clearly demonstrated a reduction in the development of long-term COVID, early administration of COVID-19 convalescent plasma (CCP) has demonstrated a reduction in cytokine levels and a lower odds of development of post-COVID conditions. Corticosteroids may exert a protective effect against the development of post-COVID-19 syndromes if administered appropriately to hospitalized patients with acute COVID

EXPERT: Dr Daniel Griffin, MD PhD CTropMed CTH

Credentials:
Chief, Division of Infectious Disease and Travel Medicine | Optum / Tristate
Infectious Disease Specialist / Clinical Instructor of Medicine

Columbia University Vagelos College of Physicians and Surgeons
Department of Medicine-Division of Infectious Diseases
President –Parasites Without Borders

Answer: Unfortunately, acute COVID-19, as well as Long COVID, can exacerbate many conditions, including MS.

EXPERT: Dr Daniel Griffin, MD PhD CTropMed CTH

Credentials:
Chief, Division of Infectious Disease and Travel Medicine | Optum / Tristate
Infectious Disease Specialist / Clinical Instructor of Medicine

Columbia University Vagelos College of Physicians and Surgeons
Department of Medicine-Division of Infectious Diseases
President –Parasites Without Borders

One can open a discussion of evidence-based therapeutics for Long COVID-19 with optimism, as there are hundreds of ongoing clinical trials for Long COVID-19, the majority of which test potential therapies.  Before its consideration as a therapeutic, there were questions about the safety of vaccinating patients with Long COVID symptoms. This was followed by evidence suggesting that COVID-19 vaccines had therapeutic benefits for patients with Long COVID if given after the development of Post-COVID sequelae. Vaccination has also been shown to reduce the severity and impact of Long COVID on patient’s social, professional, and family lives. 

It appears that the benefits of COVID-19 vaccines on Long-COVID are present with a single vaccine dose but increases with a second and even more with a third dose of vaccine. COVID-19 vaccination in the context of PCC is associated with reduced symptoms, increased well-being, and downregulation of systemic markers of inflammation.

EXPERT: Dr Daniel Griffin, MD PhD CTropMed CTH

Credentials:
Chief, Division of Infectious Disease and Travel Medicine | Optum / Tristate
Infectious Disease Specialist / Clinical Instructor of Medicine

Columbia University Vagelos College of Physicians and Surgeons
Department of Medicine-Division of Infectious Diseases
President –Parasites Without Borders