It was another fascinating day of lectures at the conference. This day is Long Covid and ME/CFS intensive.
Neurovascular Dysregulation During Exercise in POTS, ME/CFS, and Long Covid. By David Systrom MD.
- Dr. Systrom thinks of ME/CFS and POTS as being akin to studying two sides of the same coin.
- Dr. Systrom is a Pulmonologist. It is great to have someone from his field weigh in.
- There is a great deal of overlap in POTS, ME/CFS, and Long Covid in certain pulmonary-related dysfunctions.
- Preload failure- This is the most common finding among these groups. Preload failure refers to an inadequate filling pressure in the ventricles.
- Left to right shunting- I believe this means that not all the oxygenated blood actually gets pumped out to the body, some of it goes straight back to the lungs.
- Mitochondrial dysfunction
- A deficiency of ubiquitous citrate synthase is commonly seen in patients with mitochondrial dysfunction.
- There is currently a clinical trial underway with a delta modifier drug to treat this issue. Early anecdotal reports are promising.
- Preload failure contributes to exercise intolerance in ME/CFS.
- Mestinon improves preload failure.
- Mestinon works neurally, so based on the study showing that Mestinon improves preload failure, it seems that ME/CFS is a neurovascular disease.
- Small fiber neuropathy is also frequently seen in patients with POTS, ME/CFS, and Long Covid.
- Hyperventilation is common in POTS, ME/CFS, and Long Covid. It can cause physiological changes that lead to shortness of breath. It is currently unknown why hyperventilation occurs.
- Cerebral blood flow decreases upon being in an upright position in both POTS and Long Covid. When the amount of hyperventilation was corrected for in the metrics, POTS levels of cerebral blood flow appear more regular, but Long Covid levels of cerebral blood flow do not. This may indicate that Long Covid causes an intrinsic abnormality of the vasculature.
Long Covid Autonomic Dysfunction. By Mitchell Miglis MD and Charlie McCone.
- Charlie is a Long Covid patient. My heart goes out to him as I can sympathize with much of what he has/is going through. He went from being a very active individual to his life being turned upside down.
- Long Covid is not just lingering symptoms, but it is common to have an onset of new symptoms over time.
- Long Covid occurs in roughly 10-30% of people who get Covid. This means 8.9-26.7 million Americans have Long Covid.
- 67% of patients in a Long Covid cohort had Compass 31 scores of 20 of higher, suggesting moderate to severe autonomic dysfunction.
- Both Long Covid and POTS demonstrate a reduction of blood flow and CO2 in the brain upon standing.
- Small fiber neuropathy is very common in Long Covid.
- One study showed the rate at 89% among Long Covid patients and 60% among POTS patients.
- A different study put the percentages at 50% for Long Covid.
- Interestingly, 63% of Long Covid patients in a small study had the presence of phosphorylated alpha-synuclein deposited in their autonomic nervous system. This is the same protein that is responsible for Parkinson’s Disease. The question is, does Covid propagate this or is the protein already present and predisposes an individual to Long Covid?
- Unlike other infections, the acute severity of Covid infection does not indicate the likelihood of developing Long Covid.
- Potential mechanisms of Long Covid
- Tissue injury
- The virus infects and damages almost any cell.
- Immune mediated mechanisms
- Many autoimmune diseases and manifestations are triggered.
- G protein coupled receptor autoantibodies are identified.
- Viral persistence
- A disturbing study demonstrates that Covid RNA can still be present in patient’s feces several months after infection. The viral load in feces tends to correlate with severity of Long Covid symptoms.
- Microclotting
- Mast cell activation
- There is a link between mast cell activation and autoantibodies that can stimulate early maturation of mast cells. This leads to an over-activation of the mast cell system.
- Baroreflex impairment
- Covid can bind in areas of the brain that control blood pressure.
- Deconditioning
- Deconditioning doesn’t cause Long Covid, but it makes it worse.
- Gender Physiology
- First of all, rude.
- Women have less skeletal muscle mass and smaller hearts.
- Women are more prone to pelvic venous pooling.
- Women are more prone to autoimmune diseases.
- Sex hormones may play a role in the pathophysiology of Long Covid, POTS, etc.
- Tissue injury
- Treatment of Long Covid
- Rule out cardiopulmonary and thromboembolic disease.
- Symptomatic treatment if orthostatic intolerance is present such as volume expanders and compression.
- Graduated exercise being mindful of post-exertional malaise.
- Immunomodulatory therapies such as IVIG if autoimmune disease if present
- Symptomatic pharmacologics. An example would be a beta blocker to lower heart rate.
- Anti-inflammatory medications such as: Low dose naltrexone (LDN), low dose aripiprazole, and a fermented diet.
- Roughly 50% of patients experience improvement with LDN. It mostly improves fatigue, pain, and brain fog. It does not typically help autonomic symptoms.
- In Dr. Miglis’ opinion, it is the best drug for Long-Covid patients at this time.
- Neuromodulators and vagus nerve stimulation
- Antivirals such as Paxlovid
- Brain fog due to Long Covid is not well understood.
- Hypotheses include:
- Neuroinflammation
- Cerebral hypoperfusion
- Tissue damage
- Product of chronic systemic disease
- A study that looked at MRI’s in patients before and after Covid infections showed gray matter loss in areas that control the olfactory system.
- Hypotheses include:
Brain Imaging in Long Covid Cognitive Dysfunction. By Anna Nordvig MD.
- At least 20% of patients report cognitive impairment post-Covid.
- Dr. Nordvig thinks that brain fog is a primary process driven by systemic inflammation.
- 77% of post-Covid cerebrospinal fluid is abnormal which indicates neuroinflammation.
- Most Long Covid patients that have cognitive impairment had mild or moderate Covid.
- 90% of brain fog patients had new or worsened mood symptoms.
- There is evidence of white matter hyperintensities post-Covid. These indicate inflammation.
- There has been occasional evidence of other abnormalities in post-Covid brain scans such as venous sinus stenoses.
- Dr. Nordvig isn’t as alarmed by the grey matter atrophy study as the media portrayed it.
- Specialized testing indicates decreased brain metabolism of glucose and cerebral blood flow abnormalities in Long Covid patients with cognitive impairment.
- Dr. Nordvig thinks patients with POTS or Long Covid should ask for brain imaging if their cognitive dysfunction is debilitating i.e. cannot return to work.
Exercise Intolerance and Chronotropic Incompetence in Long COVID: Insights From the LIINC Study. By Matthew Durstenfield MD.
- LIINC= Long-term impact of infection with novel coronavirus
- This research group did cardiopulmonary exercise testing on Long Covid patients.
- Their exercise capacity was reduced
- The most common cause was chronotropic incompetence (60% of patients in this study)
- Chronotropic incompetence is the inability to increase the heart rate to meet the body’s metabolic demands.
- A cause of this could be autonomic dysfunction
- Chronotropic incompetence was associated with worsened heart rate variability which indicates autonomic dysfunction.
- Inflammatory markers were associated with reduced exercise capacity.
- Other causes of reduced exercise capacity include: deconditioning, hyperventilation/dysfunctional breathing, changes in peripheral oxygen extraction or utilization, less cardiac stroke volume augmentation during exercise despite normal resting cardiac function/preload failure, and endothelial dysfunction. All of these except deconditioning could be related to autonomic dysfunction.
- The most common cause was chronotropic incompetence (60% of patients in this study)
- Their exercise capacity was reduced
- Cardiopulmonary exercise testing would be indicated for patients with significant decreases in exercise capacity.
- More research needs to be done to determine how to apply these findings.
Autonomic Rehabilitation Approaches to Long COVID Care. By David Putrino PT PhD.
- Dr. Putrino and his group have found that traditional cardiac rehab is not the proper tool for Long Covid. This is because their symptoms are not correlated with structural cardiac pathologies.
- Recommended starting point for Long Covid management
- Avoiding known triggers such as:
- Physical or cognitive exertion- work on pacing/energy conservation strategies
- Stress- use emotion regulation strategies
- Note- Stress worsens Long Covid and Dysautonomia symptoms but does not cause them
- Dehydration- use a hydration plan with electrolytes
- Weather changes- use environmental management strategies ex. strategies to cope with heat
- Consuming large meals- use meal planning strategies
- Premenstrual period- awareness, monitoring, and preparation
- Alcohol and caffeine- be mindful of consumption
- Breathwork protocols
- Used to improve the end tidal CO2 levels in patients that have this issue without dysfunctional breathing patterns.
- Dr. Putrino recommends the Stasis program.
- Generally, he suggests 4-7-8 breathing.
- Autonomic rehabilitation
- This is not used to treat deconditioning. It retrains the autonomic nervous system to manage autonomic challenges.
- An example would be a heel slide while laying down. This motion will tend to increase the heart rate and breathwork strategies are employed to control the heart rate response.
- It is important to screen for post-exertional malaise during this process.
- Autonomic rehabilitation is not curative, the goal is improvement in symptoms. It has demonstrated improvement in fatigue, number of symptoms, and walking speed over the 3 month program.
- This work could be beneficial to Dysautonomia in a broad sense as well, not just Long Covid.
- Avoiding known triggers such as:
- Lauren Stiles said that she hopes the Dr. Putrino and others will develop a new protocol alternative to the Levine Protocol that would be more attainable for where many patients are starting from. The Levine Protocol excludes many patients, especially those with post exertional malaise. This is not to say that the Levine Protocol is “bad”, but it is too high of a starting point for many patients.
- Dr. Putrino recommends the resource Long Covid Physio.
Panel Discussion: POTS and ME/CFS: Similarities, Differences, and Finding the Right Exercise Approach. By Tae Hwan Chung MD, Satish Raj MD, and David Systrom MD.
- In these doctors’ experience, most POTS patients meet ME/CFS criteria. Among ME/CFS patients, roughly 25% have POTS. 95% of ME/CFS patients have abnormally low filling pressures in an upright position and symptoms of orthostatic intolerance
- Post-exertional malaise is the defining characteristic of ME/CFS. The plasma of ME/CFS patients show an inflammatory response to exercise.
- Among these doctors, the crux of their advice on exercise is to meet the patient where they are at. Each patient is unique in their abilities and responses, and therefore the exercise prescription cannot be a “one size fits all” approach. It is also important that changes in exercise are slow and incremental.
Mechanisms of Chronic Pain and Fatigue: Dysautonomia, Inflammation, and Ehlers-Danlos Syndrome. By Jessica Eccles MD ChB PhD.
- The erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) levels in fibromyalgia and ME/CFS patients are elevated compared controls. This demonstrates inflammation.
- The levels tend to predict the severity of fatigue and pain.
- There is a tendency among this group of patients to have an autonomic (tilt) induced change in pain and fatigue. This happens among patients whether there is a POTS diagnosis or not.
- Most likely mechanism of autonomic induced pain would be joint hypermobility.
- Most likely mechanism of autonomic induced fatigue would be inflammation.
- Gene expression differs between patients in this cohort and controls. It was noted that a difference in gene expression was seen in genes pertaining to mitochondrial and ribosomal function.
- Dr. Eccles’ group is working on a study using brain scans during an autonomic challenge. There would be a special chamber on the lower body mimicking being upright since you cannot tilt a brain scan machine.
- The implications of this study on management would be:
- Controlling autonomic dysfunction
- Controlling inflammation
- More research is needed to see which anti-inflammatory agents would be most effective.
- Dr. Eccles has a background in Psychiatry and clarified that disorders like Fibromyalgia and ME/CFS are NOT psychiatric disorders. They are disorders involving brain and body reactions.
Vagus Nerve Stimulation and Mestinon in POTS. By Andre Dietrich MD PhD.
- Dr. Dietrich is involved with the Italian group looking at transcutaneous vagus nerve stimulation (tVNS) and POTS.
- In prior studies, tVNS has demonstrated the ability to improve inflammation, heart rate variability, POTS symptoms severity, and a modest decrease in heart rate upon standing for POTS patients.
- The most recent study this group did was looking at tVNS and either galantamine or Mestinon and their effects on TNFa levels in POTS patients. TNFa is an inflammatory marker.
- Galantamine has more central effects (brain), Mestinon has more peripheral effects (cannot cross the blood brain barrier).
- Among the different combinations, only tVNS plus Mestinon decrease TNFa levels.
- They used a tVNS device that stimulates the concha cymba and concha cavum parts of the ear because they are innervated by the auricular branch of the vagus nerve.
- Dr. Dietrich does not recommend that patients try to do tVNS on their own without the oversight of a knowledgeable provider. It can negatively impact hearing if used improperly.
- It is difficult to obtain proper devices in the US.
- tVNS may be indicated for other types of Dysautonomia as well, but more research needs to be done.
What were your takeaways from the information provided on Day 2 of the conference?
Disclaimer: I am not a medical professional. Statements on this site are not meant to be taken as medical advice. These statements reflect my personal experiences having mild-ish post-viral POTS and ME. Due to the wide spectrum of these diseases, comorbidities, and everyone being different, your experiences may be very different than mine.
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