It’s very good to see this case report. Chronic fatigue syndrome (ME/CFS) experts are now bringing decades of experience to bear on treating long-COVID patients. Many are using treatments that long-COVID patients may not even know exist. Case reports like the one below give doctors of all stripes access to potential new treatments. Let’s hope that many will read this one.
Peter Rowe MD has been researching and treating chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS) for decades. He was one of the first to document orthostatic intolerance (problems standing) in ME/CFS, was the first to describe neuromuscular restrictions, and with two Dutch researchers (Visser, Van Campen), has been uncovering the blood flow problems present.
That Visser-Van Campen-Rowe team was responsible for what I believe is one of the most significant findings to come out of the ME/CFS field in the last decade – that blood flows to the brain are reduced upon standing not just in people with documented orthostatic intolerance but in virtually everyone with ME/CFS.
Rowe has also documented the existence of orthostatic intolerance (when being upright causes symptoms)and reduced blood flows to the brain in long COVID. In fact, blood flows to the brain were more severely impaired in the ten long COVID patients in the study than in many people with ME/CFS.
Like other ME/CFS experts, Rowe has his own slant. He’s heavily focused on the autonomic nervous system and orthostasis, the functioning of the spine, restricted ranges of motion, joint hypermobility, and mast cells.
The Case Report
Lindsay Petrachek (first author) and Rowe (senior author) published the case study, “A Case Study of Successful Application of the Principles of ME/CFS Care to an Individual with Long COVID“, of how a 19-year-old returned to near complete health.
The patient was 19 years old with a history of allergic inflammation. His mild coronavirus case was confirmed with PCR. Over the next two months, he noted an increase in heart rate as well as problems exercising that caused him to take to bed for several days. Other than a “mildly reduced peak oxygen uptake” (84%), cardiovascular testing revealed no abnormalities.
His main symptoms were constant fatigue, unrefreshing sleep, lightheadedness, post-exertional malaise after mild increases in activity, bi-frontal and bi-temporal headaches, occasional cough, chest pain, leg pain, and mild anxiety and depression. His overall wellness score (100 before COVID) was 45, indicating a “moderate to severe impairment in function”.
Rowe has found an increased risk of joint hypermobility in his adolescent patients.
Restricted Range of Motion
Rowe brought the issue of a restricted range of motion (ROM) or “neuromuscular strain” to the fore in ME/CFS, and uses various assessments (seated slump testing, ankle dorsiflexion, passive straight leg raise, brachial plexus strain testing, prone knee bend, prone press up).
Rowe has also pioneered the use of structural spinal assessments for spinal stenosis, Chiari malformation, and craniocervical instability in ME/CFS/FM, and has produced case reports of ME/CFS patients who’ve recovered after spinal work. Rowe uses the presence of “brisk reflexes” and the presence of the “Hoffman sign” to initially assess if these problems might be present.
The Hoffman sign is a quick and easy test to determine if spinal cord compression is present. Note that anxiety, hyperthyroidism, and the use of nervous system stimulants can produce positive results. If someone has a positive Hoffman’s sign on only one side, though, that is apparently more likely to indicate a nervous system injury.
To perform the Hoffman test:
- Hold out your hand and relax it so that the fingers are loose.
- Have someone hold your middle finger straight by the top joint with one hand.
- Have them place one of their fingers on top of the nail on your middle finger.
- Then have them flick your middle fingernail with their fingernail.
If the index finger and thumb of that hand move, the test is positive. If the index finger or thumb of that hand doesn’t move, the test is negative.
NASA Lean Test
Noting that “over 95% of adolescent and young adult ME/CFS patients” show evidence of orthostatic intolerance, Rowe does an “inexpensive, ten-minute passive standing test” in everyone with ME/CFS. First, the patients lie down for five minutes, then stand quietly with their shoulders against a wall for ten minutes while their heart rate and blood pressure are taken. Also called the NASA lean test, this is a test that can easily be done at home.
Rowe also does the following tests:
- complete blood count (CBC) with differential white blood cell count (WBC),
- erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP),
- serum chemistry panel,
- free T4 and thyroid stimulating hormone (TSH),
- iron studies (ferritin or iron/total iron binding capacity),
- vitamin B12,
- celiac screening.
He may also assess histamine, chromogranin A [in those not on proton pump inhibitors], tryptase, and other mast cell mediators if allergic and mast cell symptoms are present, and in this patient’s case, he also did a Lyme screen.
The authors validated their mast cell testing regimen based on the known mast cell connections with POTS, the patient’s long history of allergic inflammation, his symptoms after exposure to cherries, cashews, and carrots, and his parents’ similar history.
They also make a case for suspecting mast cell activation syndrome (MCAS) in long COVID. One study found MCAS inhibitors were helpful, while other studies suggest that H1 antagonists may have antiviral properties, and may inhibit ACE2 activity, while H2 blockers such as Famotidine may inhibit G protein-coupled receptors. Cromolyn, ketotifen, ebastine, and loratadine were also found to reduce mast cell degranulation after a SARS-CoV-2 challenge.
This young man’s Beighton score did not quite meet the criteria for hypermobility. His ROM (range of motion) tests revealed several limitations and his Hoffman sign was positive on both sides. A cervical spine MRI, however, showed no cervical stenosis (a narrowed spinal cord canal that is pressing on the spinal cord or “cerebellar tonsillar descent below the foramen magnum”; i.e. no evidence of Chiari malformation.
The NASA Lean Test, or passive standing test, showed that his heart rate increased 70 beats per minute (bpm) upon standing – well above the cutoff range for postural tachycardia syndrome (>40 bpm) (POTS). His headache also increased.
His blood results were normal except for high total bilirubin, plasma histamine and chromogranin A – resulting in him meeting the criteria for a “consensus-2 definition” of mast cell activation syndrome (MCAS).
The testing results suggested that this patient’s primary problems appeared to be:
- profound postural tachycardia syndrome
- allergic inflammation, the elevated histamine and chromogranin A that were suggestive of mast cell activation syndrome (MCAS)
- an increase in sensory sensitivity
- reduced range of motion on physical therapy screening tests.
Rowe has taken his own slice at ME/CFS. While his list of possible other comorbidities contains some that any ME/CFS expert will probably look for (migraine, gut motility, Ehlers-Danlos Syndrome), others demonstrate how aware he is of structural abnormalities that can cause or contribute to these diseases. They include:
- neurogenic thoracic outlet syndrome
- venous insufficiency (pelvic congestion syndrome with ovarian and internal iliac vein varices, May Thurner syndrome with compression of the left common iliac vein)
- neuroanatomic abnormalities (Chiari malformation], cervical spinal stenosis, atlantoaxial instability, or craniocervical instability).
The authors began with non-pharmacologic therapies but moved “relatively rapidly to pharmacologic therapy as indicated”.
They started off with simple things to do for orthostatic intolerance:
- increasing fluid intake, aiming for at least 2 L of oral fluids per day
- increasing the intake of high-sodium foods, liberal use of the salt shaker, and, if needed, using salt tablets and electrolyte packets
- compression garments (stockings, abdominal compression, and body shaper garments), usually at 20–30 mm Hg for stocking compression but up to 40 mm Hg for those who could tolerate them
- standing with the legs crossed, shifting weight when standing, sitting with the knees elevated above the hips (for example, resting the feet on a knapsack or camping stool), or leaning forward when sitting.
In moderately impaired patients, they move to drugs within a couple of weeks. Three classes of drugs are used – often eventually together – as they go through them, one by one, in an attempt to find the best solution.
The three main drug categories are drugs to: (1) improve vasoconstriction, (2) improve blood volume, and (3) control heart rate and catecholamine release or effect. As the charts show, the Rowe team tried 15 different drugs. Interestingly, of the 7 drugs known to be helpful in POTS, 4 actually ended up increasing the patients’ fatigue, while two (methylphenidate/clonidine) were effective and retained.
The high failure demonstrates how heterogeneous a condition POTS is – some drugs designed to help can make things worse. The POTS saga also demonstrates how patient both the doctor and patient have to be. It took time to hit on the right drugs at the right dosages.
Mast Cell Activation Treatment
The mast cell drugs and supplements, on the other hand, were much better tolerated and had a higher success rate. Of the seven drugs/supplements, only 2 were ineffective, none produced side effects, and four (Fexofenadine, famotidine, oral cromolyn, quercetin) were eventually retained. That’s quite an outcome for a field that gets almost no research and is almost totally neglected by general practitioners.
Note that fexofenadine (Allegra) and quercetin are over-the-counter drugs or supplements that are readily available and famotidine (Pepsid) is a generic drug that doctors are familiar with. Loratidine (Claritin) was effective but didn’t end up being used. It, too, is over the counter. The upshot is that mast cell activation syndrome – which apparently played a big role in this person’s illness – can, in some cases ,be treated quite easily and cheaply.
Low-dose naltrexone (LDN ) is commonly used by ME/CFS experts. It requires a prescription and a trip to a compounding pharmacy but is very affordable. It improved this patient’s energy and overall function. Low doses of an antidepressant, escitalopram (Lexapro), helped to calm his nervous system down and help with sensory issues and stress.
For the first year of his illness, the patient was able to take online college courses. A year after his initial infection, his remaining symptoms included daily fatigue, unrefreshing sleep, and post-exertional malaise. Lightheadedness and headaches were infrequent. He was able to handle a virtual 40-hour-a-week internship.
By fall, 15 months after his infection, he had the stamina to attend in-person courses and to walk around his university campus.
At this point, he began physical therapy to address his movement restrictions. After these had been treated, he began a graduated stationary biking regimen. Note that Rowe did not start him on an exercise regimen for almost a year and a half, or after his condition had improved and until his orthostatic intolerance and his movement restrictions had been addressed with physical therapy. The authors stated that:
“Our experience has been that it is critical to treat orthostatic intolerance before advancing aerobic activity and that such advances need to be flexible and conducted in a manner designed to avoid the provocation of PEM.”
David Systrom has a similar approach; he does not recommend exercise therapy until Mestinon or other treatments have resulted in improvement.
With the movement restrictions removed and his health improved, this patient was able to increase his exercise levels fairly quickly without provoking post-exertional malaise. By September 2021, he was biking 15 min twice a week; by October, 20 min three times a week, by November, 25 min four times a week, and by January of last year, he was biking 30 min four times a week without any symptom exacerbation. It took him just four months to be able to bike 120 minutes a week.
In March 2022, he began to slowly resume a more challenging upright exercise – running. Again, he started slowly – 10 min four times a week. Charting his heart rate levels and watching for symptoms of post-exertional malaise, he slowly increased his running time by two minutes each week. Seven months later, in October 2022, he was able to compete in an 8K cross-country event. The only disappointment was that his race time was considerably slower than before he was ill; i.e. he’s not completely back.
Orthostatic Intolerance – A Common Missed Diagnosis?
The passive standing test indicated that this young man did have POTS, but what about people who don’t test positive for POTS? Does that mean they don’t have orthostatic intolerance? In light of the Visser-Van Campen-Rowe team’s results – which were obtained using specialized equipment – I asked Rowe how he dealt with ME/CFS and long-COVID patients who don’t meet the criteria for POTS or other types of orthostatic intolerance. He noted that most people with ME/CFS actually don’t meet the criteria for POTS!
“van Campen and Visser show that although 58% of adults with ME/CFS have no evidence of POTS or delayed orthostatic hypotension during a 30-minute head-up tilt test, and might have been at risk of being dismissed as “normal” if we used only the HR and BP numbers.”
Therefore, in their clinic:
“we look carefully at the history of how people do when in quiet upright postures, asking specifically how they feel when standing in line, shopping, showering, going to a museum, or at receptions. Keep in mind that not everyone with OI reports lightheadedness, but they will report feeling unwell in those positions, especially when upright posture is combined with a warm environment.”
“we do not require that people have an abnormal HR or BP response in order to offer empiric trials of therapy. If one were to insist on demonstrating HR and BP abnormalities during tilt or standing, then this would withhold therapy from the majority of adults who have objective cerebral blood flow evidence of treatable orthostatic intolerance.”
With his focus on the autonomic nervous system and structural issues, Rowe provides a different cut at these diseases than many other doctors. He’s not a miracle worker and not everybody responds as well as this young man did. The authors reported that “many patients experience improvement with multi-modal therapy directed at their symptoms, although such improvement is not universal”. The authors also note that this person might also have gotten better on their own. Rowe, though, is using techniques he’s honed over the years that studies and his own experience have found can work well in people with ME/CFS, POTS, and similar disorders.
Interestingly, Rowe was apparently able to help return this long-COVID patient to approximate health without using any of the kind of hot-button treatments being tried in long COVID such as anticoagulants or antivirals. Nor (except for quercetin) were supplements, dietary changes (except for increased intake of salty foods), or heavy-duty immunomodulators part of his treatment package.
Note that many people with ME/CFS or long COVID do not meet the criteria for POT but still have orthostatic intolerance. Rowe uses the passive standing test and careful questioning to determine if symptoms of orthostatic intolerance are present and then treats accordingly.
The study is free to download and print out and take to your doctor, if you wish. (Rowe, it should be noted, is a pediatric specialist and typically has a long wait list.) Except for the MRI, the testing regimen appears to be relatively inexpensive and certainly within any doctor’s or RN’s capabilities. You might also want to print out Rowe’s earlier paper “Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” which documented the existence of orthostatic intolerance and reduced blood flows to the brain in long COVID.
For more on how ME/CFS experts treat their patients, check out the U.S. ME/CFS Clinical Coalition, which provides diagnostic, testing, and treatment recommendations.
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