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The GIST

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Diagnosis

Tracy’s ME/CFS diagnosis seemed right for many years – then more symptoms showed up.

The signs that something was going on were there early. As a child, Tracy had low endurance – she’d hit the wall after about 20 minutes of tennis – and was often sick in the mornings. It wasn’t until her mid-30s, following years of persistent widespread pain, the inability to keep up energetically with others her age, and two serious car accidents, though, that she was diagnosed with fibromyalgia.  A few years and a few doctors later she got a chronic fatigue syndrome (ME/CFS) diagnosis by an ME/CFS expert which she said “seemed right.”

Indeed, lab results including an on-and-off Epstein-Barr virus reactivation and the mast cell activation pointed an arrow straight at ME/CFS.  Aside from low-dose naltrexone (LDN) which rescued her from pain that felt “life-threatening,” nothing much helped and her fatigue only worsened over time.

Other (seemingly disconnected) experiences also presented over the years: intermittent choking when eating or sometimes just taking a sip of water; her eyes tired easily; whenever she was given a course of antibiotics, severe fatigue would persist for weeks or months.

THE GIST

  •  As a child, Tracy had low endurance and was often sick in the mornings, but it wasn’t until her mid-30s, following years of persistent widespread pain, the inability to keep up energetically with others her age, and two serious car accidents, though, that she was diagnosed with fibromyalgia and then ME/CFS.
  • At times, she had some odd experiences: intermittent choking when eating or sometimes just taking a sip of water; tired eyes, severe fatigue after taking antibiotics. In 2020, she began experiencing breathing difficulty (COVID was ruled out), and a new batch of symptoms showed up less than two weeks after getting the second in the series of two Pfizer vaccination shots.
  • At dinner one night, she had trouble moving her tongue in her mouth. Problems with swallowing and chewing followed. Intermittent choking continued. Later would come late-day speech impairment (slurred speech), heavy and drooping eyelids, and worsened fatigue.
  • It took some time, but she was ultimately diagnosed with myasthenia gravis – a rare autoimmune disease that inhibits signals from the nerves from activating the muscles.
  • That brought up a question: Could she have had a milder case of myasthenia gravis (MG) which suddenly erupted after the vaccine, or did she have ME/CFS and now she has ME/CFS and myasthenia gravis (MG)?
  • MG often, but not always, first manifests itself as eye weakness (strained, blurred or double vision). Other common manifestations include trouble chewing and swallowing food, frequent choking, slurred or nasal speech, difficulty raising the arms above your head, gait problems, shortness of breath, and… feeling very tired.
  • Because muscle weakness can impact the diaphragm, affecting one’s ability to breathe, severe cases can require a home ventilator and can lead to what’s known as a “myasthenic crisis” resulting in a trip to the ER.
  • The list of similar symptoms in MG and ME/CFS is a long one. MG, too, involves extreme fatigue, has “flares” that mimic ME flares or crashes, and poses difficulty with the mundane tasks of daily living much like ME.
  • People with MG can feel too weak to simply brush their teeth or comb their hair; have difficulty showering; have difficulty rising from their chair without pushing themselves up with their arms; experience tired eyes from reading; find it difficult to chop food or cook because their arms feel too heavy or their legs are too tired to stand; are unable to grocery shop due to lack of endurance…or have trouble, as Tracy reports, “just breathing,”.
  • Other MG symptoms that mimic ME/CFS, and sometimes long COVID include exercise intolerance, intolerance of hot temperatures (heat is especially challenging; even hot showers worsen MG), bright lights/sunlight, and problems with alcohol.
  • Like ME/CFS, MG is a “snowflake” disease. Every patient manifests differently; the various symptoms can occur in any constellation; symptoms often fluctuate hour to hour, day to day, month to month, or year to year; flares can arise from both known and unknown triggers; and symptoms can also go into complete remission for random periods of time with no known reason.
  • Interestingly, the first-line drug for MG is Mestinon, a drug that is now being used in ME/CFS, POTS and Ehlers Danlos Syndrome as well.
  • MG is listed as a differential diagnosis for ME/CFS, but it was assumed that Tracy’s symptoms were all associated with her ME/CFS/FM. It was not until her problems with swallowing got so bad that her primary care physician told her to go to a neurologist that she got tested.
  • One good thing about MG is that, unlike ME/CFS and FM, it has a clear diagnostic pathway and can be definitively diagnosed via a variety of tests. Because, unlike ME/CFS, the problem has been clearly identified in MG, despite the fact that it’s a rare disease, many drugs have been approved for it and more appear to be on the way. As a consequence, some people with MG are able to lead near normal lives.
  • Having MG and not being diagnosed with it, on the other hand, can be dangerous because if untreated it can lead to very serious (hence the “gravis” in the name) consequences.
  • While MG is an autoimmune disease (typically treated by rheumatologists), it’s actually diagnosed and treated by neurologists — and best, a “neuromuscular” neurologist — if you can find one.

Then in 2020, she began experiencing breathing difficulty (COVID was ruled out), and a new batch of symptoms showed up less than two weeks after getting the second in the series of two Pfizer vaccination shots. (She got her shots six months apart due to a long-lasting poor reaction to the first shot and her doctor’s recommendation that she wait six months to get the second.)

At dinner one night, she had trouble moving her tongue in her mouth. Problems with swallowing and chewing followed. Intermittent choking continued. Later would come late-day speech impairment (slurred speech), heavy and drooping eyelids, and worsened fatigue.

Tracy surmised with one gastroenterologist that eosinophilic esophagitis might explain the choking, but she was not tested for it. She was, however, tested and found negative for esophageal dysmotility by an ear, nose, and throat (ENT) specialist at Mass General in Boston. But the testing took place in the morning and her symptoms typically emerged in the afternoon. At Mass General, she was then referred to an occupational therapist who suggested she could solve her swallowing and choking problem by practicing mindfulness when eating — a suggestion Tracy could appreciate since she teaches mindfulness meditation, but as it turns out, a lack of mindfulness was not the issue.

Then she got lucky. A trip to a neurologist and a simple blood test gave a name to her symptoms: she had myasthenia gravis (MG). Given her long history with ME/CFS and FM, she was a bit shocked to find that a simple test for a disease existed, but it did.

While various tests (neurological exam, ice test, nerve conduction, EMG) are used to diagnose myasthenia gravis (MG), the positive antibody result aced her diagnosis. (Eighty to eighty-five percent of people with MG test positive for it.)

Her diagnosis brought up a question: Could she have had a milder case of myasthenia gravis which suddenly erupted after the vaccine, or did she have ME/CFS and now she has ME/CFS and myasthenia gravis? (A review found that a small number of MG cases were associated with a vaccination but concluded that the number was too small to conclude that they resulted from the vaccination. Ironically, one study showed that people who already had MG and had been vaccinated did better with COVID-19 than those who had not been vaccinated.

Nobody knows, and Tracy assumes she had ME/CFS and that the vaccine triggered underlying myasthenia gravis, but the connection between ME/CFS and Myasthenia Gravis is intriguing indeed — because of the overlapping symptoms and because the drug called pyridostigmine bromide, or Mestinon, used to treat some with ME/CFS is a primary treatment for MG.

There’s a lot about MG that can make it difficult to distinguish from ME/CFS or long COVID, so knowing the specific symptoms of MG, and that unlike ME/CFS, you can be easily tested for MG, and treated for it, can make a meaningful difference in a life.

It’s time for a closer look at Myasthenia Gravis and ME/CFS.

Is it Myasthenia Gravis (MG) or ME/CFS?

Myasthenia gravis

Myasthenia gravis (MG) is a rare autoimmune disease that often goes undiagnosed. Many of its symptoms overlap with ME/CFS.

Myasthenia Gravis (fr. Greek for grave muscle weakness) or MG is aptly named. In MG, antibodies block or destroy the receptors on the muscles that respond to the neurotransmitter acetylcholine.

Lacking enough nerve signals to move properly, the muscles in the eyes, face, throat, neck, torso (diaphragm), and limbs fail to respond, causing problems with vision, speech, swallowing, chewing, using the hands and arms, walking, and breathing.

More specifically, eye weakness manifests as strained, blurred or double vision (often but not always the first recognized symptom, and sometimes the only manifestation of MG, known as Ocular MG). Other common manifestations include trouble chewing and swallowing food, frequent choking, slurred or nasal speech, difficulty raising the arms above your head, gait problems, shortness of breath, and… feeling very tired.

In MG, muscle weakness can impact the diaphragm, affecting the ability to breathe. As such, some patients need a home ventilator. When these muscles begin to fail completely, a myasthenic crisis occurs, requiring a trip to the ER and sometimes intubation.

Being prepared to educate ER professionals is part of MG patient indoctrination since, like ME/CFS, most ER professionals are not well educated about the disease; results for MG patients can be fatal. For example, many drugs — including but not limited to magnesium, beta-blockers, calcium channel blockers, verapamil, ciproflaxin antibiotics, muscle relaxants, and even anti-anxiety and sleep medications — can make MG worse. (If you’ve had a bad reaction to some of these drugs, it might be a reason to test for MG.)

An ME/CFS Long COVID Mimic?

Mimic

Fatigue, problems swallowing, breathing, exercise intolerance and others can be found in both diseases.

MG may be confused with ME/CFS because MG too involves extreme fatigue, has “flares” that mimic ME flares or crashes, and poses difficulty with the mundane tasks of daily living much like ME.

People with MG can feel too weak to simply brush their teeth or comb their hair; have difficulty showering; have difficulty rising from their chair without pushing themselves up with their arms; experience tired eyes from reading, find it difficult to chop food or cook because their arms feel too heavy or their legs are too tired to stand; are unable to grocery shop due to lack of endurance…or have trouble, as Tracy reports, “just breathing,”. Many people with more severe ME/CFS, of course, experience these symptoms.

Other MG symptoms that mimic ME/CFS, and sometimes long COVID, include exercise intolerance, intolerance of hot temperatures (heat is especially challenging; even hot showers worsen MG), bright lights/sunlight, and problems with alcohol.

The muscle pain is not uncommon in MG. Caused by overtaxed, weakened muscles, it can also mimic fibromyalgia. While the results are not definitive, some studies have found increased levels of AChR antibodies and increased rates of polymorphisms in AChR genes in ME/CFS, and reviews indicate that COVID-19 increases the risk of coming down with MG.

Like so many autoimmune diseases, fatigue is a major complaint and, as in ME/CFS, exercise can exacerbate MG. While the textbooks say the fatigue in MG is localized; i.e. specific to the muscles that are affected by it, many patients report having generalized fatigue and even brain fog, though this is often attributed to insomnia from the steroid prednisone prescribed for treatment.

Further, like ME/CFS and long COVID, MG symptoms often improve with rest; and flares can result from surgery, infections, stress, and menstruation.

Lastly, like ME/CFS and long COVID, MG is a “snowflake” disease. Every patient manifests differently; the various symptoms can occur in any constellation; symptoms often fluctuate hour to hour, day to day, month to month, or year to year; flares can arise from both known and unknown triggers; and symptoms can also go into complete remission for random periods of time with no known reason.

Because Tracy was already seeing a specialist for ME/CFS, MCAS and fibromyalgia, it was presumed that these diagnoses alone were the cause of most of her symptoms and that what was not clearly understood was part of the usual ME/CFS mystery. Nothing more was pursued — until her difficulty with swallowing her own saliva became so severe that she could not eat, and her very caring and concerned primary care physician recommended seeing a neurologist…”promptly!”

Mestinon, Myasthenia Gravis (MG), ME/CFS, and Allied Diseases

The two diseases share many symptoms, but the Mestinon connection may be the most intriguing. Mestinon – the first-line treatment for MG – allows more acetylcholine to be available by inhibiting the acetylcholinesterase enzyme (AChE) from breaking down acetylcholine. Acetylcholine affects a variety of nerves, including the vagus nerve.

Mestinon is used off-label in chronic fatigue syndrome (ME/CFS), fibromyalgia, postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), Ehlers Danlos Syndrome (EDS), and long COVID. Case reports of Mestinon use in ME/CFS date back to the 1990s and its been successfully trialed in fibromyalgia.

Mestinon for Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, POTS, and Long COVID

Exactly what Mestinon is doing in ME/CFS, POTS, and long COVID is unclear, but David Systrom believes it helps increase blood flow to the muscles in ME/CFS by triggering the release of norepinephrine. It may also improve parasympathetic nervous system (vagus nerve) functioning.

Systrom’s ME/CFS study suggests Mestinon can improve oxygen uptake, end-tidal carbon dioxide levels, and ventilatory efficiency during exercise. The Open Medicine Foundation’s LIFT clinical that contains both Mestinon and low-dose naltrexone should tell us a lot more about what Mestinon is doing in ME/CFS.

Lifting ME/CFS: The OMF’s Unique Two-Drug Clinical Trial to Begin Soon

Missed Diagnosis?

Mayo clinic

The Mayo Clinic’s Essentials of Diagnosis lists MG as a disease to watch out for when diagnosing ME/CFS.

Tracy’s MG diagnosis after decades of ME/CFS/FM brings up the question of whether some people who have been diagnosed with ME/CFS might actually have MG or might also have MG. Like ME/CFS, MG is not well taught in medical school and many people with MG go years before being diagnosed. Rheumatologists, who typically diagnose autoimmune issues and often see fibromyalgia patients, can miss the diagnosis because MG affects nerves and muscles.

The Mayo Clinic’s 2021 “Essentials of ME/CFS Diagnosis and Management” lists myasthenia gravis as one of the “medical conditions that present similarly to ME/CFS”. As Tracy’s case showed, though, even the best of ME/CFS doctors may miss it. With even neurologists routinely missing the diagnosis, that’s not surprising. (“Neuromuscular” neurologists are especially helpful when seeking diagnosis.)

Who might be most likely to have MG? Here are some ideas. Note that, as with ME/CFS, symptoms can vary widely.

  • People who present with any of these core MG symptoms: problems chewing, swallowing or speaking (slurred speech or nasal tone), choking, double or blurred vision, drooping eyelids, shortness of breath, muscles that tire easily.
  • People who respond well to Mestinon or IVIG or people who respond poorly to drugs/supplements like beta-blockers, calcium channel blockers, verapamil, magnesium, ciproflaxin antibiotics, muscle relaxants, or any of the many other drugs on the Myasthenia Gravis Cautionary Drugs List.
  • People whose symptoms manifest or worsen later in the day, a classic experience in MG.

Clear Diagnostic Pathway

The nice thing about MG is that, in contrast to ME/CFS and long COVID, a clear diagnostic pathway exists that catches most, if not all, MG cases. The diagnostic algorithm goes something like this: clinical history is taken followed by tests of specific muscle groups, and sometimes for ocular MG, an ice test. (If an eye muscle proves weak, placing ice on it will result in the muscle strengthening). If those results are positive, next comes a variety of antibody tests (acetylcholine receptor antibody (AChR), anti-muSK antibody test (MuSK), a nerve stimulation test, and an EMG test.

Positive results would end up with a clear diagnosis of myasthenia gravis.

And positive results are followed by an MRI for thymus or thymus tissue, as removal of the thymus, when present, can improve MG.

What Kind of Doctor to See?

While MG is an autoimmune disease (typically treated by rheumatologists), it’s actually diagnosed and treated by neurologists — and best, a “neuromuscular” neurologist if you can find one.

Benefits

Pills

Besides alerting a patient to a potentially dangerous situation, being diagnosed with MG does open the door to new treatment possibilities.

While being diagnosed with an autoimmune disease might seem daunting, it could have some advantages. Unlike ME/CFS, a suite of drugs have been FDA-approved to treat MG.

Longstanding proven treatments including prednisone, mycophenolate mofetil (Cellcept), azathioprine (Imuran), IVIG, plasmapheresis, and pyridostigmine bromide (Mestinon). Plus, new-and-improved, more targeted treatments have arrived in the last several years, including eculizumab (Soliris®). efgartigimod (Vyvgart®), ravulizumab (Ultomiris®), rozanolixizumab-noli (Rystiggo), and zilucoplan (ZILBRYSQ®), and research trials are currently underway involving stem cell transplantation and gene therapy.

Ultimately, getting diagnosed with or ruling out MG is critical because to have MG and not be diagnosed may risk death. As the neurologist who diagnosed Tracy explained: “myasthenia means ‘muscle weakness’ and gravis means ‘grave’ — because that’s where it used to put people and can still put you if you go untreated.”

Today, most MG patients improve with treatment, and many even return to “normal” lives.

Why so many drugs for MG but not ME or Long COVID?

Why does a rare disease like MG (70,000 – US) have so many FDA-approved drugs while a much more prevalent disease like ME/CFS (@3 million US) has none? It’s not because ME/CFS is being ignored. It’s because we know exactly where the problem lies in MG (the neuromuscular junction) and we don’t know that in ME/CFS.

That’s allowed researchers to uncover a wide range of autoantibodies that are attacking it, to be able to subset patients more effectively, to develop a variety of immune-related treatments for it, and to reduce the percent of false negative diagnoses. In short, finding the explicit target makes it profitable for drug companies to develop drugs even for a rare condition like MG.

Thanks to Tracy for her help with this blog. 

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