David Systrom, researcher, Brigham and Women's Hospital, USA

There's a group in Würzburg who found that, too, if I remember correctly.

 

Hi Hutan, I first supplied my GP some links on Mestinon and she contacted my former specialist at Wellington hospital for advice on its safety or benefit. The specialist said it would do no harm in the low start up dose, compared to the potential benefit. I'll give the specialist's name via private message as I don't think she would want her name up on the internet for the world to see. Does this website have a private chat?

 

@SamF Have you seen this thread /research?

 

I don’t know how many here have tried Mestinon, but it was tried here. It did not prevent crashes, or PEM. It was used for about 2 years.

Thus far nothing has ever addressed this horrid symptom of malaise,for lack of a better word.

Any exertion just makes it skyrocket. It’s always there low level, but trying to read a few emails for instance, brings it on big time, as they say.

 

Mestinon has worked well for my daughter. (ME, OI, EDS) Went from lying in bed/sofa to sitting and able to walk a little in 3 months with immediate improvement with OI. She started low doses and built up. Now she can work part time from home and takes it when she needs it.

 

Dear Helen
Wonderful news you recount. My daughter did not have this luck as I wrote above; she reacted poorly to the medication, and it did not prevent 'crashes.' Bravo for you folks!

 

Below is the text from the pamphlet Systrom's team provided to me after my initial visit late last year. It outlines the testing and treatment protocol he follows for ME/CFS patients.


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AUTONOMIC DYSFUNCTION INFORMATION


WHAT IS AUTONOMIC DYSFUNCTION?

Autonomic dysfunction or dysautonomia is a condition characterized by reduced signaling from nerves to the veins of the body resulting in poor squeezing of those veins. The resulting low blood pressure in those veins with poor blood return to the heart is called preload failure. With less blood entering the heart, there is a suboptimal amount of blood pumped out of the heart resulting in symptoms. Vein squeezing occurs automatically under 2 circumstances; standing and exertion. With standing, the veins need to squeeze to maintain vein blood pressure as gravity will drive the blood in the veins towards the feet, lowering overall blood pressure, typically leading to lightheadedness, dizziness, and passing out. With exertion, more overall blood pressure/flow is needed to meet the increased needs of the body; the veins squeeze more blood into the heart to accomplish this. This does not happen with dysautonomia resulting in shortness of breath and fatigue.

WHAT CAUSES THIS CONDITION?

Unfortunately, the cause is often unknown. However, in some cases there is an autoimmune cause. In these case, people often start to experience symptoms after an illness (bacterial or viral) or a significant inflammatory event (trauma or surgery) that triggers the immune system to attack and destroy the nerves that stimulate veins to squeeze blood back into the heart.

WHAT ARE THE COMMON SYMPTOMS?

• Shortness of breath
• Fatigue/tiredness
• Lightheaded/dizzy/fainting
• Chest pain
• Heart racing or pounding
• Fluctuating high/low heart rate
• Fluctuating high/low blood pressure
• Nerve pain (numbness/tingling/burning/pins and needles)
• Mild ankle swelling

​

WHAT DIAGNOSTIC TESTING IS REQUIRED?

Invasive Cardiopulmonary Exercise Test (iCPET)

WHAT TREATMENT OPTIONS EXIST?

NON-MEDICATION OPTIONS:

Discontinue or reduce the dose of medications that can worsen this condition (if possible): Diuretics, certain blood pressure medications (like beta blockers and clonidine), antianginal drugs (nitrates), alpha agonists (like tamsulosin), and some antidepressants.

Increase salt intake to at least 2000 mg per day AND increase fluid intake to at least 2 liters (or 68 oz) per day: Sodium attracts and keeps fluid in the veins, helping blood return to the heart, so increased sodium and fluid intake must be done together. Eating packaged foods that contain more sodium is the best way to accomplish taking in 2000 mg per day. At least some of the fluid intake should be from sports drinks like sugar-free Gatorade, as they contain sodium. Caution should be taken if the person’s blood pressure runs high.

Recumbent exercise: This is exercise done in a more horizontal position, such as with a recumbent stationary bike or a rowing machine. Swimming is also a possible form of exercise if the person does not pass out with exertion. People with this condition can exercise much longer in the recumbent position than upright as blood flow back to the heart is not fighting gravity in this position. Exercise will train the nervous system, over 6-12 months, to increase vein squeezing above and beyond what medications can accomplish. Slowly increasing the duration of exercise, as tolerated, to at least 30 minutes 5 times a week is the goal.

Raise the head of the bed 20 to 30 degrees. Placing wood blocks under the head bedposts to accomplish this sleeping angle will keep gravity resisting vein blood flow, forcing the nervous system to constantly stimulate vein squeezing to counteract gravity during sleep. This prevents the nervous system from becoming sluggish to respond in the morning after being “turned off” overnight resulting is less lightheadedness, dizziness, and poor breathing upon waking. Doing this also helps prevent high blood pressure with lying flat when taking Midodrine, Northera, or Florinef.

Compression stockings can possibly increase the blood pressure in the leg veins by a small amount and will help reduce any leg swelling.

Physical maneuvers, like squatting, can increase vein blood pressure and alleviate mild to moderate lightheadedness and dizziness with standing. Those with severe symptoms, like feeling they will pass out, should quickly find a place to sit or lay down if this occurs.

Avoid symptom triggers like overexertion in hot weather or standing up quickly.

MEDICATION TREATMENT OPTIONS:

Mestinon, Midodrine, and Northera all stimulate the nervous system (in different ways) to increase the vein squeezing signal to improve blood flow back to the heart.

Midodrine, Northera, and Florinef side effects– The main side effect to look for is a large increase in blood pressure. Check and record blood pressure at least once lying down AND mid-day, every day for a week, AND if headache or vision changes occur. You may have to borrow or purchase a home blood pressure cuff or go to a local pharmacy. If any level is > 180/100 mmHg, stop the medication and call our office. If the blood pressure is consistently > 140/90 mmHg after a week, call our office for instructions.

Mestinon – Start at 30 mg three times a day (WITH FOOD to prevent stomach discomfort). Can cause muscle cramping/twitching. One Magnesium vitamin daily (400-500 mg) and tonic water (with Quinine) as needed helps this. Increase gradually to 60 mg three times a day as tolerated.

Midodrine – Start at 2.5 or 5 mg by mouth three times a day at least 3-4 hours apart. Avoid taking a dose after the evening meal and/or within 4 hours of bedtime. Can increase dose weekly by 2.5 to 5 mg three times a day to a maximum dose of 20 mg three times a day. Stop increasing once symptoms resolve.

Northera – Start at 100 mg 3 times a day and increase by 100 mg 3 times a day every 24 to 48 hours until symptoms resolve or the maximum dose of 600 mg 3 times a day is reached. Afternoon dose should be at least 3 hours before bedtime.

Florinef – Start at 0.1 mg once daily (in the morning with breakfast to prevent stomach aches) and increase to 0.2 mg once daily a week later if symptoms not resolved.

Salt Tablets – Start at 1 gram 3 times a day and increase to 2 grams 3 times a day if still symptomatic after a week. Dose can be reduced to 1 gram twice daily if stomach pain side effect present.

Neuropathic pain management – There are many forms of nerve pain treatment that should be discussed and prescribed by a primary care physician, neurologist, or pain management physician.

Normal Saline Fluid Infusions – Central line placement is required (IV line in the chest). Infusions of fluid can be done in the home after being trained by a home infusion nurse. Typically, 1 bag (1 liter) is infused through the chest line over 1 hour every day, but the infusions can be as few as once a week or up to 2 bags (2 liters) daily to improve symptoms.

TESTING FOR AN AUTOIMMUNE CAUSE?

Autoantibody blood testing – Blood testing of the most common autoantibodies to see if a person is prone to any type of attack by their own immune system.

Skin Biopsy – a 3 mm piece of skin tissue is removed from the side of the calf in the clinic to see if the density of nerves is reduced due to autoimmune attack/destruction. The skin nerves are the same type of nerve that connects to the veins of the body, so if skin nerves are being destroyed, so are vein nerves.

POSSIBLE AUTOIMMUNE TREATMENTS?

These treatments are only done if the treatments above have failed and the skin biopsy is positive for an autoimmune cause.

IVIG – 2 IV infusions a month at home or at an infusion center for several months to block the autoimmune attack and attempt to reset the immune system to prevent future attacks allowing nerves to regenerate. Infusions will conclude when symptoms improve and stabilize. Symptom improvement is usually not seen for at least 2-3 months. Significant headaches can occur but can usually be treated.

Rituximab – 2 infusions 2 weeks apart to halt immune system cells from making auto-antibodies, resetting the immune system, and allowing nerves to regenerate. Repeat in 3 months if symptoms not fully resolved.

Plasmapheresis – Done within a plasmapheresis clinic where blood is filtered through a machine removing auto-antibodies from the blood. These sessions take place weekly for 6 months while taking a medication called Cellcept to help prevent further auto-antibodies from being made. This does require a central catheter being placed, similar to the normal saline infusions mentioned earlier.

DETERMINING TREATMENT EFFECTIVENESS?

Symptom improvement

SHAPE Test (exercise test done in the office at initial and follow up appointments)

INNOCOR Exercise Test (iCPET without the IVs)

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Notes:

Although the pamphlet recommends a seemingly impossible amount of recumbent exercise, his practice is not doctrinaire about this. He seems to recognize that exercise is impossible and contraindicated in many moderate/severe patients, unless medication improves symptoms.

Although the pamphlet states that the oral medication northera is an option for treatment, it was never mentioned to me in any conversation I had with his physician's assistants. Apparently, his first choice drug is mestinon. If it is not tolerated, the other choices are midodrine and florinef.

Nobody in his practice ever mentioned to me placement of a central line for saline infusions.

In my discussions with his physician's assistant, Systrom will only consider prescribing IVIG (first choice) or Rituxan (second choice) in patients with a positive skin biopsy for small fiber neuropathy who fail to improve or worsen symptomatically while on oral medication. These patients have to be willing and able to undergo a second (non-invasive) CPET at their follow-up appointment 6-8 months after their iCPET. Apparently, Systrom needs the objective data from the second CPET to convince health insurers to authorize a trial of IVIG, since it is extremely expensive. Also, out-of-state patients who cannot easily get to Brigham & Women's Hospital need to find a local physician to oversee IVIG infusions if he decides it is worth trying.

 

This struck me as funny:

"...Swimming is also a possible form of exercise if the person does not pass out..."

 

That made me laugh out loud!!!

 

Now if only there were actual benefits to exercise.

Oh, how I would love that. I miss exercise, of any type. I was the type to randomly do push-ups and crunches during the day.

 

I tried once to follow the recommendation in the pamphlet to exercise, getting on a recumbent bike in the gym of my apartment building about two weeks after my iCPET. I pedaled for 3 minutes against slight resistance, at which point I stopped to hopefully prevent PEM. That did not work: I felt horrible the following three days - nonstop headache, general exhaustion, nausea - and I could barely walk due to worsened muscle pain and leadenness in my legs.

I have heard of a few patients with POTS who responded well to mestinon and were able to follow the exercise recommendations afterwards. But those cases are the rare exceptions.

 

Copied post

https://www.theguardian.com/science/2022/jun/26/can-our-mitochondria-help-to-beat-long-covid


But why do the mitochondria of these patients become sluggish in generating ATP? David Systrom, a pulmonary and critical care doctor at Brigham & Women’s Hospital, Boston, believes he has found answers through studying patients with ME/CFS, an illness that in many cases is precipitated by viral infections such as Epstein-Barr and bears many similarities to long Covid.


When Systrom studied the mitochondrial DNA of these patients it appeared to be normal, but after taking a deep look and conducting muscle biopsies, he identified abnormalities at the electron level, deep within the mitochondria.


“In both ME/CFS and long Covid it’s most likely that these are acquired forms of mitochondrial dysfunction, perhaps related to the initial infection itself or an autoimmune response to a virus or both,” Systrom says. “This impedes the mitochondrial machinery, but doesn’t affect the DNA itself, and it means the mitochondria then fail to generate appropriate amounts of ATP to serve the needs of the muscles.”


Systrom is now running his own clinical trial in both ME/CFS and long Covid patients, in partnership with Japanese drug company Astellas, which has developed a drug that aims to restore normal mitochondrial metabolism.

 

Posts moved from
UK: Invest in ME Conference 2023
2023 Invest in ME Conference


David Systrom's talk on YouTube.

"And I will make a blanket statement here I don't think it's hyperbole I have not yet met a patient with bona fide ME/CFS or long Covid who doesn't have preload failure. This is ubiquitous."

 

Watched a bit of his talk. Looks thorough. Hats off to the patients taking part. Invasive and exhausting.

Q: is preload failure recognised as disabling and debilitating by cardiologists and medics in general? Or is this not that well understood or known about?

Q2: if the testing by this method highlights an exercise intolerance issue, could that mean that a 2 day CPET is therefore not needed?

 

We need a diagnostic test that's not invasive and doesn't require complex devices and the attention of several highly trained specialists for 30-60 minutes.

 

We might like a simple diagnostic test - but that doesn't mean ME/CFS is amenable to one.

 

That's the interesting one, isn't it. Utility and reliability of a test, and wider acceptance of it, are different things.

It's notable how often clinicians working with contested diagnoses are accused of dubious inventions that in another context would be called scientific advances.

 

Extracardiac Abnormalities of Preload Reserve (2021, Circulation: Heart Failure) —

Unexplained Dyspnea on Exertion: The Difference the Right Test Can Make (2022, Circulation: Heart Failure) —

The right test in this case report was doing the studies with the patient upright.

 

Thanks for that. I shall have a wee read