Reprinted with the kind permission of Cort Johnson and Health Rising.
By Cort Johnson
She'd had chronic fatigue syndrome (ME/CFS) for twenty-eight years and has left no stone unturned in her attempts to get well. She’s traveled widely and seen some of the best ME/CFS doctors in the world. Despite being connected to the hilt in the ME/CFS, her results have been all too familiar; her health has improved a bit but she, a former fitness buff, has never been able to exercise.
She'd had a really tough year. Multiple surgeries including a gall bladder removal, multiple emergency room visits and a mysterious drug reaction had laid her as low as she had ever been.
Many people might have given up after that (and several decades of mostly fruitless searching) but last year there she was in a pulmonary specialist’s office with a catheter in her arm working away on an exercise test.
There she was, almost 30 years later, doing an exercise test in an attempt to figure what had gone wrong.
Her goal – to determine if the latest hot topic in ME/CFS – mitochondrial issues – were it for her. It turned out that they weren’t – her mitochondria appeared to be working fine. Nor, despite the sarcoidosis she had, was her lung capacity diminished – she still had the lungs of an athlete.
Her autonomic nervous system, however, was decidedly off. Her heart was beating way too fast and her blood was pooling in her legs instead of getting pushed back up to her heart, leaving her heart without much blood to pump. Her doctor, David Systrom at Brigham’s Women’s Hospital in Boston, turned to her and suggested Mestinon (pyridostigmine bromide). It’s helped, he said, with fatigue in patients like you have.
Now she’s at the upper limit prescribed for people with myasthenia gravis (180 mgs/day). She hasn’t been able to exercise without paying for it for almost three decades but it was clear within a couple of weeks that something was different. She described suddenly feeling like “going for a run” – a feeling she hadn’t had in decades. She was tired afterwards but the dreaded PEM never materialized.
Then she went cross-country skiing – one of the most energy intensive exercises there is. She’s now running 3 plus miles a couple of days a week and working out in the gym. She has one side effect that’s apparently caused by the medication; after exercise sometimes she feels lightheaded.
Other symptoms improved. She does take sleeping pills but now they seem to be working better and she was able to cut down her sleep by an hour or two a night. She’s able to work full days. Much of her alcohol intolerance has disappeared. Her very high resting heart rate has returned to normal. She’s not healthy but she’s improved enormously and she can exercise (!).
Imagine her shock when she learned that the drug that has done so much for her has been around for decades. It’s even prescribed for the orthostatic intolerance she has, but until Dr Systrom no one had ever mentioned it.
Systrom is an interesting figure. He doesn't appear to be interested in ME/CFS per se, but is very interested in exercise intolerance and is apparently bumping into ME/CFS patients from time to time. He’s at the same Boston hospital – Brigham and Woman’s Hospital – as Dr. Komaroff . (I believe but am not sure that a graduate student of his presented an abstract at the San Francisco IACFS/ME conference. )
I know of one other ME/CFS patient who has seen him. She, too, had preload failure and no mitochondrial issues but didn’t respond to Mestinon. Systrom is also connected with Dr. Oaklander who is doing small fiber neuropathy studies in FM.
Mestinon (Pyridostigmine bromide)
Mestinon is a drug that stimulates the parasympathetic nervous system (parasympathomimetic) by inhibiting the breakdown of the neurotransmitter (acteylcholine ) the PNS runs on. It does this knocking down the enzyme, acteylcholinesterase, that does breaks up acetylcholine. (It’s a cholinesterase inhibitor). That should mean more acetylcholine availability and more PNS activity – just what the doctor ordered for ME/CFS.
(Ironically Mestinon is produced by Valeant Pharmaceuticals – a poster child for rapacious price gouging in the pharmaceutical industry. Valeant’s former CEO is in jail and it’s under investigation from Congress, federal prosecutors and the Securities and Exchange Commission for its practice of buying up old drugs and raising their prices astronomically.)
Mestinon is primarily used in myasthenia gravis (MG), an autoimmune neuromuscular disease characterized by muscle weakness and fatigue. MG is usually caused by antibodies that attach to and block the acetylcholine receptors at the neuromuscular junction. Blocking the receptors makes it impossible for acetylcholine to tell the muscles to contract which leads to weakness and fatigue.
Myasthenia gravis is similar to ME/CFS in that it occurs more frequently in women, but is different in that it usually causes muscle weaknesses that show up in such symptoms as eyelid drooping and difficulty swallowing. Still the fatigue and weakness problems were similar enough to lead some Japanese researchers to suspect neuromuscular problems might be present in ME/CFS as well.
Their case study of three ME/CFS patients in 2003 suggested Mestinon might be helpful in ME/CFS. Each of the Japanese patients had a similar profile to the patient in this blog.
All three cases involved women with excessive fatigue whose extensive lab workup’s had been for the most part distressingly normal; clinical findings, blood chemistry, spinal fluid, cancer screen, urinalysis, stool, ECG, EKG, and motor conduction studies were all normal.
All displayed some evidence of EBV reactivation, however, and had mild autonomic problems (altered postganglionic sympathetic function and the heart rate response to deep breathing) and substantially reduced muscle activity (compound-muscle action amplitude at baseline).
Treatment with 30 mg of pyridostigmine bromide caused one young woman’s three year case of ME/CFS to promptly disappear, and her muscle strength to return to normal. After a month on pyridostigmine bromide another woman’s ten year problem with fatigue improved significantly with her “muscle-action amplitude” more than doubling. The last woman with 15 years of chronic fatigue syndrome experienced significant relief on the drug. The authors noted the “dramatic effects” Mestinon had on their patients.
The authors proposed that calcium channel problems perhaps caused by antibodies were impairing acetylcholine release at the neuromuscular junction in their patients. They suggested that Epstein-Barr virus may induce B-cells to produce antibodies which then cross-reacted with the calcium channels in the nerves. The inhibited calcium channels reduced acteylcholine release which in turn caused muscle weakness, fatigue and autonomic nervous system dysfunction.
They proposed that trials be done, but that was the last mention of Mestinon and ME/CFS in the scientific literature that I can find.
Orthostatic Intolerance and Mestinon
Mestinon, is also used to treat orthostatic intolerance. A large study (n=172) of postural orthostatic tachycardia syndrome (POTS) in 2011 found that Mestinon improved the symptoms in the 52% of patients able to tolerate the drug and 42% of patients overall.
Interestingly, among the most improved symptoms was fatigue (55% reported improvement) with palpitations, dizziness and fainting showing high rates of improvement as well. The most common side effects were gastrointestinal symptoms.
An overview of five Mestinon and orthostatic intolerance studies found that Mestinon improved “hemodynamic measurements” such as heart rate and blood pressure but could not conclude that Mestinon was significantly superior to placebo in improving symptoms.
A large fibromyalgia Mestinon/exercise study in 2008 was successful but not in the way the authors intended. Instead of enhancing HPA axis functioning, Mestinon appeared to assist autonomic nervous system functioning. The authors argued that this made sense given the dysautonomia that even then was clearly present in FM.
Mestinon did not improve pain or fatigue but did reduce anxiety and improved restorative sleep. The authors believed that increased vagal tone likely accounted for the improved sleep and they traced the reduced anxiety to improved heart rate variability – a measure of autonomic nervous system functioning. (Reduced heart variability – a function of poor vagus nerve functioning – has been associated with poor sleep in ME/CFS.)
(Exercise did improve fatigue, VO2 max, strength, etc. but not pain levels. Noting that rigorous exercise increased pain levels a more moderate course of exercise was used. It included low-impact, nonrepetitive cardioaerobics training for 30 minutes, strength training for 10 minutes, flexibility training for 5 minutes, balance training for 5 minutes, and relaxation for 10 minutes 3 times a week. The intensity goal was 40–50% of the patient’s maximum heart rate or a perceived exertion of 10–12 of a total of 20).
Parasympathetic Nervous System / Vagus Nerve Stimulating Options
Vagus nerve stimulation is getting ever more interesting. We’ve covered surgically implanted vagus nerve stimulators and non-invasive forms of vagus nerve stimulation on Health Rising in past stories. Now there’s Mestinon, and other possibilities are present.
A bevy of drugs, many of which have not been tried ME/CFS or FM, can improve parasympathetic nervous system functioning. They do so either by blocking aceytlcholine from being degraded (e.g. Mestinon), or by increasing acetylcholine release, or by inhibiting sympathetic nervous system activity.
Reversible parasympathomimetic drugs include Donepezil, Edrophonium, Neostigmine, Physostigmine, Pyridostigmine, Rivastigmine, Tacrine, Caffeine (non-competitive) and Huperzine A.
Drugs that inhibit sympathetic nervous system functioning (clonidine, propranolol, atenolol, methyldopa prazosin and oxymetazoline) are far more commonly used in ME/CFS and FM.
Dr. Natelson is expected to begin a non-invasive vagus nerve stimulation study in Gulf War Syndrome patients in the U.S. soon, and it’s believed that the non-invasive vagus nerve stimulator will be approved for use in the U.S. later this year as well.
The short history of Mestinon use in ME/CFS, FM and orthostatic intolerance has had mixed results. Mestinon did very well for our patient and in the three case reports from the Japanese. It’s apparently one of the few drugs that can significantly impact fatigue and exercise in the right person. It can also help with sleep and autonomic functioning – as our case report of a patient indicated. It may also be able to impact mood.
It was helpful but had modest effects in FM and orthostatic intolerance.
The small Japanese study suggested the drug may be particularly helpful for people with EBV activation and autonomic nervous system issues. Our patient had both EBV (she’s currently on Famvir) and ANS issues, and clearly belongs to an ME/CFS subset that benefits from vagus nerve stimulation. In fact, vagus nerve stimulation is the only treatment that’s significantly moved the bar for her almost thirty years. Her doctor was not surprised that she showed benefit.
Mestinon clearly won’t help everyone but it doesn’t appear to have gotten as much attention as it could have in ME/CFS. If you’ve tried Mestinon or other forms of vagus nerve stimulation please let us know how it went.
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising.