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Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports
https://pubmed.ncbi.nlm.nih.gov/14567934

 

describes three cases who fulfill the criteria of CFS, in whom a defect of neuromuscular transmission and dysautonomia are present and who respond to acetylcholine-esterase inhibition.

 

Case 1: 18-year-old female with a 3-year history of CFS. Response of compound-muscle-action potential, recorded using surface recording electrode, over left abductor pollicis brevis muscle, to repetitive nerve stimulation (RNS) at a rate of 10 Hz showed a 42% incremental response. Composite autonomic scoring system (CASS) showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2). Serological tests for Epstein-Barr virus (EBV) revealed positive antiviral capsid antigens (anti-VCA) immunoglobulins G (IgG). Oral pyridostigmine therapy (30 mg) resulted in marked improvement in symptoms.

 

Case 2: 28-year-old female with 10-year history of CFS. RNS, using identical protocol, showed a 60% incremental response over the same muscle. CASS showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2) and this patient was also positive for EBV. This patient responded dramatically to 10-mg pyridostigmine.

 

Case 3: 29-year-old female with a history of CFS for longer than 15 years. Repetitive stimulation, using identical paradigm to left abductor pollicis brevis muscle, showed a 42% incremental response. CASS showed mildly cholinergic impairment (cardiovagal score: 2; sudomotor score: 1). EBV antibody titers were positive. Patient responded to 30-mg pyridostigmine with an improvement in her fatigue. These three cases generate the hypothesis that the fatigue in some patients with clinical CFS might be due to a combination of mild neuromuscular transmission defect combined with cholinergic dysautonomia. Support for this thesis derives from the improvement with cholinesterase inhibition

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Vagus Nerve Stimulating Drug Helps Long Time ME/CFS Patient Exercise
https://www.healthrising.org/blog/2016/06/17/mestinon-chronic-fatigue-vagus-nerve-stimulation-exercise

 

She’s 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 were 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.

 

Mestinon turned out to be something of a miracle for her.  She took too much at first – and had some rather drastic side-effects –  but then ratcheted it down and then back up again.

 

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 within a couple of weeks 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. Her sleeping pills are 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 (!).

 

shocked

She was shocked when she found out that the drug that helped her had been around for decades.

 

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.

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Mestinon (Pyridostigmine bromide)

Mestinon is a cholinesterase inhibitor that stimulates the parasympathetic nervous system by inhibiting an enzyme called acteylcholinesterase that breaks down a crucial PNS neurotransmitter called acteylcholine. Taking Mestinon should result in  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.)

 

acetylcholinesterase

Mestinon is an acetylcholinesterase inhibitor (say that fast three times…)

 

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 between the two 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 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.

 

sleep mestinon

Perhaps by its effects on the vagus nerve Mestinon improved sleep in FM patients

 

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. in the study 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.

 

Conclusion

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.

 

Vagus nerve

Time will tell how important the vagus nerve is in ME/CFS and FM

 

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

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https://ammes.org/treatment/mestinon-pyridostigmine

Pyridostigmine (brand: Mestinon) is an acetylcholinesterase inhibitor. Pyridostigmine is poorly absorbed in the gut and does not cross the blood-brain barrier.

 

Pyridostigmine works by preventing the breakdown of acetylcholine (ACh) in nervous system synapses. This leads to an increase in acetylcholine, a neurotransmitter widely found in both the peripheral and central nervous systems. Acting as both an excitatory and inhibitory neurotransmitter, acetylcholine performs a variety of functions. Within the skeletal muscular system it contracts muscle, allowing for movement. It slows the heart, and promotes REM sleep. In the central nervous system, ACh is closely associated with learning, attention, and short-term memory.

 

Pyridostigmine is mainly prescribed for myasthenia gravis, an autoimmune condition in which acetylcholine is blocked, leading to profound muscle weakness. In spite of the fact that it does not cross the blood-brain barrier, pyridostigmine is also used to enhance memory in people with Alzheimer's disease. Pyridostigmine has been administered as a treatment for the paralysis caused by organophosphate pesticide poisoning. In a similar vein, the military administered pyridostigmine as a prophylactic to soldiers during the Gulf War to block potential exposure to Soman, a nerve gas which acts on acetylcholine in much the same manner as organophosphate pesticides. Recently, pyridostigmine has been used to treat orthostatic intolerance.

 

USES IN ME/CFS: In his book, Betrayal by the Brain, Dr. Jay Goldstein proposed that pyridostigmine could be used in ME/CFS with much the same results as in patients with myasthenia gravis, namely the alleviation of muscle weakness. Surprisingly, Dr. Goldstein found that even though pyridostigmine does not cross the blood-brain barrier it increased mental clarity in his ME/CFS patients. He noted that because pyridostigmine helps increase the secretion of growth hormone (GH), it might be of benefit to ME/CFS patients, who tend to have low levels of GH.

 

In 2003 a group of Japanese researchers published a study in which low-dose pyridostigmine was administered to three ME/CFS patients with dysautonomia and positive Epstein-Barr virus (EBV) titers. In all three cases, a one-month course of pyridostigmine relieved fatigue and muscle weakness. The authors speculated that EBV infection induces antibodies, which, through an inhibition of calcium influx at motor terminals, reduces acetylcholine release and causes muscle weakness and cholinergic autonomic dysfunction. The authors concluded that their case studies “strongly suggest therapy using a small dose (10 mg per day) of oral pyridostigmine in patients with CFS who have had more than a 40% amplitude increase in response to the RNS repetitive nerve stimulation test, positive anti-VCA IgG of EBV and mild impairment of autonomic functions.”

 

Based on findings that pyridostigmine increases growth hormone, a 2008 study of fibromyalgia patients in Portland, Oregon was conducted comparing exercise, diet and treatment with pyridostigmine. While the researchers did not find that either pyridostigmine alone or pyridostigmine plus exercise produced an improvement in most FM symptoms, they did find that pyridostigmine improved anxiety and sleep. The authors speculated that pyridostigmine may have improved vagal tone, thus alleviating sleep and anxiety symptoms

 

                           Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome
(click to open)Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports https://pubmed.ncbi.nlm.nih.gov/14567934 continued Three years prior to admission, she felt incapacitating fatigue during day. She was admitted to a local clinic. At that time, the general practitioner did not find any defects after physical and laboratory examinations. Her gestation, delivery, and developmental milestones were normal. General physical findings on admission were unremarkable. Her mental state, cranial nerve, sensation, and coordination were normal. She felt a symmetrical muscle weakness mainly in the shoulder and pelvic girdles. Her strength was MRC (Medical Research Council) scale grade (5) in the deltoid and iliopsoas, and normal in other muscle. She did not have ptosis and had no difficulty swallowing. There was no muscle atrophy and fasciculation. The deep tendon reflexes were normal and no pathological reflexes were elicited. Her blood chemistry levels including electrolytes, creatine kinase and thyroid hormones were normal. Cerebrospinal fluid biochemistry and cytology were normal. An extensive work up for neoplastic disease including total body computerized tomography scan was negative. Serologic tests for Epstein/Barr virus (EBV) revealed positive antiviral capsid antigens (anti-VCA) immuno-globulins G (IgG) and anti-EB-nuclear antigen anti-bodies, with a negative anti-VCA IgM. Urinalysis, stool examination, electrocardiogram (ECG), as well as chest and abdominal X-rays were all normal. She had abnormalities with post ganglionic sympathetic function and the heart rate response to deep breathing. The composite autonomic scoring system (CASS) showed three points (cardiovagal score: sudomotor score: 2) indicating mild autonomic impairments (Table 1). The serum titer of acetylcholine receptor antibodies had negative and the anti-P/Q-type auto antibody to the voltage-gated calcium-channel (VGCC) titer was not detected. ECG and electroencephalogram were normal. Magnetic resonance imaging (MRI) of the brain was normal. Edrophonium hydrochloride administered intravenously in a dose of 10 mg produced mild improvement in fatigability of the muscle. Motor conduction studies of median and ulnar nerves revealed conduction velocities of 45 and 42 m/s, respectively. The response to repetitive nerve stimulation (RNS), detected by surface electrodes overlying the left abductor pollicis brevis, showed a slight incremental response at a stimulation rate of 10 Hz (42% increment) and 3 Hz (10% increment). The amplitude of compound muscle action potential at baseline was 8.69 mV (Fig. 1). After the examination, oral treatment with 30 mg of pyridostigmine was given her and 1 week later, she relieved of her symptoms. Electrophysiologic improvement paralleled the increases in strength. The amplitude of compound-muscle-action potential at baseline was 14.49 mV at 1-month treatment 28-year-old female visited our hospital complaining of easy fatigue.  She had experienced chronic easy fatigability for greater than 10 years. Previous medical examinations at local clinics revealed no physical or laboratory abnormalities. The patient had no diplopia, ptosis, numbness, bladder symptoms or difficulty swallowing.  Her gestation, delivery, and developmental milestones were normal There were no abnormalities on general physical examination.  Neurological examination was normal except for the neuromuscular system. The patient felt symmetrical muscle weakness mainly in the shoulder and pelvic girdles. Her strength was MRC grade (5) in the deltoid and iliopsoas, and normal in other muscles. There was no muscle atrophy and fasciculation. The deep tendon reflexes were normal and no pathological reflexes were elicited. Her blood chemistry levels were normal. Cerebrospinal fluid biochemistry and cytology were normal.  An extensive work up for neoplastic disease was negative. Serologic tests for EBV revealed positive anti-VCA IgG and anti-EB-nuclear antigen antibodies, with a negative anti-VCA IgM. Urinalysis, stool examination, ECG, and chest and abdominal X-rays were all normal. The serum titer of acetylcholine receptor antibodies had negative and the anti-P/Q-type autoantibody to the VGCC titer was not detected. England electroencephalogram were normal. MRI of the brain was normal. She had abnormalities with post-ganglionic sympathetic function and the heart rate response to deep breathing. The CASS showed three points (cardiovagal score: 1; sudomotor score: 2) and meant mild autonomic impairment (Table 1). Motor conduction evaluations of median and ulnar nerves revealed conduction velocities of 44 and 46 m/respectively.  An incremental response of 60% was recorded over the left abductor pollicis brevis upon repetitive stimulation of the median nerveat10Hzandof 15% recorded at 3 Hz. The amplitude of compound-muscle-action potential at baseline was 8.28 mV (Fig. 1). A couple weeks of pyridostigmine administration with pyridostigmine (10 mg, p.o.), the patient was resulting in clinical improvement of fatigability.  After 1-monthtreatment, compound-muscle-action potential amplitude at baseline was 16.22 mV 29-year-old female visited our hospital complaining of general fatigue.  The patient had suffered from chronic fatigue for roughly 15 years and during this time, after consulting with colleagues, she attempted to treat herself using various drugs, including autoregressive agents, without any noticeable effect. The patient was admitted to our hospital in an attempt to confirm the diagnosis of Cashmere were no abnormalities presented upon general physical examination. Her mental state, cranial nerve, sensation, and coordination were normal. She felt asymmetrical muscle weakness mainly in the shoulder and pelvic girdles. There was minimal weakness of the deltoid and iliopsoas (MRC grade:  5_/) but other muscles were normal. She did not have ptosis or swallowing difficulty.  No atrophy, fasciculation, or reduced muscle tone were found.  The deep tendon reflexes were normal and no pathological reflexes were elicited. Her blood chemistry levels including electro-lutes, creatine kinase and thyroid hormones were normal. Cerebrospinal fluid biochemistry and cytology were normal. Neoplastic disease was not found. Serologic tests for EBV revealed positive anti-VCA IgG andante-EB-nuclear antigen antibodies, with a negative anti-VCA IgM. Urinalysis, stool examination, ECG, as well as chest and abdominal X-rays were all normal. The serum titer of acetylcholine receptor antibodies had negative and the anti-P/Q-type autoantibody to the VGCC titer was not detected and electroencephalogram showed normal. She had abnormalities with post ganglionic sympathetic function and the heart rate response to deep breathing. Her CASS score was three points (cardiovagal score: 2; sudomotor score: 1) indicating mild autonomic impairments (Table 1). MRI of the brain was normal. Motor conduction evaluations of median and ulnar nerves revealed conduction velocities of 48 and 50 m/s, respectively. The response to RNS, detected by surface electrodes over-lying the left abductor pollicis brevis, showed a slightly increased response at a stimulation rate of 10 Hz (60%increment) and 3 Hz (10% increment). The amplitude of compound-muscle-action potential at baseline was 13.11mV (Fig.  1).  The patient experienced relief of her symptoms after 1 month of oral treatment with 30 move pyridostigmine and the amplitude of compound-muscle-action potential at baseline was 15.14 mV (Table2 According to the diagnosis definition of CFS, Dyck etal.8, we diagnosed three cases as CFS. Our Cessations had the following four common characteristics:(1) the response to RNS detected by surface electrodes overlying the left abductor pollicis brevis was 42_/60%increased at a stimulation rate of 10 Hz; (2) the CASS showed mild cholinergic impairment; (3) serological tests for EBV revealed positive anti-VCA IgG; (4) drug therapy, using a small dose of oral pyridostigmine, had a dramatic effect on our patients. The RNS test gives direct electrophysiological evidence of neuromuscular transmission impairment and is the test of choice in neuromuscular transmission dis-orders. In LEMS, a remarkable increment of successive muscle action potentials occurs when performing a high rate of nerve stimulation test (10_/30 Hz). However, in normal subjects, both decremental and incremental responses have been reported when performing a high rate of nerve stimulation test9. Unfortunately, there are no clear-cut clinical neurophysiological diagnosis criteria of LEMS.  The  upper  limit  of  incremental increase of the response by high rate of nerve stimulation test in normal subjects is from 42.4 to 98.6%10.Although the increase of the responses by high-rate nerve stimulation in these three patients did not indication abnormal range, our data speculate that an increase of  40%  or  greater  in  patients  with  CFS  suggest  a neuromuscular transmission defect especially consider-Ing that a small dose of oral pyridostigmine therapy proved to be dramatically effective for our patients. CASS was determined by measuring the distribution and severity of postganglionic deficits, cardiovagal function and both peripheral alpha- and beta-adrenergic function and allotting four points for adrenergic and three points each for sudomotor and cardiovagal failure. This autonomic laboratory test is useful in grading the degree of autonomic failure with many neurological disorders such as Parkinson’s disease, multiple systematrophy11, diabetic neuropathy12, Guillain_/Barresyndrome13 and chorea-acanthocytosis14. It is well known that LEMS patients have autonomic dysfunctions such as dry mouth, impotence, gastrointestinal dysfunction and abnormal pupil responses15. O’Suil lea bhain et al.16 studied the autonomic functions of 30LEMS patients using CASS and observed sudomotor and cardiovagal dysfunctions. Their data is very similar to the results of CASS in our cases. The path physio-logic basis of autonomic symptoms in LEMS is under-stood less well than that of neuromuscular symptoms. The moderate autonomic improvement that follows administration of 3,4-diaminopyridine is consistent with presynaptic impairment of neurotransmitter release in autonomic nerve. Reports of improved autonomic symptoms following immunotherapy and tumor ablation  therapy  also  suggested  that  autonomic  neural function may be impaired by immune response17. Approximately, 50_/60% of patients with LEMS have an underlying tumor such as small-cell lung carcinoma, breast cancer, Hodgkin’s lymphoma, although 40% flams patients are non-cancer-associated cases15,18. Radioimmuno assays  reveal that  more than  90%  of patients with LEMS produce antibodies to VGCCs on-, P/Q- and L-type19,20. These antibodies inhibit calcium influx at motor nerve terminals by cross-linking calcium channels and presumably triggering their inter-nalization21,22. This reduce acetylcholine release and muscle weakness. Channels mediating neurotransmitter release from pre- and post-ganglionic autonomic neurons are not as well characterized, but current evidence implicates N-type channels23,24. Although none of our patients had antibodies to VGCCs, the EMG and CASS data strongly suggests that there was impairment of neurotransmitter release in the autonomic nervous system, which was induced, by calcium-channel impairment there is a ubiquitous DNA in the herpes virus family, which is transmitted from the upper respiratory tract and is one of the pathogenesis factors of CFS25. Neurological disorders of EBV infection that have been reported include central nervous systemic disorders, such as meningoencephalitis 26 and transverse myelitis 27,28, and peripheral nervous system disorders, such as a demyelinating polyradiculoneuropathy 27,29, mono-neuritis  multiplex30, multiple cranial neuropathy31,32, brachial plexopathies32 and  lumbosacralradiculoplexitis33. The pathogenesis of EBV associated neurological disorders is not completely known activates B-lymphocyte production of antibodies. This immune response to EBV may cross-react with calcium channels at the nerve terminal34.Lo ́ per-Navidad et al. reported a case of CFS with Reinfection. Their case showed improvement after under-going acyclovir therapy suggesting the possibility of a relationship between CFS and EBV infection35. These previous studies combined with our three case studies lead to speculation on possible mechanism causing CFS. First, all these patients had EB viral infection. EBV induces antibodies, which might cause amid cross-reaction to calcium channel at the nerve terminal and then inhibiting calcium influx at motor nerve terminals. This reduces acetylcholine release and causes very mild muscle weakness and cholinergic autonomic dysfunction. There is little in the way of established therapy, such as cognitive behavior therapy and short-term grouptherapy4,8, for CFS.  Our cases studies strongly suggest therapy using a small dose (10 mg per day) of oral pyridostigmine in patients with CFS who have had more than a 40% amplitude increase in response to the RNS test, positive anti-VCA IgG of EBV and mild impairment  of  autonomic  functions.  Although  the number of patients may be too small to make a definite conclusion,  we  suggest  that  a  small  dose  of  oral pyridostigmine study varies with regard to scientific trial study for CFS treatment back to top of article to click to close                                                                                                                                           click to closeNew Findings Elucidate Potentially Treatable Aspects of ME/CFSNew evidence of cardiopulmonary and nervous system abnormalities in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) yields clues to the etiology of their exercise intolerance and points to potential treatments. The findings were presented during the 2-day Accelerating Research on ME/CFS Meeting sponsored by the National Institutes of Health (NIH) and held on its main campus. The meeting brought together researchers from a range of scientific and clinical disciplines along with patients and patient advocates. Much of the focus on the clinical side centered around two key facets of the illness: postexertional malaise (PEM) and orthostatic intolerance (OI). According to the 2015 Institute (now Academy) of Medicine (IOM), definition of ME/CFS, PEM — described as a "crash" or worsening of all symptoms after even minor exertion — is required to make the diagnosis, along with at least 6 months of profound and disabling fatigue, and unrefreshing sleep. A fourth criterion is either OI or cognitive dysfunction. David M. Systrom, MD, a pulmonary and critical care medicine specialist and director of the Invasive Cardiopulmonary Laboratory at Brigham and Women’s Hospital (BWH), Boston, described results from invasive cardiopulmonary testing that show  that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, in which the major defect is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow compared with VO2 max, indicating left-to-right shunting. In addition, Systrom found that a large proportion of ME/CFS patients with these cardiopulmonary defects also have biopsy-demonstrated small fiber polyneuropathy, suggesting that PEM may be due to an underlying autonomic nervous system dysfunction. Also at the meeting, Peter C. Rowe, MD, director of the Children's Center Chronic Fatigue Clinic and professor of pediatrics at Johns Hopkins University School of Medicine, Baltimore, presented his colleagues' findings showing that, in patients with ME/CFS who have OI, cerebral blood flow drops significantly compared with controls on tilt-table testing even without changes in heart rate or blood pressure. And this was true regardless of VO2 max or recorded steps, suggesting again that the phenomenon isn't simply due to illness-related inactivity. In an interview with Medscape Medical News, Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, Utah, called the new data "huge." And regarding OI, she said, "I honestly think it's one of the biggest, most missed clinical finding that's amenable to supportive treatment." Systrom is now conducting a phase 3 clinical trial testing pyridostigmine bromide (Mestinon, Valeant Pharmaceuticals) in patients with ME/CFS. The drug is currently approved by the US Food and Drug Administration for the treatment of myasthenia gravis. The rationale for using pyridostigmine in ME/CFS, Systrom said, is that enhancement of cholinergic stimulation of norepinephrine release at the postganglionic synapse may improve venoconstriction at the site of exercising muscles, leading to improved return of blood to the heart and better distribution of oxygenated blood to the skeletal muscle mitochondrion during exercise Both Rowe and Bateman have used pyridostigmine off-label in ME/CFS patients with some success. Rowe told Medscape Medical News in an interview, "For some of our patients it can be transformative, even if they have not responded to fludrocortisone, midodrine, or beta-blockers." And Bateman, during a talk at the meeting, said that in her experience using pyridostigmine in patients with both ME/CFS and postural orthostatic tachycardia syndrome (POTS), "It's been an interesting and very effective intervention." "Preload Failure" Characterizes Many With ME/CFSAt BWH, Systrom and colleagues developed an invasive cardiopulmonary exercise test (iCEPT) to investigate patients with exertional intolerance that's not explained by the usual less-invasive cardiopulmonary evaluations. The test involves placement of radial and pulmonary arterial catheters that allow for direct measurement of systemic and pulmonary vascular pressures, systemic and mixed venous oxygen, and cardiac output during 6-8 minutes of cycling. The iCEPT was originally developed to detect early heart and heart-lung conditions, "but along the way what we found were patients with un- or under-explained exertional intolerance coming to us, many of them ending up with an ME/CFS clinical diagnosis. So I think we have something to offer with this test, which was initially developed to detect other diseases," Systrom said. Indeed, for the past 3 to 4 years, about half of the 10 or so weekly iCEPT tests done at BWH have been for patients who meet the IOM criteria for ME/CFS, he noted. During cycling, many ME/CFS patients will have relatively normal VO2 max levels but abnormally low filling pressure, particularly the right atrial pressure. That phenomenon, which Systrom and colleagues have called "preload failure," is seen in nearly all patients evaluated with iCEPT who meet ME/CFS criteria. In a study Systrom and colleagues published in 2016 on 49 patients with this phenomenon, giving two saline boluses corrected the problem in most cases. The authors concluded that inadequate ventricular filling related to low venous pressure is a clinically relevant cause of exercise intolerance. "In retrospect, most of those patients had evidence of ME/CFS," he observed. In addition, the difference between arterial and mixed venous oxygen content at peak exercise, a reflection of oxygen extraction in the periphery and the muscle, is abnormal in most ME/CFS patients. This could be a result of vascular dysregulation and peripheral left-to-right shunting, but also could be due to intrinsic mitochondrial dysfunction in the limb skeletal muscle, he speculated. These two defects differ from the cardiac output abnormality normally seen in people who are merely deconditioned, he emphasized, noting that prior studies have suggested increased, rather than decreased, biventricular filling pressures in deconditioning. Other data suggest that impaired systemic oxygen extraction is mildly affected in deconditioning or not at all. In a new, soon-to-be-published finding, 40% of 160 patients with ME/CFS and preload failure had evidence of small-fiber polyneuropathy on skin biopsy. That work was conducted with Anne Louise Oaklander, MD, PhD, a neurologist who directs the Nerve Unit and neurodiagnostic skin biopsy laboratory at Massachusetts General Hospital, Boston. Oaklander also spoke at the NIH meeting about her findings with small-fiber polyneuropathy in fibromyalgia, which shares some features of ME/CFS and often co-occurs in patients. She'll be presenting new data on that at the upcoming American Academy of Neurology meeting. Orthostatic Intolerance: A Major, Manageable Component of ME/CFSRowe has been investigating the relationship of OI to ME/CFS for over 20 years. In 1995, he and colleagues reported that an abnormal response to an upright 70-degree tilt-table test was seen in 22 of 23 patients with ME/CFS compared with just four of 14 controls. In that study, the tilt-table test elicited nausea and lightheadedness in 22 of the 23 patients (96%), diaphoresis in 19 (83%), blurred vision and abdominal discomfort in 18 each (78%), and syncope/fainting in 10 (43%). Other investigators have reported similar findings since, Rowe said. For example, a study published in 2012 demonstrated a link between increasing orthostatic stress and neurocognitive functioning in ME/CFS patients and POTS. As the level of tilt increased, subjects made more errors and had more delayed responses, typical of the so-called "brain fog" associated with ME/CFS Two phenomena appear to be contributing to the OI simultaneously, Rowe said: increased pooling of blood in the legs and decreased vasoconstriction, along with a decrease in circulating blood volume. But in a new and potentially paradigm-shifting finding, van Campen and colleagues used transcranial Doppler echography of the internal carotid and vertebral arteries during the tilt-table test in over 400 ME/CFS patients. They displayed a greater than 20% reduction in cerebral blood flow compared with a 6% reduction found previously in healthy volunteers "It was quite a profound change," Rowe said, noting, "Maybe we've been looking in the wrong place. If symptoms are due to decreasing cerebral blood flow, maybe that's where we should focus." The finding was seen even among the patients who did not demonstrate heart rate and blood pressure changes during the tilt test. And, arguing against the notion that the phenomenon is merely a result of deconditioning, the degree of cerebral blood flow decline was nearly identical between the 18 patients with VO2 max above 85% and the 59 with VO2 max below 85%, and didn't differ by the number of steps the patients took based on activity monitors. "Upright posture consistently aggravates ME/CFS symptoms, even in the absence of heart rate and blood pressure changes, often for days, consistent with orthostatic stress being a cause of post-exertional malaise," Rowe said. But, Rowe also noted, "OI is one of the most treatable problems in this illness." Indeed, during the meeting, Bateman, whose center provides information on how to perform a lean test, shared her tips for managing OI. She recommends teaching patients to stay hydrated and increase their salt intake and prescribing medications such as fludrocortisone. Compression socks can be helpful, as can intravenous saline, if available. She also prescribes low-dose beta-blockers and pyridostigmine to selected patients, and uses the 10-minute lean test to assess treatment efficacy. "Orthostatic intolerance is the low-hanging fruit. It is diagnosable and treatable and we have a lot of literature about how to deal with it," Bateman said, noting that, although it isn't a cure for ME/CFS, "Improving OI improves symptoms and function and gives patients more control over activity intolerance 'mestinon really seems to help get me up in the mornings and keep me functioning through the day'mestinon is being researched for cfs by dr david systrom in massachusetts right now, and he posits it helps pump blood back to the heart and muscles (because cfs causes the usual blood flow to become dysfunctional). he has noticed it helps with exercise intolerance in a subset of patients and generally the drug itself helps about 30% of cfs patients. im not sure if this is placebo but i’ve been on mestinon for two months now and i feel pretty terrible and not really able to get up in the mornings until my first dose has kicked in. it’s a weird feeling but it does seem like it really helps me with something energy wise, and not fake energy. but helps in the sense that it just corrects something that is a bit out of wack so my body can function a little bit better back to top of article to click to close                                                                                                                                            click to closeback to top of article

 

ME Specialists and Mestinon https://livingwithchronicfatiguesyndrome.wordpress.com

 

Pulmonologist, Dr. David Systrom, specialises in patients with disorders beneath the exercise intolerant umbrella. As cardinal symptoms of ME include post-exertional malaise and exercise intolerance, Dr. Systrom has begun to focus on this patient cohort. He has conducted invasive cardiopulmonary exercise testing on ME patients that can determine oxygen usage and blood flow abnormalities.

 

Over the past three years, Dr. Systrom has given Mestinon to hundreds of his exercise intolerant ME patients with autonomic nervous system anomalies. He has found that it has provided many patients with their lives back and “really helped many people.” Dr. Systrom encourages his ME patients to slowly increase their exercise levels, typically on a recumbent bike while on Mestinon. Dr. Systrom’s ME theories and rationale for using Mestinon can be found here.

 

An ME patient of Dr. Systrom experienced a miraculous recovery on Mestinon and her story can be found here. She gradually titrated her dosage upwards to 180mg a day, presumably taken in smaller doses e.g. 60mg three times per day.

 

Dr. Goldstein has included Mestinon in a list encompassing his favourite drugs for ME patients. He has noted that it has improved patients’ fatigue, cognitive impairment, muscle weakness and muscle aches. Dr. Goldstein believes that Mestinon may benefit ME patients due to the drug increasing growth hormone levels which are typically low in ME patients. His recommended dosages are in the 30mg-60mg a day range.

 

Dr. Teitelbaum has written briefly on Mestinon and has an interest in its ability to increase growth hormone in ME patients. He cites research by Dr. Robert Bennett that has found low growth hormone levels in ME patients. Dr. Teitelbaum also parrots Dr. Bennett’s finding that Mestinon can increase growth hormone levels when used at a dosage of 30-60mg taken 3-4 times daily. Renowned cardiologist, Dr. Blair Grubb, also has many of his POTS patients on Mestinon.

 

Studies

A Japanese case study by Kawamura et al. found that all three ME patients experienced positive “dramatic effects” from the Mestinon. The subjects had experienced ME for 3, 10 and 15 years and had dysautonomia and EBV titers. The patients responded to a daily dose of either 10mg or 30mg of Mestinon and were on the drug for one month. The authors concluded by strongly recommending small doses of oral Mestinon (10mg per day) in ME patients with:

 

Mild impairment of autonomic functions.

A positive EBV test (anti-VCA IgG).

An increase (40% plus) in response to the repetitive nerve stimulation test.

 

A Fibromyalgia study by Jones et al. found that patients experienced a significant improvement in sleep and anxiety after taking Mestinon. 154 out of the 165 Fibromyalgia patients completed the study with the authors theorising that the Mestinon helped due to improving vagal tone and therefore sleep and anxiety.

 

A study by Kanjwal et al. examining Mestinon usage on POTS patients found that 168 out of the 203 subjects were able to tolerate the drug. 55% experienced a reduction in fatigue after taking the treatment. 51% of those who tolerated the Mestinon experienced an improvement in orthostatic intolerance.

 

A study by Arvat et al. found that 60mg of Mestinon causes an increase in growth hormone. A study by Berwaerts et al. found that ME patients tended to have reduced nocturnal secretions of growth hormone. At one stage, Dr. Cheney believed low growth hormone was instrumental in the pathogenesis of ME. His musings about this can be found here.

 

Potential Mechanisms of Action in ME Patients

Mestinon may benefit ME patients due to:

• Increasing oxygen and blood flow to the muscles’ mitochondria.
• Increasing growth hormone levels.
• Improving parasympathetic nervous system and vagus nerve functioning.
• Increasing acetylcholine and thus promoting REM sleep, improving muscle movements and enhancing cognitive faculties.
• Raising exercise tolerance.

 

My Experience with Mestinon

My planned Mestinon dosing schedule involved an initial dose of 15mg and if tolerated, a gradual increase to 15mg taken 4 times a day. If I didn’t reap any benefits at this dose, I planned to venture up to 60mg taken 3 times per day (180mg per day total). I began a 15mg dose of Mestinon on the afternoon of the 1st of September. What followed was quite extreme sleepiness and drowsiness for the next 7 hours until I went to sleep at my normal bedtime.

 

The next day I trialled 15mg of Mestinon taken just before bedtime with the hope that this Mestinon-induced drowsiness would improve my sleep. Unfortunately my sleep was worse than normal! I would continuously wake just before my normal waking time. I also experienced more severe restless legs syndrome during this period. Another downside of the Mestinon was the next day sleepiness I would still inevitably endure. After a week of taking the 15mg dose of Mestinon before bedtime that was inducing continual poor sleep and RLS, I decided to cease the medication.

 

Dosage and Side Effects

In myasthenia gravis, the dosage of Mestinon is typically in the ballpark of 180mg a day (often taken in several smaller dosages). ME patients have generally used much lower doses, generally 30mg a day, although some patients have ventured up to 180mg a day. The Kawamura et al. case study on ME patients taking Mestinon recommended 10mg a day. In contrast, Dr. Systrom seems to encourage patients to gradually increase the dosage to 180mg a day if lower doses are tolerated. Dr. Goldstein is more moderate in his approach, recommending ME patients take 30-60mg per day.

 

Dr. Systrom states that any side effects are generally minor and may include diarrhea, gastrointestinal issues or twitching muscles. Anecdotally online, some ME patients have reported side effects that are typically gastrointestinal and transient. The Kanjwal et al. POTS study found the most common side effects to be gastrointestinal in nature with 19% experiencing this symptom. The Jones et al. Fibromyalgia study found that Mestinon was generally well tolerated. Mestinon should be used with caution in patients with diabetes or asthma.

 

Conclusion

Due to the side effects of sleepiness and also ironically, poor sleep, I only managed to take a low dosage of Mestinon for one week. It is therefore difficult to ascertain if it would have evoked any positive effects if taken longer and at a higher dose. The patients that may benefit most from Mestinon are; exercise intolerant patients with autonomic nervous system anomalies, patients with low levels of growth hormone, those with POTS or those with EBV and an increase in response to the nerve stimulation test. Mestinon is generally well tolerated with gastrointestinal side effects the most likely. Anecdotally online, there are a reasonable number of patients who have taken Mestinon, with some calling it a “miracle drug” for them, on the flip side, others have reported no effect or side effects

 

 

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