Chronic Fatigue Syndrome

Correcting the Missing Piece in Chronic Fatigue Syndrome – Part 1: Discovery

G

enetic Disease Investigators; January 2016

Abstract

Symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) can involve the central nervous system (cognition, executive function, short-term memory), the peripheral nervous system (muscle weakness, fatigue with exertion), and the autonomic nervous system (heart rate, blood pressure, breathing, digestion). A close analysis of 177 symptom checklists collected from CFS/ME patients over 4.5 years revealed a previously unreported commonality among patients. The majority of patients present with some level of anticholinergic syndrome – a dramatic deficiency of acetylcholine, which could be responsible for symptoms affecting the central, peripheral and autonomic nervous systems. This is the first time that low acetylcholine levels have been suggested as a cause of many disabling symptoms in CFS/ME.

Prevalence estimates of Chronic Fatigue Syndrome range from 0.5% to 3% in the United States (2-9 million sufferers), and yet effective treatment continues to elude practitioners. A syndrome similar to Chronic Fatigue Syndrome has been described as far back as the mid-18th century[1], but the medical community struggles for consensus. Indeed, even the name Chronic Fatigue Syndrome is a point of contention. Chronic Fatigue Syndrome may be called systemic exertion intolerance disease (SEID), myalgic encephalomyelitis, chronic fatigue, and immune dysfunction syndrome, among others.[2] Currently, most sources use a combined term, Chronic Fatigue Syndrome/Myalgia Encephalomyelitis (CFS/ME) to describe this disorder.

Frequency of Symptoms Occurring in Chronic Fatigue Syndrome

Symptom

Percent of patients

Easily fatigued

100

Difficulty concentrating

Headache

Sore throat

Tender lymph nodes

Muscle aches

Joint aches

Feverishness

Difficulty sleeping

Psychiatric problems

Allergies

Abdominal cramps

Weight loss

Rash

Rapid pulse

Weight gain

Chest pain

Night sweats

Figure 1. Straus, SE, J Infect Dis 1988; 157:405.[3]

Countless patients are clearly suffering from a constellation of debilitating
symptoms, yet there is a frustrating lack of objective biomedical findings. As such,
clinicians struggle to even make the diagnosis of CFS/ME, much less provide
effective treatment.

©2016 Genetic Disease Investigators, LLC
There is no ǲtypicalǳ presentation of CFS/ME, yet there are some features common
to many patients with the syndrome. Most patients are highly functioning prior to
illness and experience a sudden onset of symptoms, usually after a viral illness,
trauma or extreme stress. Excessive physical activity exacerbates fatigue and
related symptoms.

Many patients describe certain triggers that bring about or worsen symptoms such
as emotional distress, physical trauma, decreased sleep quantity/quality, infection,
and standing or sitting up for an extended period.4, 5, 6 Each of these triggers taxes
the patient and is, in one form or another, an exertion. Indeed, post-exertional
malaise is often included as a diagnostic criterion. Post-exertional malaise is an
exacerbation of some or all of an individual’s CFS/ME symptoms that occurs after
physical or cognitive exertion and leads to a reduction in functional ability.7 Exertion
exacerbates fatigue, cognitive symptoms, pain, delayed recovery of muscle function,
increased severity and incidence of sleep problems, and inappropriate autonomic
responses.4, 8, 9

A large number of additional symptoms, beyond fatigue, are present in a majority of
CFS/ME sufferers, and often, these symptoms can come and go. These symptoms
can include sore throat, tender lymph nodes, muscle and joint pain, feverishness,
insomnia, tachycardia, abdominal pain and others (see Figure 1). Attempts to locate
the underlying cause(s) of such disparate symptoms have been unsuccessful to date.
Some of the leading hypotheses are viral infection3, 10 immune dysfunction,11
endocrine/metabolic dysfunction,12, 13 neutrally – mediated hypotension,14,15 genetic
disorders,16, 17 disordered sleep,18 and complicated depression.19

Clearly, multiple systems of the body are involved simultaneously in CFS/ME.
Symptoms of CSF/ME involve the central nervous system (cognition, executive
function, short-term memory), the peripheral nervous system (muscle weakness,
fatigue with exertion), and the autonomic nervous system (heart rate, blood
pressure, breathing, digestion).

Central Nervous System in Chronic Fatigue Syndrome

The cognitive symptoms of CFS/ME can be every bit as debilitating as the physical
symptoms. Patients report phenomena ǲbrain fog,ǳ confusion, and the inability to
concentrate.5 Short-term memory deficits and slowed information processing are
common; the latter may be experienced as a mental fatigue similar to the physical
fatigue of the condition.20, 21

In CFS/ME, the prevalence of attention deficits may be as high as 93% and 85% for
memory disturbances.22 Three quarters of patients experience substantial difficulty
finding the correct words during verbal tasks.22 Problems remembering, difficulty
expressing thoughts, difficulty paying attention, slowness of thought,
absentmindedness, and difficulty understanding are orders of magnitude more
common in people with CFS/ME than in healthy volunteers.23

Peripheral Nervous System in Chronic Fatigue Syndrome

The peripheral nervous system (which controls muscles) has been found to affect
CFS/ME patients and not uncommonly, patients complain of weakness. Fulcher, et al
found that patients with CFS/ME were weaker than sedentary and depressed
controls, suggesting that weakness was not psychosomatic or secondary to
deconditioning. Their study found that CFS/ME patients had significantly higher
submaximal oxygen uptakes during exercise, and multiple regression models
suggested that exercise incapacity was directly related to quadriceps muscle
weakness.24

Autonomic Nervous System in Chronic Fatigue Syndrome

The autonomic nervous system controls bodily functions such as heart rate, blood
pressure, pupil dilation, digestion, and salivation. It coordinates the activity of
various organ systems without requiring conscious effort.

Many CSF/ME patients have abnormal autonomic nervous system
function.[2] Orthostatic intolerance (the inability to adjust heart rate and blood
pressure when changing position) is included in the updated diagnostic criteria for
Chronic Fatigue Syndrome. Orthostatic intolerance includes symptoms of
lightheadedness, dizziness, faintness, or syncope when vertical. Patients may
present with neurally mediated hypotension, extreme pallor, nausea, irritable bowel
syndrome, heart palpitations with or without cardiac arrhythmias, urinary
frequency and bladder dysfunction, and exertional dyspnea and/or postural
orthostatic tachycardia syndrome (POTS).7, 25

What anomaly can tie together disorders of peripheral, central and autonomic
nervous systems?

In order to look for clues to answer this question, between June 2011 and April
2015 Genetic Disease Investigators, LLC collected symptom questionnaires from
192 individuals with CFS/ME, resulting in 177 viable checklists. Each questionnaire
contained 156 potential symptoms listed alphabetically.

Not surprisingly, autonomic symptoms were common. Percentage of respondents
suffering with the following autonomic symptoms included:

Symptom

Constipation

Difficulty breathing

Dry eyes

Dry mouth

Gastroparesis

Light sensitivity

Large pupils

Lack of perspiration

Decreased blood pressure when standing

Bradycardia or tachycardia

Increased body temperature

Urinary retention

Central nervous system symptoms were also common. The percentage of respondents suffering with the following central nervous system symptoms included:

Symptom

Agitation

Abnormal mood swings – almost bipolar presentation

Confusion

Disorientation

Illogical thinking

Difficulty concentrating

Memory problems

Brain fog

Easily startled

Irritability

Peripheral nervous system symptoms were also common and were reported with the following frequency:

Symptom

Extreme fatigue

100

Tremor

Shaking

Wakeful myoclonic jerks

Loss of coordination (ataxia)

Additional symptoms not currently regarded as typical for CSF/ME (yet often present in anticholinergic syndrome) were reported with the following frequency:

Symptom

Seeing periodic flashes of light

Seeing “dancing lines, spiders or insects

Double vision

Hallucinations – auditory or visual

Textured surfaces bother you visually

Tunnel vision

Visual snow

Warping or waving of surfaces and edges

Sensitivity to sudden sounds

When viewed as a whole, the above 36 symptoms are the symptoms of Acute Anticholinergic Syndrome. This syndrome must be identified by presentation (not via blood work) because acetylcholine breaks down rapidly. These symptoms suggest, but do not prove, that the majority of patients with CFS/ME suffer from symptoms of extremely low levels of acetylcholine.

Could CSF/ME patients be suffering with extremely low levels of the neurotransmitter, acetylcholine, resulting in symptoms involving the peripheral, central and autonomic nervous system?

The actions of acetylcholine in the central, peripheral, and autonomic nervous systems

To understand abnormalities in acetylcholine, one must first understand where and how it acts under normal circumstances. Acetylcholine is the neurotransmitter of neuromuscular junctions, ganglia in the autonomic nervous system, and is present in discrete locations throughout the brain.[26]

In the central nervous system (the brain and spinal cord), acetylcholine is critical for memory formation and recall. For example, there are acetylcholine receptors in the hippocampus, Neil cortex, and amygdala — the main memory forming structures in the brain.[27] Likewise, acetylcholine is the major neurotransmitter in the basal nucleus of Meynert, which degenerates in Alzheimer’s disease.[28]

Acetylcholine is integral to the proper function of the peripheral nervous system and is the main neurotransmitter at every skeletal neuromuscular junction in the body. All conscious muscular movement requires acetylcholine.

Acetylcholine is a major component of the autonomic nervous system and is required for proper vagus nerve function.

Acetylcholine and Chronic Fatigue Syndrome

As a syndrome, CFS/ME is a constellation of symptoms. It is difficult to envision a single pathological process that gives rise to all of the various symptoms. Nevertheless, abnormalities in the acetylcholine system could explain many, if not most of the symptoms of CFS/ME.

The effects of acetylcholine deficiency are understood primarily because of the actions of atropine. Atropine blocks acetylcholine receptors, thus preventing the neurotransmitter from interacting with postsynaptic neurons. Acetylcholine deficiency (brought on by atropine) causes ventricular fibrillation, tachycardia (rapid heart rate), dizziness, nausea, blurred vision, loss of balance, dilated pupils, photophobia, dry mouth, dry eyes, extreme confusion, dissociative hallucinations, and excitation in addition to unusual symptoms such as visual snow and seeing “dancing lines, spiders and insects”.[29] [30]

The link between CFS/ME and acetylcholine has been subject of ongoing research with particular attention to potential autoimmune conditions that could affect acetylcholine receptors. For example, some researchers found autoantibodies against muscarinic cholinergic receptors in over half of people with CFS/ME.[31] [32]

Spence, Khan, and Belch showed that patients with CFS/ME have abnormalities in the acetylcholine (cholinergic) system.[33] The researchers showed the acetylcholinesterase inhibitor, edrophonium, applied to the skin reacts abnormally in patients with chronic fatigue syndrome. The same research group has confirmed the results of their research in several papers.[34] [35] [36] [37]

Yamamoto, et al (2012) used a radioactive agent that specifically binds to muscarinic acetylcholine receptors in the brain. They report decreased levels of receptors in the brain, but normal activity of acetylcholinesterase.[38]

Taken together, these results suggest an interesting possibility that explains the disparate findings of all of these researchers: CFS/ME patients may have abnormally low levels of acetylcholine.

Could CFS/ME patients improve by boosting levels of acetylcholine?

If this hypothesis was true, one could treat many symptoms of chronic fatigue syndrome by increasing acetylcholine levels within the synapse. Indeed, researchers have attempted to do this very thing. Kawamura and co-authors report three cases in which a small dose of oral pyridostigmine, an acetylcholinesterase inhibitor which increases acetylcholine levels in synapses, improved symptoms of chronic fatigue syndrome.[39] Many patients with POTS (Postural Orthostatic Tachycardia Syndrome) have improved gastrointestinal symptoms (gastroparesis, constipation) with the use of pyridostigmine.[40]

But because pyridostigmine does not cross the blood-brain barrier, it cannot boost acetylcholine in the brain and assist with central nervous system symptoms.

Acting on the evidence of low acetylcholine levels as exhibited by symptomology, Genetic Disease Investigators, LLC began to search for a compound that could cross the blood-brain barrier and boost acetylcholine in the central nervous system as well as effectively replace acetylcholine in the autonomic nervous system and the peripheral nervous system.

References

[1] Kim E. A brief history of chronic fatigue syndrome. JAMA. Oct 5 1994;272(13):1070-1071.

[2] White P. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Institute of Medicine.(Pp. 282; ISBN 978-0-309-31689-7; $£ 29.99; paperback.) The National Academies Press: Washington. 2015. Psychological Medicine.1-1.

[3] Straus SE. The chronic mononucleosis syndrome. J Infect Dis. Mar 1988;157(3):405-412.

[4] Davenport TE, Stevens SR, Baroni K, Mark Van Ness J, Snell CR. Reliability and validity of Short Form 36 Version 2 to measure health perceptions in a sub-group of individuals with fatigue. Disability and rehabilitation. 2011;33(25-26):2596-2604.

[5] US Food and Drug Administration. The voice of the patient. A series of reports from the US Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. Chronic fatigue syndrome and myalgic encephalomyelitis. 2013.

[6] Ocon AJ, Messer ZR, Medow MS, Stewart JM. Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome. Clinical Science. 2012;122(5):227-238.

[7] Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. Journal of chronic fatigue syndrome. 2003;11(1):7-115.

[8] Cordero D, Sisto S, Tapp W, LaManca JJ, Pareja J, Natelson B. Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome. Clinical Autonomic Research. 1996;6(6):329-333.

[9] LaManca JJ, Peckerman A, Sisto SA, DeLuca J, Cook S, Natelson BH. Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise. Psychosom Med. 2001;63(5):756-764

[10] Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause? JAMA. May 1 1987;257(17):2297-2302.

[11] Landay AL, Jessop C, Lennette ET, Levy JA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet. Sep 21 1991;338(8769):707-712.

[12] Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. Dec 1991;73(6):1224-1234. doi:10.1210/jcem-73-6-1224

[13] Bennett AL, Mayes DM, Fagioli LR, Guerriero R, Komaroff AL. Somatomedin C (insulin-like growth factor I) levels in patients with chronic fatigue syndrome. J Psychiatr Res. Jan-Feb 1997;31(1):91-96.

[14] Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. Sep 27 1995;274(12):961-967.

[15] Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. Am J Med. Sep 28 1998;105(3A):15S-21S.

[16] Smith AK, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics. Apr 2006;7(3):387-394. doi:10.2217/14622416.7.3.387

[17] Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics. Apr 2006;7(3):475-483. doi:10.2217/14622416.7.3.475

[18] Togo F, Natelson BH, Cherniack NS, FitzGibbons J, Garcon C, Rapoport DM. Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Arthritis Res Ther. 2008;10(3):R56. doi:10.1186/ar2425

[19] Taerk GS, Toner BB, Salit IE, Garfinkel PE, Ozersky S. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med. 1987;17(1):49-56.

[20] Constant EL, Adam S, Gillain B et al. Cognitive deficits in patients with chronic fatigue syndrome compared to those with major depressive disorder and healthy controls. Clin Neurol Neurosurg. May 2011;113(4):295-302.

[21] Lauren L, Malterud K. Identity and coping experiences in chronic fatigue syndrome; a synthesis of qualitative studies. Patient Educ Couns. 2007 Dec;69(1-3):20-8.

[22] De Becker P, McGregor N, De Meirleir K. A definition‐based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. Journal of Internal Medicine. 2001;250(3):234-240.

[23] Jason LA, Sunnquist M, Brown A, et al. Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Fatigue: biomedicine, health & behavior. 2014;2(1):40-56

[24] Fulcher Kym White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 Sept;69(3):302-7.

[25] Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Paper presented at: Mayo Clin Proc2012.

[26] Purves D, Augustine GJ, Fitzpatrick D, et al. Acetylcholine. 2001.

[27] van der Zee EA, Luiten PG. Muscarinic acetylcholine receptors in the hippocampus, neocortex and amygdala: a review of immunocytochemical localization in relation to learning and memory. Prog Neurobiol. Aug 1999;58(5):409-471.

[28] Liu AK, Chang RC, Pearce RK, Gentleman SM. Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease. Acta Neuropathol. Apr 2015;129(4):527-540. doi:10.1007/s00401-015-1392-5

[29] Das G. Therapeutic review. Cardiac effects of atropine in man: an update. Int J Clin Pharmacol Ther Toxicol. Oct 1989;27(10):473-477.

[30] Robenshtok E, Luria S, Tashma Z, Hourvitz A. Adverse reaction to atropine and the treatment of organophosphate intoxication. Isr Med Assoc J. Jul 2002;4(7):535-539.

[31] Tanaka S, Kuratsune H, Hidaka Y, et al. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med. Aug 2003;12(2):225-230

[32] Loebel M, Grabowski P, Heidecke H, et al. Antibodies to beta adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. Sep 21 2015. doi:10.1016/j.bbi.2015.09.013

[33] Spence VA, Khan F, Belch JJ. Enhanced sensitivity of the peripheral cholinergic vascular response in patients with chronic fatigue syndrome. Am J Med. Jun 15 2000;108(9):736-739.

[34] Khan F, Kennedy G, Spence VA, Newton DJ, Belch JJ. Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure. Clin Sci (Lond). Feb 2004;106(2):183-189. doi:10.1042/cs20030246

[35] Khan F, Spence V, Kennedy G, Belch JJ. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clin Physiol Funct Imaging. Sep 2003;23(5):282-285.

[36] Spence VA, Khan F, Belch JJ. Enhanced sensitivity of the peripheral cholinergic vascular response in patients with chronic fatigue syndrome. Am J Med. Jun 15 2000;108(9):736-739.

[37] Spence VA, Khan F, Kennedy G, Abbot NC, Belch JJ. Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. Apr 2004;70(4):403-407. doi:10.1016/j.plefa.2003.12.016

[38] Yamamoto S, Ouchi Y, Nakatsuka D, et al. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One. 2012;7(12):e51515. doi:10.1371/journal.pone.0051515

[39] Kawamura Y, Kihara M, Nishimoto K, Taki M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology. May 2003;9(3):189-194.

[40] Kanjwal K, Karabin B, Sheikh M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardia syndrome: a single-center experience. Pacing Clin Electrophysiol. 2011 Jun;34(6):750-5.

Correcting the Missing Piece in Chronic Fatigue Syndrome – Part 2: Treatment

G

enetic Disease Investigators; January 2016

Abstract

After discovering the majority of patients with CFS/ME appeared to suffer with anticholinergic syndrome, attempts to formulate a compound to boost acetylcholine in the central, peripheral, and autonomic nervous system began. Objective measure of success included the ability of the compound to trigger the postganglionic vagus nerve, resulting in a bowel movement. Out of 27 patients studied, 88% reported a bowel movement within 90 minutes of ingesting the patented compound (Parasym Plus™). A dramatic increase in mental/physical energy was reported by 93%. Parasym Plus™ can be effective in reversing many symptoms of CFS/ME.

Genetic Disease Investigators conducted an analysis of signs and symptoms reported by 177 patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Results revealed that the majority of patients suffered with symptoms and signs of anticholinergic syndrome (low acetylcholine levels). Symptoms involved abnormalities in the autonomic nervous system, the central nervous system and the peripheral nervous system.

Research then turned to why acetylcholine levels were low, and importantly, to explore the possibility of providing patients immediate relief by increasing levels of acetylcholine. If successful, many symptoms of autonomic dysfunction (orthostatic intolerance, tachycardia, gastroparesis, poor digestion, poor gall bladder function and others), central nervous system dysfunction (brain fog, cognitive decline, mood swings, irritability and others) and peripheral nervous system symptoms (extreme fatigue, tremor, loss of coordination and others) could potentially be alleviated.

Because acetylcholine is required for multiple nervous systems of the body, a replacement compound needs to be available in the brain (central nervous system), the muscles (peripheral nervous system) and the organs (autonomic nervous system). Because acetylcholine itself is not a drug (it is broken down immediately by the body), a replacement compound needed to be created that was easily and safely absorbed by the body. Additional goals for this compound were as follows:

The ingredients needed to assimilate in the body rapidly in order to stimulate the (postganglionic) vagus nerve to assist with all aspects of digestion (autonomic nervous system). Such vagus nerve stimulation could also improve immune system function and decrease systemic inflammation.
The levels of acetylcholine needed to increase in the central nervous system (brain) to help alleviate symptoms of “brain fog”, cognitive decline and poor short-term memory. To accomplish this, all ingredients needed to cross the blood-brain barrier.
The ingredients could not activate histamine-producing cells (or any aspect of inflammation).
The ingredients needed to be within what the FDA has already determined to be safe.
The combination of ingredients needed to be effective regardless of genetic defects involving the production of acetylcholine, should such defects be present.

The vagus nerve in CFS/ME

The vagus nerve (part of the autonomic nervous system) controls most aspects of digestion, inflammation and immune function, and because abnormalities in all of these conditions are considered significant contributors of symptoms in CFS/ME, focus on vagus nerve response was a critical aspect of research. The ability of the compound to trigger the (postganglionic) portion of the vagus nerve was an essential goal.

The vagus nerve controls most aspects of proper digestion including peristalsis of the food down the esophagus and through the intestines, opening of the pyloric valve at the base of the stomach (allowing food to pass into the intestines), the proper production of stomach acid required for digestion (and the absorption of numerous vitamins), the release of bile by the gall bladder, the release of digestive enzymes by the pancreas, and the opening of the Sphincter of Oddi (allowing the release of bile and pancreatic enzymes into the intestines). Many patients with CFS/ME suffer with delayed gastric emptying/gastroparesis/constipation, and other manifestations of gut dysfunction and irritable bowel syndrome (IBS).[1] [2] Gut inflammation has been proposed to be a significant contributor of symptoms in this population. [3]

Immune system function has also been found to be adversely affected in CFS/ME. [4] [5] Studies have found evidence of dramatic disturbances of immunity, including alteration in cytokine profiles in CFS/ME patients.[6] [7] Numerous aspects of cellular immunity have been found to be abnormal and are considered to be a key component to the disease.[8] [9] Proper functioning of the vagus nerve is critical for normal immune system function because the vagus nerve controls the function of the spleen, a key organ in both innate and adaptive immunity.[10] [11]

As the cholinergic anti-inflammatory pathway of the body, proper triggering of the vagus nerve can also decrease systemic inflammation.[12] [13] [14] The vagus nerve helps control inflammation both through its innervation of the spleen and through its control of inflammatory cells. [15] These inflammatory cells contain alpha-7 subunit containing nicotinic acetylcholine receptors which, when properly stimulated by the vagus nerve, control the release of inflammatory cytokines. This control links the inflammatory reflex to immunity, and proper functioning is critical to control abnormal inflammation often found in CFS/ME. Disorders of the inflammatory pathway can exhibit as neuroinflammation, cardiovascular disorders and gut inflammation in CFS/ME and appear to be a critical component to symptoms of illness.[16] [17] ²

Results of Treatment Trials

When eliciting response to treatment, objective measures are preferable to subjective responses. The objective finding of a bowel movement within 90 minutes of ingesting the compound (repeatable over two consecutive days) was considered an objective, positive response (indicating vagus nerve stimulation). Subjective responses (improvement in cognition, mental and physical energy) were also collected.

Twenty-seven (27) patients with CFS/ME volunteered to participate in treatment trials of the compound (now known as “Parasym Plus™”). All patients were over the age of 12 and were not taking Adderall, opioids, cholinergic or anticholinergic medications (medications which could mask the vagus nerve response). Patients were instructed to take the compound on an empty stomach, preferably in the morning prior to eating.

# of patients tested

Percent

Female n

93%

Age y

32 +/- 13

Positive for bowel movements within 90 minutes

88%

Increase in mental/physical energy

93%

Response of patient testing was dramatic. Twenty-four (24) out of 27 patients reported a bowel movement within 90 minutes of taking the ingredient mix, despite long-standing constipation/gastroparesis. This response was repeatable (occurring two consecutive days, at a minimum). Additionally, 25 out of 27 patients reported a significant improvement in both physical and mental energy.

Although preliminary, such dramatic response suggests that the majority of patients with CFS/ME may indeed be suffering with low levels of acetylcholine, contributing to illness. Perhaps more importantly, this demonstrates that effectively replacing the acetylcholine appears to alleviate many symptoms of illness.

These findings also suggest alternative explanations for many cases of POTS – Postural Orthostatic Tachycardia Syndrome, a commonly overlapping condition with CFS/ME. Currently, research has considered abnormal receptors of the autonomic nervous system (acetylcholine receptors) as a cause of autonomic dysfunction in POTS and CFS/ME. As stated by Loebel, et al, “autonomic dysregulation in CFS/ME points to an autoimmune disease directed against the neurotransmitter receptors”.[18] Such abnormalities can be found in autoimmune autonomic gangliopathy and research has delved deeply into the search for obscure autoimmune conditions that may be affecting these patients. [19] [20] [21]

Instead, this new research indicates that rather than a disorder affecting (acetylcholine) receptors, the majority of these patients may be suffering with a neurotransmitter problem (low acetylcholine levels).

The research of Genetic Disease Investigators, LLC continues to investigate the cause of acetylcholine decline, and to determine if the (initial) decrease of acetylcholine could be the cause of changes to the receptors found in some patients. Meanwhile, boosting acetylcholine levels while simultaneously stimulating the postganglionic portion of the vagus nerve (with patented Parasym Plus™) is effectively reversing numerous symptoms of CFS/ME.

References

[1] Burnet R, Chatterton B. Gastric emptying is slow in chronic fatigue syndrome. BMC Gastroenterol. 2004;4:32.

[2] Gamborone JE, Gorard DA, Dewsnap PA, eta l. Prevalence of irritable bowel syndrome in chronic fatigue. J R Coll Physicians Lond. 1996 Nov-Dec;30(6):512-3.

[3] Lakhan S, Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010;7:79.

[4] Thayer J, Sternberg E. Neural aspects of immunomodulation: Focus on the vagus nerve. Brain Behav Immun. 2010 Nov;24(8):1223-1228.

[5] Pavlov VA, Tracey KT. Neural circuitry and immunity. Immunul Res. 2015 Dec;63(1-3):38-57.

[6] Lorusso L, Mikhaylova SU, Capelli E. Immunological aspects of chronic fatigue syndrome, Autoimmun Rev. 2009 Feb;8(4):287-91.

[7] Natelson B, Haghighi M, Ponzio N. Evidence for the presence of immune dysfunction in chronic fatigue syndrome. Clin Diagn Lab Immunol. 2002 Jul;9(4):747-752.

[8] Barker E, Fujimura SF, Fadern MB, et al. Immunologic abnormalities associated with chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S136-41.

[9] Pollack S. Chronic fatigue syndrome and immune dysfunction: cause or effect? Isr Med Assoc J. 2002 Nov;4(11 Suppl1):883-5.

[10] Trion Am, Vasilescu C. Role of the spleen in immunity. Immunologic consequences of splenectomy. Chirurqia (Bucur). 2008 May and Jun;103(3):255-63.

[11] Wluka A, Olszewski WC. Innate and adaptive processes in the spleen. Ann Transplant. 2006;11(4):22-9.

[12] Ulloa L. the vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov. 2005 Aug;4(8):673-84.

[13] Martelli D, McKinley MJ, McAllen RM. The cholinergic anti-inflammatory pathway: a critical review. Auton Neuroscr. 2014 May;182:65-9.

[14] Pavlov V, Tracey K. the vagus nerve and the inflammatory reflex – linking immunity and metabolism. Nat Rev Endocrinol. 2012 Dec;8(12):743-754.

[15] Matteoli G, Gomez-Pinilla PJ, Nemethova A, et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut. 2014 Jun;63(6):938-48.

[16] Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: An C-(R)-PK11195 PET study. J Nucl Med. 2014 Jun;55(6):945-50.

[17] Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders of the inflammatory and oxidative and nitrosative stress (IO & NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett.2009;30(6):677-93.

[18] Loebel M, Grabowski P, Heidecke H, et al. Antibodies to beta adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. Sep 21 2015. doi:10.1016/j.bbi.2015.09.013

[19] Li J, Zhang Q, Liao Y, et al. The value of acetylcholine receptor antibody in children with postural tachycardia syndrome. Pediatr Cardiol. 2015;36:165-170.

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