Genetic Disease Investigators; January 2016
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, 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. 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|
|Tender lymph nodes||80|
|Figure 1. Straus, SE, J Infect Dis 1988; 157:405.|
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.
There is no “typical” 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.   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. Exertion exacerbates fatigue, cognitive symptoms, pain, delayed recovery of muscle function, increased severity and incidence of sleep problems, and inappropriate autonomic responses.  
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 infection  , immune dysfunction, endocrine/metabolic dysfunction , neutrally – mediated hypotension  , genetic disorders , disordered sleep, and complicated depression.
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 “brain fog,” confusion, and the inability to concentrate. 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. 
In CFS/ME, the prevalence of attention deficits may be as high as 93% and 85% for memory disturbances. Three quarters of patients experience substantial difficulty finding the correct words during verbal tasks. 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.
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.
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. 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). 
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:
|Lack of perspiration||46|
|Decreased blood pressure when standing||78|
|Bradycardia or tachycardia||81|
|Increased body temperature||57|
Central nervous system symptoms were also common. The percentage of respondents suffering with the following central nervous system symptoms included:
|Abnormal mood swings – almost bipolar presentation||41|
Peripheral nervous system symptoms were also common and were reported with the following frequency:
|Wakeful myoclonic jerks||74|
|Loss of coordination (ataxia)||77|
Additional symptoms not currently regarded as typical for CSF/ME (yet often present in anticholinergic syndrome) were reported with the following frequency:
|Seeing periodic flashes of light||63|
|Seeing “dancing lines, spiders or insects”||42|
|Hallucinations – auditory or visual||28|
|Textured surfaces bother you visually||45|
|Warping or waving of surfaces and edges||29|
|Sensitivity to sudden sounds||96|
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.
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. Likewise, acetylcholine is the major neurotransmitter in the basal nucleus of Meynert, which degenerates in Alzheimer’s disease.
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”. 
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. 
Spence, Khan, and Belch showed that patients with CFS/ME have abnormalities in the acetylcholine (cholinergic) system. 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.   
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.
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. Many patients with POTS (Postural Orthostatic Tachycardia Syndrome) have improved gastrointestinal symptoms (gastroparesis, constipation) with the use of pyridostigmine.
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.
 Kim E. A brief history of chronic fatigue syndrome. JAMA. Oct 5 1994;272(13):1070-1071.
 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.
 Straus SE. The chronic mononucleosis syndrome. J Infect Dis. Mar 1988;157(3):405-412.
 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.
 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.
 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.
 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.
 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.
 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
 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.
 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.
 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
 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.
 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.
 Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. Am J Med. Sep 28 1998;105(3A):15S-21S.
 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:10.2217/146224220.127.116.117
 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:10.2217/14622418.104.22.1685
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
 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.
 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.
 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.
 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.
 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
 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.
 Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Paper presented at: Mayo Clin Proc2012.
 Purves D, Augustine GJ, Fitzpatrick D, et al. Acetylcholine. 2001.
 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.
 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
 Das G. Therapeutic review. Cardiac effects of atropine in man: an update. Int J Clin Pharmacol Ther Toxicol. Oct 1989;27(10):473-477.
 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.
 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
 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
 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.
 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
 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.
 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.
 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
 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
 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.
 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.
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