Chronic Fatigue Syndrome and Dry Eye Syndrome


Chronic Fatigue Syndrome also known as Myalgic Encephalomyelitis (ME) and Dry Eye Syndrome





Patients with conditions from an uncertain cause and, in many cases, with no objective molecular proof of a molecular abnormality, have always represented a challenge to all medical and surgical specialties. Chronic Fatigue Syndrome (CFS) and Dry Eye Syndrome or Dry Eyes (DES) have led to a debate in medicine and ophthalmology for years. How can we prove that what the patient is experiencing is real?


When I was at college at Columbia University in NYC my best friend’s soon to be husband was about to experience the frustration of not being believed. He graduated with my friend from Columbia Law School and soon came down with a undefined condition that would eventually after many years of negative testing be diagnosed as Chronic Fatigue Syndrome. This affected their marriage hard and after many years my friend and he amicably separated. Years later, he regained his strength, though not perfectly and is able to work in his profession as a lawyer. 


For many years everyone, even his family, thought he was burnt out from the intensive law school experience. Like many patients with CFS, he went from doctor to doctor with no help and no definitive diagnosis. 


Dry Eye Syndrome, similarly, until recently, was a very subjective diagnosis. Often and still patients complain of terrible dry eyes and our better than ever but not perfect diagnostic tests reveal everything to be normal. Why does this happen?


There is new research showing the role of biofilms in CFS and changes in the Central Nervous System (CNS) that could explain why the experience of pain and irritative symptoms in the eyes and throughout the body, such as in Fibromyalgia, Irritable Bowel Syndrome, TMJ, affect some patients and not others who have similar exams, tests, and physiology. 




Below are some new studies that help shed light on CFS and DES and their connection.
It is still very difficult for a physician in some cases to make the claim that the CFS is causing the DES when all their usual tests are essentially normal (ie, when the SJO or all early Sjogrens test markers are normal, all blood work is negative, the Lipiview and Lipiscan, RPS, Tear Osmolarity, Tear Break Up time is normal.) 


Still there is a great deal eyeMDs do not know about DES:
1. What are the goblet cells really doing? 
2. Are the goblet cells decreased or damaged in this patient? 
3. Are the corneal nerves damaged? 
4. What aqueous output is the lacrimal gland producing? 
5. Is the molecular structure of the mucin, aqueous, meibum “normal”?
6. Do the cells under the eyelid properly lubricate the cornea without any scar tissue or abnormalities of those cells (ie, is there truly lid wiper epitheliopathy?)
7. Does the patient blink fully and strongly enough to pump the oil out of the meibomian gland? 
8. Is the conjunctiva truly flat on the sclera and not leading to disruptions in the tear film (ie, does the patient have Conjunctivochalasis?) 


If we had these answers in addition to what objective (mostly) information we have, we would likely be able to pick up more objective abnormalities. 


Below are some good articles and sites that begin to break into the subjectivity of CFS & DES and show the underlying physical issues.
Sandra Lora Cremers, MD, FACS

A patient sent me this link which shows a study beginning to help patients with CFS & DES. 
http://www2.le.ac.uk/offices/press/press-releases/2015/january/eye-health-could-help-diagnose-people-with-chronic-fatigue-syndrome
    Eye health could help diagnose people with ME

Research details

  • Type of funding: Fight for Sight / Thomas Pocklington Trust Small Grant Award
  • Grant Holder: Dr Claire Hutchinson
  • Institute: University of Leicester
  • Region: East Midlands
  • Start date: June 2015
  • End Date: May 2016
  • Priority: Emerging threats
  • Eye Category:

Overview

People with myalgic encephalomyelitis (ME) consistently report having trouble focussing on images, eye strain, vision-related headaches, slow eye movements and tracking moving objects, in addition to hypersensitivity to light and dry eye. So it’s possible that one or more of these symptoms experienced together with fatigue could be a defining feature of the condition. If so, it would make it easier for doctors to diagnose it, especially as none of the other symptoms people may experience are specific to ME.
In this project, the research team is testing 50 participants who have been diagnosed with ME to get an objective picture of eye problems that may be linked to the condition. They’ll be looking for information such as

  • how often and how severely dry eye happens,
  • how the participants’ pupils respond to light,
  • how well they can focus on objects at different distances,
  • clarity and depth of vision and
  • the ability to perceive colour.

The team will also scan images of the participants’ eyes to find out whether the shape of the eye is affected and examine the retina at the back of the eye (which contains the ‘photoreceptor’ cells that detect light). This information will be compared to results from a control group of 50 participants without ME.
ME is also sometimes known as ‘chronic fatigue syndrome’.

References: 
 2014 Feb;34(2):191-7. doi: 10.1007/s00296-013-2850-9. Epub 2013 Sep 3.

A possible genetic association with chronic fatigue in primary Sjögren’s syndrome: a candidate gene study.

Norheim KB1, Le Hellard S, Nordmark G, Harboe E, Gøransson L, Brun JG, Wahren-Herlenius M, Jonsson R, Omdal R.

Abstract

Fatigue is prevalent and disabling in primary Sjögren’s syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS <50 denominated “low fatigue” (n = 53) and VAS ≥50 denominated “high fatigue” (n = 140). We detected signals of association with pSS for one SNP in SLC25A40 (unadjusted p = 0.007) and two SNPs in PKN1 (both p = 0.03) in our pSS case versus control analysis. The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002). One SNP in PKN1 displayed an association in the case-only analysis of pSS high fatigue versus pSS low fatigue (p = 0.005). This candidate gene study in pSS did reveal a trend for associations between genetic variation in candidate genes and fatigue. The results will need to be replicated. More research on genetic associations with fatigue is warranted, and future trials should include larger cohorts and multicentre collaborations with sharing of genetic material to increase the statistical power.


 2016 Jan;95(4):e2607. doi: 10.1097/MD.0000000000002607.

Dry Eye Syndrome Risks in Patients With Fibromyalgia: A National Retrospective Cohort Study.

Abstract

The coexistence of fibromyalgia (FM) and dry eye syndrome (DES) has been previously reported. However, there are few studies on how patients with FM may develop concomitant DES. Patients with chronic widespread pain, like FM, chronic fatigue syndrome, and irritable bowel syndrome (IBS), was concerned for the rheumatic or psychosomatic disorders which might adequately reflect the long-term risk of DES. We retrieved data on FM patients from the National Health Insurance Research Database of Taiwan covering the years 2000 to 2011. Our FM population consisted of 25,777 patients versus 103,108 patients in the non-FM group: the overall incidence of DES in these populations was 7.37/10,000 and 4.81/10,000, respectively. Male FM patients had a higher incidence of DES, with a 1.39-fold DES risk for males and a 1.45-fold for females after adjustment for confounding factor. Notably, FM patients aged ≤49 years had an elevated 80% risk of DES compared with the non-FM group. Without comorbidities, FM patients had an approximately 1.40-fold risk of DES than those without FM. The additive effects of FM and IBS or FM and sleep disturbance were pointed out that the risk for DES would be elevated when the FM patients with IBS or sleep disturbance. FM patients have a higher incidence of DES than that of non-FM patients. They carry long-term DES risks from a relatively young age, particularly those with psychiatric problems. Risk stratification for a timely psychiatric medication intervention and risk modifications are not intended.

Science to share with your doctor.

Microbes in the human body

According to a recent National Institutes of Health (NIH) estimate, 90% of cells in the human body are bacterial, fungal, or otherwise non-human.1 Although many have concluded that bacteria surely enjoy a commensal relationship with their human hosts, only a fraction of the human microbiota has been characterized, much less identified. The sheer number of non-human genes represented by the human microbiota – there are millions in our “extended genome”2 compared to the nearly 23,000 in the human genome – implies we have just begun to fathom the full extent to which bacteria work to facilitate their own survival.

The NIH’s ongoing initiative, the Human Microbiome Project, aspires to catalog the human microbiome, also referred to as the human metagenome. Emerging insights from environmental sampling studies have shown, for example, that in vitro based methods for culturing bacteria have drastically underrepresented the size and diversity of bacterial populations. One environmental sample of human hands found 100 times more species than had previously been detected using purely culture-based methods. Another study which also employed high throughput genomic sequencing discovered high numbers of hydrothermal vent eubacteria on prosthetic hip joints, a species once thought only to persist in the depths of the ocean.


http://autoimmunityresearch.org/science/

https://mpkb.org/home/pathogenesis

Science behind Pathogenesis

The Marshall Pathogenesis, upon which the Marshall Protocol is grounded, is a description for how bacteria interfere with the innate immune response. These pathogens survive and reproduce by disrupting the Vitamin D Nuclear Receptor, an evolutionarily consistent mechanism for survival, which leads to the development of chronic inflammatory diseases. Because these diseases are fundamentally bacterial in nature, the conditions are referred to as the “Th1 diseases.” The Marshall Pathogenesis is supported by an emerging array of evidence, including clinical evidence, evolutionary evidence, some in silico data, and environmental sampling studies.

Microbes in the human body

According to a recent National Institutes of Health (NIH) estimate, 90% of cells in the human body are bacterial, fungal, or otherwise non-human.1) Although many have concluded that bacteria surely enjoy a commensal relationship with their human hosts, only a fraction of the human microbiota has been characterized, much less identified. The sheer number of non-human genes represented by the human microbiota – there are millions in our “extended genome”2) compared to the nearly 23,000 in the human genome – implies we have just begun to fathom the full extent to which bacteria work to facilitate their own survival.
The NIH’s ongoing initiative, the Human Microbiome Project, aspires to catalog the human microbiome, also referred to as the human metagenome. Emerging insights from environmental sampling studies have shown, for example, that in vitro based methods for culturing bacteria have drastically underrepresented the size and diversity of bacterial populations. One environmental sample of human hands found 100 times more species than had previously been detected using purely culture-based methods. Another study which also employed high throughput genomic sequencing discovered high numbers of hydrothermal vent eubacteria on prosthetic hip joints, a species once thought only to persist in the depths of the ocean.

Successive infection and variability in disease

Chronic diseases manifest in patients and within patient populations with a high degree of variability. Some people have five chronic diseases, and others have one. Some patients experience symptoms of disease early in life while others not until they are very old. According to the Marshall Pathogenesis, this variability can be attributed to several factors.
Over the course of a lifetime, patients pick up the approximately 90 trillion bacteria to which they play host.3) While some researchers refer to each person’s unique microbiota as an individual’s “pathogen burden” and other terms,4) 5) we have referred to it as a person’s “pea soup.” In everyday language, the term pea soup is otherwise used to refer to a dense fog – an apt metaphor for the human microbiota. The promiscuity with which bacteria exchange DNA as well as the sheer number of bacteria to which any given person plays host are both factors which severely limit researchers’ ability to accurately predict species-species and species-disease interactions.
The process by which a person accumulates the bacteria which drive disease is known as “successive infection.” In successive infection, an infectious cascade of pathogens slow the immune response and allow for subsequent infections to proliferate, resulting in dysbiosis (microbial imbalances). In patients sick with chronic inflammatory diseases, successive infection is ongoing and has additive properties: generally speaking, the more sick people are, the more sick they tend to become. Like a person’s pea soup, the process by which a person accumulates additional bacteria via successive infection has an inherent variability to it.

Transmission of chronic disease

Pathogens that grow slowly and accumulate over the course of decades may play a strong role in many chronic diseases. These bacteria are transmitted in a variety of ways: mother to fetus, sperm to embryo, and among families and social groups. Particular patient groups without the benefit of a fully functioning immune system, specifically newborn infants, people who already have illnesses, and the elderly, are uniquely susceptible to pathogens.
Those who use or consume any of the foods, drugs, and supplements which exert immunosuppressive effects are also uniquely predisposed to acquire new bacteria and permit them to reproduce. These substances include: immunosuppressants, beta-lactam antibiotics such as penicillin, high levels of vitamin D, and corticosteroids.
The acquisition of new bacteria is only one factor in the when and why chronic diseases strike. Bacteria are capable of rapidly changing their genetic structure – and can become more pathogenic and harder to kill with traditional therapies – through processes like horizontal gene transfer. Also, bacteria are allowed to proliferate because of a disabled immune response, for which they themselves are at least partially responsible.

Koch’s postulates

Main article: Koch’s posutlates
Microbiologist Robert Koch was born in 1843. Koch’s postulates are a series of ground rules to determine whether a given organism can cause a given disease. Koch theorized that a pathogen must be:
  • found in all cases of the disease examined
  • prepared and maintained in a pure culture
  • capable of producing the original infection, even after several generations in culture
  • retrievable from an inoculated animal and cultured again
For all their lingering influence, Koch’s postulates never anticipated the era of the human metagenome in which thousands of difficult or impossible-to-culture species of bacteria contribute to a single disease state. Koch’s century-old ideas have held science back from understanding how chronic disease occurs because they make no provision for these facts.
The Marshall Pathogenesis is consistent with mounting evidence that Koch’s postulates no longer apply to discerning the vast amounts of microbes in the human body.

Horizontal gene transfer

Main article: Horizontal gene transfer
Horizontal gene transfer (HGT), sometimes referred to as lateral gene transfer, is any process in which a bacterium inserts genetic material into the genomes of other pathogens or into the genome of its host. HGT represents a substantial blow to the validity of Koch’s postulates, which state that any given infectious disease is caused by a single discrete and well-defined pathogen.
Increasingly, studies of genes and genomes are indicating that considerable horizontal gene transfer has occurred between bacteria.
James Lake, Molecular Biology Institute at the University of California
In fact, due to increasing evidence suggesting the importance of the phenomenon in organisms that cause disease, molecular biologists such as Peter Gogarten at the University of Connecticut have described horizontal gene transfer as “a new paradigm for biology.“
Gorgarten insists that horizontal gene transfer is “more frequent than most biologists could even imagine a decade ago” and that this reality turns the idea that we can classify organisms in a simple “tree of life” on its head.
Instead Gogarten suggests that biologists use the metaphor of a mosaic to describe the different histories combined in individual genomes and use the metaphor of a net to visualize the rich exchange of DNA among microbes.

Innate immune response and Th1 inflammation

The innate immune response is the body’s first line of defense against and non-specific way for responding to bacterial pathogens.6)Located in the nucleus of a variety of cells, the Vitamin D nuclear receptor (VDR) plays a crucial, often under-appreciated, role in the innate immune response.
When functioning properly, the VDR transcribes between hundreds7) and thousands of genes8) including those for the proteins known as the antimicrobial peptides. Antimicrobial peptides are “the body’s natural antibiotics,” crucial for both prevention and clearance of infection.9) The VDR also expresses the TLR2 receptor, which is expressed on the surface of certain cells and recognizes foreign substances.
The body controls activity of the VDR through regulation of the vitamin D metabolites. 25-hydroxyvitamin D (25-D) antagonizes or inactivates the Receptor while 1,25-dihydroxyvitamin D (1,25-D) agonizes or activates the Receptor.
Greater than 36 types of tissue have been identified as having a Vitamin D Receptor.10)
Another component of the innate immune response is the release of inflammatory cytokines. The result is what medicine calls inflammation, which generally leads to an increase in symptoms.
Before the Human Microbiome Project, scientists couldn’t link bacteria to inflammatory diseases. But with the advent of DNA sequencing technology, scientists have detected many of the bacteria capable of generating an inflammatory response. All diseases of unknown etiology are inflammatory diseases.

Vitamin D

Main article: Science behind vitamin D
A number of studies have suggested that patients with chronic inflammatory diseases are deficient in 25-hydroxyvitamin D (25-D) and that consuming greater quantities of vitamin D, which further elevates 25-D levels, alleviates disease symptoms.
Some years ago, molecular biology identified 25-D as a secosteroid. Secosteroids would typically be expected to depress inflammation, which is in line with the reports of short-term symptomatic improvement. The simplistic first-order mass-action model used to guide the early vitamin studies is now giving way to a more complex description of action.
When active, the Vitamin D nuclear receptor (VDR) affects transcription of at least 913 genes and impacts processes ranging from calcium metabolism to expression of key antimicrobial peptides. Additionally, recent research on the Human Microbiome shows that bacteria are far more pervasive than previously thought, dramatically increasing the possibility that the spectrum of chronic diseases is bacterial in origin.
Emerging molecular evidence suggests that symptomatic improvements among those administered vitamin D is the result of 25-D’s ability to temper bacterial-induced inflammation by slowing VDR activity. While this results in short-term palliation, persistent pathogens that influence disease progression proliferate over the long-term.

Th1 Spectrum Disorder

<mainarticle> Th1 Spectrum Disorder
Th1 Spectrum Disorder refers to the group of chronic inflammatory diseases, which are hypothesized to be caused by the Th1 pathogens, a microbiota of bacteria which include L-form, biofilm, and intracellular bacterial forms. Although the exact species and forms of bacteria, as well as the location and extent of the infection, vary between one patient suffering from chronic disease and the next, the disease process is common: bacterial pathogens persist and reproduce by disabling the innate immune response.
Although patients who become infected with the Th1 pathogens are given a variety of diagnoses, there are often no clear cut distinctions between one disease and the next. Rather, symptoms frequently overlap creating a spectrum of illness in which diseases are more connected to one another than mutually exclusive disease states.
The evidence that chronic disease is ultimately a spectrum disorder with a common cause includes:
  • comorbidity of inflammatory diseases overlap observed between patients suffering distinctly defined diseases
  • the infrequency with which patients suffer from just a single disease or condition
  • failure of diagnostic compartmentalization: the frequent difficulty doctors have in clearly and definitively diagnosing a patient

Incidence and prevalence of chronic disease

The last half century has seen a steady increase in the incidence and prevalence of chronic inflammatory diseases with further increases expected. According to the Marshall Pathogenesis, a number of factors are to blame:
  • misuse of antibiotics especially Beta-lactam antibiotics
  • vitamin supplementation including folic acid but especially vitamin D
  • presence of environmental factors which suppress immunity
  • novel vectors for sharing pathogens including blood donation
  • widespread adoption of compulsory mass vaccinations

Familial aggregation

Main article: Familial aggregation
Familial aggregation refers to occurrence of a given trait shared by members of a family that cannot be readily accounted for by chance. For example we hear that certain diseases “run” in families, or we note that an entire family unit suffers from an inflammatory disease such as obesity. While it has long been understood that acute infections like tuberculosis, polio, and HIV are communicable, it is less well appreciated that the same can be said for the chronic pathogens which cause Th1 diseases.
The reigning explanation for familial aggregation is that people pass down faulty genes to their offspring. However, the theory is not supported by solid evidence. Scientists have failed to find genes that might cause any major chronic inflammatory disease. In the case that they have found a relationship between a gene and a disease, statistical significance is usually so low that environmental influences such as bacteria could easily be causing the genetic mutations. To date, no form of gene therapy has proven effective for treating inflammatory disease.

Evolutionary perspective on disease

One useful way to determine if a disease is caused by faulty human genes is look towards the central principle of evolutionary biology: evolutionary fitness. Evolutionary fitness is defined as the extent to which an organism is adapted to or able to produce offspring in a particular environment. The fitness concept can be applied to the problem of disease causation to distinguish evolutionarily feasible hypotheses of causation from marginally feasible or untenable ones.11) 12)
Generally speaking, diseases have three major causes: genetic, environmental, and infectious. Each disease affects, to some degree, an organism’s ability to reproduce, that is, their reproductive fitness. As a general rule, infectious disease confers no reproductive benefit but genetic diseases do, either currently or historically.

Evidence that chronic disease is caused by pathogens

The mainstream, but antiquated, view about chronic disease is best expressed by a certain physician thusly: “Of our thousand bacterial species, I only have to worry about a couple dozen” while a 2002 Nature paper concludes, “Multicellular organisms live, by and large, harmoniously with microbes.13)
However, there is substantial evidence that chronic diseases are caused by pathogens as opposed to other causes. This evidence includes:
  • researchers’ failure to identify any kind of telltale genetic connection in disease in twins and other studies
  • familial aggregation of disease and incidence in small communities in close contact
  • migration studies
  • single region changes in incidence
  • transmission of disease through blood and tissue donation
  • inferential evidence from what is known about evolution and reproductive fitness
In addition, it seems highly likely that supposedly non-infectious chronic diseases are in fact caused by pathogens when one considers their clinical features, histology, treatment response, microbe populations, presence of co-infections, the ease with which co-infections proliferate, and the failure of systematic lifestyle interventions.
According to the Marshall Pathogenesis, humans accumulate a plethora of pathogenic bacteria during their lifetimes, and it is the genetic mutations which result from active infection that play a major role in what is commonly thought of as “genetic susceptibility.”
Besides the absence of proof implicating human genes as the major causative factor, there is a range of evidence – including strong epidemiological and compelling evolutionary evidence – suggesting that pathogens cause chronic diseases.

Alternate models for chronic disease

The evidence supporting a bacterial cause for chronic disease is strong. Still, there are other competing explanations including the acid/alkaline imbalance theory, autoimmune disease theory, the genetic predisposition theory, the single pathogen theory, and the spontaneous remission theory. Some have argued that viral co-infections are to blame for diseases of unknown etiology despite the evidence which has accumulated to the contrary.

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References

1) , 3)

The human microbiome project.
Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI
Nature449p804-10(2007 Oct 18)
2)

Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches.
Cevenini E, Caruso C, Candore G, Capri M, Nuzzo D, Duro G, Rizzo C, Colonna-Romano G, Lio D, Di Carlo D, Palmas MG, Scurti M, Pini E, Franceschi C, Vasto S
Curr Pharm Des16p609-18(2010)
4)

Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry.
Epstein SE, Zhu J, Burnett MS, Zhou YF, Vercellotti G, Hajjar D
Arterioscler Thromb Vasc Biol20p1417-20(2000 Jun)
5) Mitchell S.V. Elkind et al. “‘Infectious Burden’ – New Insights into Stroke Prevention.” European Neurological Review, 2010;5(1):34–38.
6)

Innate recognition of intracellular pathogens: detection and activation of the first line of defense.
Rasmussen SB, Reinert LS, Paludan SR
APMIS117p323-37(2009 May)
7)

A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.
Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton SM, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC
Genome Res20p1352-60(2010 Oct)
8)

Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes.
Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, Bourdeau V, Konstorum A, Lallemant B, Zhang R, Mader S, White JH
Mol Endocrinol19p2685-95(2005 Nov)
9) , 13)

Antimicrobial peptides of multicellular organisms.
Zasloff M
Nature415p389-95(2002 Jan 24)
10)

From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health.
Norman AW
Am J Clin Nutr88p491S-499S(2008 Aug)
11)

Infectious causation of disease: an evolutionary perspective.
Cochran GM, Ewald PW, Cochran KD
Perspect Biol Med43p406-48(2000 Spring)
12)

Chlamydia pneumoniae and cardiovascular disease: an evolutionary perspective on infectious causation and antibiotic treatment.
Ewald PW, Cochran GM
J Infect Dis181 Suppl 3pS394-401(2000 Jun)



Letter to the Editor
Etiology of sicca syndrome in a consecutive series of 199 patients with chronic fatigue syndrome
Etiología del síndrome seco en una serie consecutiva de 199 pacientes con síndrome de fatiga crónica
Rami Qannetaa,, , Ramon Fontovab, Anna Pàmiesb
a Chronic Fatigue Unit, Department of Rheumatology, Hospital Universitari Joan XXIII, Tarragona, Spain
b Department of Rheumatology, Hospital Universitari Joan XXIII, Tarragona, Spain
Dear Sir,

Chronic fatigue syndrome (CFS) is a heterogeneous and multisystemic disorder of unknown pathogenesis and etiology. It is characterized by prolonged generalized and abnormal fatigue post-exercise (98%), recurrent headache (90%) and problems of concentration and memory (85%) that have lasted for at least 6 months. It is accompanied by such other symptoms as tender lymph nodes (80%), musculoskeletal pain (75%) and psychiatric problems (65%).1,2The prevalence of CFS is estimated to be between 0.5 and 2.5%, predominantly in women (4:1).1,2 Many patients with CFS also complain of sicca symptoms in up to 30–87%, and are more likely to have thyroid disorder and sleep disruption;2,3 that may suggest an underlying role of the immune system in these patients. Primary Sjögren’ syndrome (PSS) is a systemic autoimmune disease, that presents chronic exocrine glands hypofunction leading to xerostomia and/or xerophthalmia, and extraglandular involvement, of which autoimmune hypothyroidism (AIHT) is the most common autoimmune disease developed4. Patients with PSS, also experience CFS-like musculoskeletal and neurocognitive symptoms more than 50%, and the two disorders share some similar immunologic defects.4 The purpose of this study was to determine the causality of sicca symptoms in 199 consecutive patients diagnosed as having CFS, and the possible association with PSS, although few studies that have examined this association (between 2010 and 2012 in our chronic fatigue unit of Joan XXIII University Hospital) according to the Fukuda’ criteria of 1994. One hundred sixty-seven patients (84%) were women. The age of onset of symptoms was 41±10 years. Mucosal sicca symptoms were complained by 160 patients (80.4%): 11/160 (6.8%) patients were diagnosed with PSS (9 patients were incomplete PSS and 2 patients were complete PSS by positive lower lip biopsy that had MSG focus score >1, using the American-European criteria 20025). 110/160 patients (68.75%) were mainly duo to xerogenic medications. Severe obstructive sleep apnea syndrome (OSAS) was diagnosed in 6/160 patients (3.75%) (according to the American Academy of Sleep Medicine, Chicago Criteria 1999) by polysomnographic analysis. Thirty-eight (23.75%) patients were sero-positive for thyroperoxidase antibody (TPO-Ab) and/or thyroglobulin antibody (Tg-Ab) (of these patients 33/160 (20.6%) were diagnosed as having AIHT), 15 (10.2%) had a positive antinuclear antibody (ANA) assay (titer count >1:160), and 5 (3.5%) had a positive parietal cell antibody (titer count >1:160). All were sero-negative for anti-Ro/SS-A and anti-La/SS-B. In previous studies mucosal sicca symptoms were described as one of the common clinical manifestations of CFS6,7 as seen in our serie. Nishikai et al. and Sirois et al. had found sicca symptoms in 73% and 52% of their series respectively.6,7 As possible causes in our study, we determined that the prevalence of sicca symptoms (especially xerostomia) induced by psychotropic medications with anticholinergic side effects (amitriptyline, clonazepam, etc.) was high as described in several studies. Drugs with anticholinergic actions decrease salivary gland secretion by neurochemical blockade. It is usually dose related and reversible when medication is discontinued.7 We also found a group of CFS patients with sicca symptoms that may be attributed to AIHT and OSAS. This suggests that these two disorders share common pathophysiological features with CFS. Interestingly, in patients with OSAS, CFS symptoms were improved by using continuous nasal positive airway pressure (CPAP). Any potential relationship between CFS and PSS is complicated by the lack of a sensitive test or agreement regarding the diagnostic criteria for PSS. Nishikai et al. examined a group of 75 seronegative patients diagnosed with CFS and found that 22 (29%) met the European criteria 1993 for PSS.6 Sirois et al. also examined 25 patients diagnosed with CFS and found that 32% met diagnostic criteria for PSS according to the European criteria 1993.7 These results were not similar to ours in the study we present (11 patients if we included patients with incomplete PSS) as we described previously (Table 1). In searching of causes of this poor association, several considerations have to be taken into account in our study. 1st, in our study we used the 2002 criteria that require mandatory: (1) a positive salivary gland biopsy (only done in 5 patients), or (2) the presence of antibodies to SSA/Ro and/or to SS-B/La (negative in all patients). The serological item was also met in the 1993 criteria (used by Nishikai et al. and Sirois et al.,6,7) but only if a test for rheumatoid factor or ANA was positive. This condition has probably increased the prevalence of PSS in their studies. 2nd, symptoms or signs of PSS do not always begin at the same time and that patients with incomplete SS may be will met the diagnostic criteria 2002 at some point in the future. In summary, in our study about 70% of CFS patients with sicca syndrome are related to be drug-induced. Therefore, xerogenic medications, as possible cause, must be excluded. However, we recommend that patients who have been diagnosed with CFS and manifest mucosal sicca symptoms should be also screened for SS, AIHT and/or OSAS; and should be regarded as a comorbidity of CFS, not a diagnostic exclusion criterion.

Table 1.
Causes of sicca symptoms in chronic fatigue syndrome’ patients.

Causes of sicca symptoms in chronic fatigue syndrome’ patients  N°. patients (%): 160 (80.4) 
Xerogenic medications  110 (68.75) 
Autoimmune hypothyroidism  33 (20.6) 
Primary Sjögren syndrome (incomplete/complete)  11 (6.8)(9/2 patients) 
Obstructive sleep apnea syndrome  6 (3.75) 

Conflict of interest

The authors declare no conflict of interest.

References

1

B.M. Carruthers,M.I. Van de Sande,K.L. De Meirleir,N.G. Klimas,G. Broderick,T. Mitchell
Myalgic encephalomyelitis: International Consensus Criteria
J Intern Med, 270 (2011), pp. 327-338 http://dx.doi.org/10.1111/j.1365-2796.2011.02428.x

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