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Page 1 of 25 Academiejaar 2017 2018 Chronic fatigue syndrome an update Céline VAN GUTTE Promotor 1: Prof. dr. De Muynck Martine Promotor 2: Dr. Rimbaut Steven Masterproef voorgedragen in de master in de specialistische geneeskunde Fysische geneeskunde & revalidatie

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Page 1: Chronic fatigue syndrome - Ghent University€¦ · Chronic fatigue syndrome is a widespread condition with a huge impact not only on a patient’s life, but also on society as evidenced

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Academiejaar 2017 – 2018

Chronic fatigue syndrome – an update

Céline VAN GUTTE

Promotor 1: Prof. dr. De Muynck Martine

Promotor 2: Dr. Rimbaut Steven

Masterproef voorgedragen in de master in de specialistische geneeskunde

Fysische geneeskunde & revalidatie

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Academiejaar 2017 – 2018

Chronic fatigue syndrome – an update

Céline VAN GUTTE

Promotor 1: Prof. dr. De Muynck Martine

Promotor 2: Dr. Rimbaut Steven

Masterproef voorgedragen in de master in de specialistische geneeskunde

Fysische geneeskunde & revalidatie

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Chronic Fatigue Syndrome – An Update Steven Rimbaut MD, Céline Van Gutte MD, Lina Van Brabander MD, Luc Vanden Bossche

MD, PHD

Department of Physical and Rehabilitation Medicine, University Hospital Ghent

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Abstract The objective of this review is to systematically review the recent literature on chronic fatigue

syndrome/myalgic encephalomyelitis. The published literature between January 1, 1990 and April 1,

2014 was searched using the MEDLINE, Cochrane Library, and Web of Sciences databases. The

reference lists of the selected articles were screened for other relevant articles.

Chronic fatigue syndrome is a widespread condition with a huge impact not only on a patient’s life,

but also on society as evidenced by substantial losses of productivity, informal costs and medical

expenses. The high prevalence rates (0.2% - 6.4%) and the low employment rates (27-41%) are

responsible for the enormous burden imposed on society, with loss of productivity representing the

highest cost.

Despite extensive research, none of the proposed etiological factors have shown strong, reproducible

scientific evidence. Over the years the biopsychosocial model integrating many of the proposed

hypotheses has been gaining popularity over the biomedical model where the focus is on one

physical cause. Since the etiological mechanism underlying chronic fatigue syndrome is currently

unknown, disease-specific treatments do not exist. Various treatments have been investigated but

only cognitive behaviour therapy (CBT) and graded exercise therapy (GET) have shown moderate

effectiveness.

Introduction Fatigue is a common complaint in society. For patients to be diagnosed with chronic fatigue

syndrome, unexplained fatigue must have been present for at least 6 months. Different sets of

criteria have been published, each focusing on different aspects. In literature, this condition is being

referred to as “chronic fatigue syndrome” or “myalgic encephalomyelitis”.

This review is designed to update and critically review the recent literature on CFS. We especially

focused on the recent insights concerning post exertional malaise and on the biopsychosocial model.

In addition, we collected recent literature data on the costs associated with chronic fatigue

syndrome. Because of its chronic nature, the condition has a huge impact not only on a patient’s life

but also on society as evidenced by substantial losses of productivity, informal costs and medical

expenses.

Methods The published literature between January 1, 1990 and April 1, 2015 was searched using the MEDLINE,

Cochrane Library, and Web of Sciences databases. In addition, the reference lists of the selected

studies and review articles were screened for potentially relevant citations. Only peer-reviewed

articles in English, French and Dutch were included. The following terms were used: chronic fatigue

syndrome, myalgic encephalomyelitis, history, criteria, diagnosis, epidemiology, pathogenesis,

therapy, treatment, prognosis, costs, employment. Patients had to fulfill one of the published criteria.

(Carruthers B et al. 2003;Fukuda et al. 1994;Holmes et al. 1988;Lloyd et al. 1990;Sharpe et al. 1991)

Only studies and articles on adult populations >18 years were used. Observational and interventional

designs were accepted. Results were considered significant when P<0.05.

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History Over time, many names have been used to define chronic fatigue syndrome or CFS.

In 1881, Beard (1881) described a similar syndrome as “neurasthenia”.(Beard GM 1881) The place of

outbreak was also considered in labelling the condition. (Parish 1978) In 1934, an outbreak occurred

at the Los Angeles General Hospital where 198 employees suffered from rapid muscle weakness,

clonic twitches and cramps, ataxia, severe pain aggravated by exercise and neck and back stiffness. In

1937 and 1939, two outbreaks with similar symptoms were reported in Switzerland. After an

outbreak in Iceland in 1948-1949, the term “Akuryri disease” was used. In 1955, at the Royal Free

Hospital in London, 292 patients suffered from fever and persistent fatigue. From then on, the name

“Royal Free Disease” was used.

In 1984, researchers described the chronic Epstein-Barr virus syndrome or chronic mononucleosis-

like syndrome. (DuBois et al. 1984) It was characterized by a combination of atypical symptoms

(fatigue, sore throat, fever, myalgia, painful lymph nodes, etc) in the absence of any objective clinical

signs. The hypothesis at that time suggested a latent Epstein-Barr infection, although no antibodies

were detected in the serum of patients.

Other commonly used names include chronic fatigue immune dysfunction syndrome, post-viral

syndrome and low natural killer cell syndrome, the last term being particularly used in Japan. (Aoki et

al. 1987;Straus et al. 1985)

Aspecific physical and psychological complaints emerging after the Gulf war in 1991-1992, were

designated as the Gulf war syndrome and showed similarities with CFS. (Kilshaw S 2004)

Currently chronic fatigue syndrome and myalgic encephalomyelitis are commonly used to describe

CFS.

The term chronic fatigue syndrome appeared in the 1980 to define the syndrome without knowing

the exact aetiology of the disease. (Holmes, Kaplan, Gantz, Komaroff, Schonberger, Straus, Jones,

DuBois, Cunningham-Rundles, Pahwa, & . 1988) It was worldwide accepted after the publication of a

set of criteria by the United States Centers for Disease Control and Prevention (CDC) in 1994.

(Fukuda, Straus, Hickie, Sharpe, Dobbins, & Komaroff 1994)

In 1956, Acheson (1956) described myalgic encephalomyelitis using the following characteristics:

presence of symptoms that imply damage to the brain or the spine, muscle soreness, emotional

disturbances, no irregularities in the cerebrospinal fluid and involvement of the reticuloendothelial

system. (Acheson DE 1956)

Currently, the two terms are used interchangeably despite different diagnostic criteria.

Diagnostic criteria Many sets of diagnostic criteria have been developed to confirm the diagnosis of unexplained

fatigue.

In 1988, the CDC proposed a set of major and minor criteria. (Holmes, Kaplan, Gantz, Komaroff,

Schonberger, Straus, Jones, DuBois, Cunningham-Rundles, Pahwa, & . 1988) The two major criteria

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and at least 8/11 of the minor criteria had to be met for a definite diagnosis of CFS. The major criteria

were a new onset of persistent or relapsing debilitating fatigue not resolving with bed rest and

causing reduced daily activity. Other clinical conditions that may produce similar symptoms must be

excluded. The minor symptoms consisted of low-grade fever, sore throat, tender lymph nodes,

muscle weakness, muscle pain, postexertional fatigue, headache, arthralgia, neuropsychological

complaints and sleep disturbances. These symptoms had to coincide with or follow the onset of

fatigue. In addition, the complaints must have been present for at least 6 months.

In 1994, Fukuda et al. (1994) altered those criteria to enhance the applicability in clinical practice.

(Table 1) (Fukuda, Straus, Hickie, Sharpe, Dobbins, & Komaroff 1994) The number of symptoms

required to establish the diagnosis were reduced to 9. Beyond persistent fatigue for at least 6

months, patients had to present at least 4/8 other symptoms. Other possible physical and mental

conditions had to be excluded. (Table 2) Importantly, a treated major depression was not an

exclusion criterion.

When the inclusion criteria were not met but CFS-like symptoms were present, the condition was

classified as “clinically evaluated unexplained chronic fatigue”.

Major and minor symptoms

Ma

jor

sym

pto

m

Obligatory

Clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is of new or definite onset (not lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities. The fatigue needs to be present for at least 6 months

Min

or

sym

pto

ms

4/8 required (for at least 6 months)

Tender cervical or axillary lymph nodes Sore throat Muscle pain Multi-joint pain without joint swelling or

redness Headaches of a new type, pattern or severity Unrefreshing sleep Post-exertion malaise lasting more than 24

hours Self-reported impairment in short-term

memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities

Table 1: Fukuda criteria (2)

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Permanent medical exclusions

Temporary medical exclusions

Permanent psychiatric exclusions

Organ failure Conditions that resolved (e.g., pregnancy until 3 months post-partum, breastfeeding, major surgery until 6 months post-operation, minor surgery until 3 months post-operation, major infections such as sepsis or pneumonia until 3 months post-resolution)

Bipolar affective disorders

Chronic infections Major conditions the resolution of which may be unclear for at least 5 years (e.g., myocardial infarction, heart failure)

Schizophrenia

Rheumatic and chronic inflammatory diseases

Morbid obesity (BMI>45) Delusional disorders

Major neurologic diseases Dementias

Diseases requiring systemic treatment

Organic brain disorders

Major endocrine diseases Alcohol or substance abuse within 2 years of onset of fatiguing illness

Primary sleep disorders Anorexia nervosa or bulemia nervosa

Table 2: Exclusion criteria published by Fukuda et al (2)

The more stringent Canadian criteria published in 2003, with an update in 2011, added other

categories of symptoms to the prior list, such as autonomic symptoms, neuro-endocrine symptoms

and immunological symptoms. (Carruthers B, Jain A, De Meirleir K, Peterson D, & Klimas A

2003;Carruthers et al. 2011) A small study compared CFS patients diagnosed on the basis of the

Canadian or Fukuda criteria with patients with fatigue explained by psychiatric diseases. (Jason et al.

2003) In contrast to the Fukuda criteria, the Canadian criteria selected cases with less psychiatric

comorbidity, more physical functional impairment, more fatigue/ weakness and more neurological

symptoms. Two recent studies again showed that patients meeting the Canadian criteria had more

functional impairments and more severe physical and cognitive symptoms than the subgroup only

meeting the Fukuda criteria.(Jason et al. 2013;Johnston et al. 2014)

Other sets of criteria are the Oxford criteria (1991) and the Australian criteria (1990). (Lloyd, Hickie,

Boughton, Spencer, & Wakefield 1990;Sharpe, Archard, Banatvala, Borysiewicz, Clare, David,

Edwards, Hawton, Lambert, Lane, & . 1991)

Health care workers predominantly use the Fukuda criteria to settle on a diagnosis of CFS because of

their easy applicability in clinical practice. (Fukuda, Straus, Hickie, Sharpe, Dobbins, & Komaroff 1994)

Most of the clinical trials are based on these criteria.

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Although a clinical case definition is a well-established instrument, its strict application may not

always be appropriate in the evaluation of a specific patient.

The physical and mental symptoms of CFS show a fluctuating pattern in which moderate activities are

alternated with prolonged inactivity, having a dramatic impact on the patients’ functional status and

well-being. (Wallman et al. 2005) Limitations involve every aspect of their life such as social activities,

leisures, relations, work and education.

Numerous authors developed guidelines for the approach of patients with unexplained persistent

fatigue. (Fukuda, Straus, Hickie, Sharpe, Dobbins, & Komaroff 1994;Sharpe 2002) Since there are no

investigative tools or clear physical signs to establish the diagnosis, CFS remains a diagnosis of

exclusion. First of all, patients have to meet the aforementioned diagnostic criteria. In addition,

other possible etiologies have to be ruled out by a thorough medical and psychological history,

physical examination, mental status examination, laboratory screening and other technical

investigations, if required. Exhaustive sets of technical investigations and unnecessary repetitions of

the same examination must be avoided. Detailed laboratory investigations disclose the etiology in

only 5-8% of the patients with prolonged fatigue. (Koch et al. 2009;Lane et al. 1990)

Mariman et al (2013) showed that only 23.3% of patients with chronic unexplained fatigue referred

to a tertiary care center were diagnosed with unequivocal CFS. (Mariman et al. 2013a) In 21.1% of

patients, CFS was associated with a sleeping disorder and/or psychiatric disorder. Obstructive sleep

apnea (OSA) was the most common sleeping disorder (28.7%) while a mood disorder was the most

common psychiatric comorbidity (26.5%). Accordingly, in the diagnosis of CFS, attention must be paid

to these common comorbidities and correct diagnostic steps must be taken for their exclusion.

Epidemiology Based on the available criteria, epidemiological data can be collected. Due to the different case –

definitions of CFS in use, there is a wide variance of prevalence estimates, ranging from a prevalence

of 0.2% in the UK to 6.4% in Hong Kong (Fukuda criteria). (Nacul et al. 2011;Yiu and Qiu 2005)

Researchers in Japan found a prevalence of 1.5% (95% CI 0.4-5.2%) (Fukuda criteria), while a larger

study in Korea reported a prevalence of 0.6% (95% CI 0.2-1.0%) (Fukuda criteria). (Kawakami et al.

1998;Kim et al. 2005) The first prevalence study in a developing country (Nigeria) showed a CFS

prevalence of 0.68%. (Njoku et al. 2007) Prevalence rates in the US range from 0.2% to 2.5%. (Reeves

et al. 2007;Steele et al. 1998)

An English study in which CFS patients were identified using both the Fukuda and the Canadian

criteria, found an overall prevalence rate of 0.2%. (Nacul, Lacerda, Pheby, Campion, Molokhia,

Fayyaz, Leite, Poland, Howe, & Drachler 2011) The prevalence rates of cases meeting the Fukuda

criteria was 0.19%, while only 0.11% of patients confirmed to the Canadian criteria. All but one of the

cases complying with the Canadian criteria also met the Fukuda criteria. The patients meeting the

Canadian criteria had more severe symptoms compared to the other group.

Chronic fatigue syndrome is more common in women than in men, affecting mainly 30 to 40 year

old, successful women living in developed countries. (Jason et al. 1999;Lloyd, Hickie, Boughton,

Spencer, & Wakefield 1990;Steele, Dobbins, Fukuda, Reyes, Randall, Koppelman, & Reeves 1998) A

recent Norwegian study showed 2 age peaks in the incidence of CFS: 10-19 years old and 30-39 years

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old.(Bakken et al. 2014) They found an incidence of 25.8 per 100,000 person years (95% confidence

interval (CI): 25.2 to 26.5), with a female to male incidence rate ratio of 3.2 (95% CI: 3.0 to 3.4).

A huge overlap exists between fibromyalgia (FM) and chronic fatigue syndrome. (Aaron et al. 2000) It

has been estimated that 20% to 70% of patients with FM meet the criteria for CFS. Conversely, 35%

to 70% of those with CFS also have FM. Again largely different rates have been reported.

Etiopathogenesis Over the recent decades, considerable effort has been made to identify the possible underlying

mechanism of CFS. The most widely investigated hypotheses are infectious causes, immune

dysfunction, sleeping disorders, endocrine-metabolic dysfunction and neuropsychiatric factors.

However, strong reproducible scientific evidence is yet to be produced.

Because the syndrome can start with flu-like symptoms, a huge number of possible micro-organisms

have been implicated in the development of CFS, but evidence for this hypothesis has never been

found.

One study investigated the seroprevalence of 13 viruses in patients with CFS or chronic fatigue and

healthy controls, but failed to demonstrate an association with any of the following viruses: herpes

simplex 1 and 2, rubella, adenovirus, human herpes virus 6, epstein-barr virus (EBV), cytomegaly

virus (CMV) and coxsackie B virus types 1-6. (Buchwald et al. 1996) Those viruses were suggested

because most of them persist perpetually and sporadically reactivate. A more recent study focused

on the serological status of monozygotic twins, of which one twin was diagnosed with CFS. (Koelle et

al. 2002) No significant difference was found in serological status or DNA detection for human herpes

virus-6-8, CMV, herpes simplex virus-1,2, hepatitis C virus, EBV, varicella zoster virus, John

Cunningham virus, BK virus and parvovirus B19

In 2009, Lombardi et al (2009) reported the involvement of a retrovirus, xenotropic murine leukemia

virus-related virus (XMRV), in the pathophysiology of CFS. (Lombardi et al. 2009) They identified DNA

from XMRV in 68 of 101 CFS patients compared to 8 of 218 healthy controls. Even though they

provided strong evidence for this hypothesis, subsequent studies failed to reproduce these

results.(Alter et al. 2012;Rasa et al. 2014;Simmons et al. 2011)

Lo et al studied the role of another virus, murine leukemia virus (MLV), in CFS. (Lo et al. 2010) They

detected the virus in 32 of 37 CFS patients (86.5%) compared with only 3 of 44 (6.8%) healthy

volunteer blood donors.

A multicenter blinded analysis tried to reproduce those results, but found no association between

CFS and XMR Virus and MLV. (Alter, Mikovits, Switzer, Ruscetti, Lo, Klimas, Komaroff, Montoya,

Bateman, Levine, Peterson, Levin, Hanson, Genfi, Bhat, Zheng, Wang, Li, Hung, Lee, Sameroff,

Heneine, Coffin, Hornig, & Lipkin 2012) In this study, blood samples from CFS patients and healthy

controls were sent to three laboratories that had participated in earlier studies on XMRV. The results

were all negative for DNA from XMRV or MLV. The previous positive results were most likely caused

by contamination with mouse DNA or laboratory reagents. The original report of an association

between XMRV and CFS was later fully retracted due to concerns regarding the validity of the results.

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(Lombardi, Ruscetti, Das, Pfost, Hagen, Peterson, Ruscetti, Bagni, Petrow-Sadowski, Gold, Dean,

Silverman, & Mikovits 2009)

A number of studies have suggested the possible involvement of toxins in CFS. (Devanur and Kerr

2006) Some of the toxins focused on were organophosphates, cituatera fish toxin, pesticides and

mould. Until now, no strong evidence exists that these toxins might be the cause of CFS. The same

applies to vaccinations. Various vaccines have been reported to trigger CFS, but again, substantial

evidence is lacking.

Another possible pathway to CFS is a disruption of the immune system of patients with CFS. In recent

decades, dozens of papers have been published regarding abnormalities of the immune system.

(Natelson et al. 2002) However, not a single marker was found that was consistently aberrant in the

different studies. Some of the differences seen in CFS are increased inflammation and pro-

inflammatory cytokines (IL 1, IL6 and TNF alfa). (Bansal et al. 2012) Impaired natural killer cell

function and an alteration in T cell numbers have also been shown to occur.

Although the immune system may play an important part in the pathophysiology of CFS, its exact

role remains obscure and the various studies have reported divergent, moderate and sometimes

even conflicting results regarding the involvement of an immune dysfunction in CFS.

Several metabolic abnormalities have been described, but the exact mechanism or involvement is

still elusive. Focusing on the role of the hypothalamic-pituitary-adrenal (HPA) axis, a recent meta-

analysis showed an attenuation of cortisol secretory activity, with a decreased dynamic response to

waking and variations in circadian activity. (Powell et al. 2013) However, the current evidence is not

strong enough to allow any conclusions regarding the approach to CFS patients.

Since unrefreshing sleep is one of the diagnostic criteria of CFS, many studies have investigated a

possible link with a sleeping disorder. Currently substantial evidence of significant abnormalities in

the sleeping pattern of CFS patients is lacking. (Jackson and Bruck 2012;Mariman et al. 2013b)

Mariman et al (2013) found a sleeping disorder to be present in 18.6% of CFS –patients, 22.2% were

not diagnosed with CFS because of a predominant sleeping disorder.(Mariman, Delesie, Tobback,

Hanoulle, Sermijn, Vermeir, Pevernagie, & Vogelaers 2013a) OSA was the most prevalent sleeping

disorder (28.7% of patients). A comparative study by Libman et al found no significant differences

between CFS patients with and without OSA regarding subjective sleep variables and CFS

symptoms.(Libman et al. 2009) Treating OSA with nasal continuous positive airway pressure had no

effect on those parameters. A study by Gotts et al showed a negative influence of daytime napping

on cognitive functioning and daytime sleepiness in patients with CFS. (Gotts et al. 2015)

Another possible theory is central nervous system involvement, and more in particular the role of

cerebral perfusion and alterations in grey and white matter. (de Lange et al. 2005;Lange et al.

1999;Yoshiuchi et al. 2006) To date no significant, reproducible aberrations have been found.

In a study of the serotonergic system in CFS patients, Smith et al. found three markers in the

serotonin receptor to be associated with an enhanced activity of the receptor in CFS patients. (Smith

et al. 2008) This abnormality was associated with a reduction in general health, vitality and social

function which suggests that CFS patients might experience difficulties in managing stress reactions.

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Emotional factors seem to play an important role in the etiopathogenesis of CFS. Recent studies

showed a significantly higher prevalence of CFS in abused children.(Heim et al. 2006;Heim et al.

2009;Heins et al. 2011) Particularly more prevalent was a history of emotional abuse (10.6%-13% CFS

patients vs 4%-7.7% controls), emotional neglect (11%-24% vs 7.9%-8.1%) and physical abuse (6%-9%

vs 1%-6.9%). Some characteristics were more common in patients with CFS. A recent study by

Kempke et al. showed a negative influence of self-critical perfectionism on fatigue and pain in CFS

patients. (Kempke et al. 2013)

Several surveys among CFS patients showed that doctor-patient relationships were not optimal in the

majority of patients. (Deale and Wessely 2001) Among other things, unhelpful or distressing

consultations, disbelief and miscommunication were reported. On the other hand many doctors

were dissatisfied with or uncertain about the care they provided and considered treating CFS

patients as time -consuming. These facts are in sharp contrast with the importance of a good

professional relationship between patient and health-care provider. Not only should the patient be

given the best possible support, but one should also be alert to alarming symptoms in the future.

These findings can be explained by the lack of consensus regarding the etiopathogenesis and the

standard treatment.

Cella et al (2013) studied the prevalence of comorbid psychiatric diagnoses in 640 patients with CFS.

(Cella et al. 2013) Of those patients, 14% had an anxiety disorder, 14% also had a depressive disorder

and 18% had both depression and anxiety disorders. Beliefs about damage and symptom focusing

were more frequent in CFS –patients with anxiety disorders, while CFS patients with a concomitant

depressive disorder showed more embarrassment and behavioural avoidance. Mariman et al (2013)

found lower prevalences of comorbid psychiatric disorders (only 5% of patients had a comorbid

disorder).(Mariman, Delesie, Tobback, Hanoulle, Sermijn, Vermeir, Pevernagie, & Vogelaers 2013a)

However 19.0% of patients referred to a tertiary center for unexplained fatigue were not diagnosed

with CFS because of a predominant psychiatric disorder, mainly mood disorders and anxiety

disorders. In 14.3% of patients, the diagnosis of a cluster B and C personality disorder was made.

In 2011, Light et al (2011) studied alterations in gene expression at baseline and after exercise, but

found no difference between CFS patients and healthy controls. (Light et al. 2012) Shortly after

exercise, however, the expression of adrenergic a-2A receptors was increased. This was associated

with physical and mental fatigue and pain. The increased expression was more obvious in patients

experiencing more severe symptoms. Another study showed the presence of single nucleotide

polymorphism in the genes responsible for brain function, stress reactions, emotional responses,

generation and maintenance of memory. (Goertzel et al. 2006)

A recent study investigated functional capacity and postexertion fatigue in 51 CFS patients and 10

healthy controls during two cardiopulmonary exercise tests with a 24-hour interval. (Snell et al. 2013)

All participants reached their peak workload, but in the CFS group peak workload was significantly

lower than in the control group (P=0.005). The CFS patients were unable to reproduce their

performance of the first test during the second test, in contrast to the control group. This particularly

applied to the peak workload. This study also showed a decreased workload at the ventilatory

threshold in CFS patients. Similar results were obtained by Keller et al. (Keller et al. 2014) These

findings need to be further investigated.

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Over the years, the biopsychosocial model integrating many of the earlier mentioned hypotheses,

has been gaining popularity over the biomedical model where the focus is on one physical cause.

(Figure 1) (Harvey and Wessely 2009) Certain individuals are more prone to develop CFS, eg those

with psychiatric disorders, perfectionism, psychosocial problems, childhood stressors and an

overactive lifestyle. This premorbid risk is followed by an acute event, eg infection or stress, leading

to fatigue. The developing fatigue due to the triggering event is maintained by prolonged bed rest,

negative self-efficacy, dramatic fluctuations in activity levels and biological disturbances among other

things.

· Immunological dysfunction?

· Neuro-endocrine dysfunction?

· Sleep disorders?

· Others?

· Infections

· Psychosocial stress

· Psychiatric disorders

· Personality

· Lifestyle

· Psychosocial stress

Predisposing factors

Precipitating factorsCentral nervous system

Chronic fatigue syndrome

· Wrong attributions

· Avoidance behavior

· Untreated psychiatric disorders

· Iatrogenic

Persisting factors

Possible mechanism

Figure 1: Etiopathogenesis of chronic fatigue syndrome: biopsychosocial model

Therapy Since the causes of CFS have not been identified, disease-specific treatments do not exist. Various

treatments have been researched but only cognitive behaviour therapy (CBT) and graded exercise

therapy (GET) have shown moderate effectiveness. These two therapies interfere with the

maintaining factors of the biopsychosocial model.(Harvey & Wessely 2009)

The primary goal of CBT is to obtain control of the symptoms. (Stordeur S et al. 2013) Dysfunctional

beliefs and thoughts are dealt with and harmful or unhelpful behavior is changed through

therapeutic sessions. The main principle of GET is avoidance of physical deconditioning from

prolonged rest and a gradual return to appropriate physical activities.(White et al. 2011) An exercise

program is devised by a therapist to improve the patient’s aerobic condition. This program consists of

individually set schedules, which are gradually increased with participant feedback and mutual

planning.

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Several studies showed a reduction of fatigue and functional impairment following CBT in the short

term (6-12 months). (Stordeur S, Thiry N, & Eyssen M 2013) Deal et al. followed CFS patients for 5

years after the completion of therapy. (Deale et al. 2001) The global improvement in the CBT group

was greater than in the relaxation therapy group. A recent study showed a negative influence from

solicitous responses of the partner on fatigue and disability. (Verspaandonk et al. 2015) This aspect

needs to be included in CBT-programs. The large PACE TRIAL compared CBT with GET, specialist

medical care alone and adaptive pacing therapy. (White, Goldsmith, Johnson, Potts, Walwyn,

DeCesare, Baber, Burgess, Clark, Cox, Bavinton, Angus, Murphy, Murphy, O'Dowd, Wilks, McCrone,

Chalder, & Sharpe 2011) Fatigue and physical function were improved in both the CBT and GET

groups compared to the specialist medical care group (P<0.05). Other studies comparing GET with

different treatments showed improvement of fatigue, quality of life and functional work capacity.

(Stordeur S, Thiry N, & Eyssen M 2013) Currently, there is no evidence that GET is harmful in CFS

patients. (Stordeur S, Thiry N, & Eyssen M 2013)

Mindfulness-based therapy has also achieved some positive effects such as a reduction in fatigue

levels, pain, anxiety and depression (Fjorback et al. 2013), but further research is mandatory.

Following an isometric yoga program can reduce fatigue complaints. (Oka et al. 2014)

The main goal of pacing therapy, another aspect of many of the current exercise programs, is to

achieve adaptation to the perceived illness by planning and pacing the patients’ activities according

to their available energy in order to reduce or avoid fatigue. (White, Goldsmith, Johnson, Potts,

Walwyn, DeCesare, Baber, Burgess, Clark, Cox, Bavinton, Angus, Murphy, Murphy, O'Dowd, Wilks,

McCrone, Chalder, & Sharpe 2011) In this way, exacerbations can be prevented. Increased activities

are encouraged as long as they do not trigger an exacerbation of the symptoms. The largest study on

the pacing theory did not show a significant reduction of fatigue compared with specialist medical

care.

An Australian study showed that CFS patients use a large variety of medications and supplements,

with an average of 5 per patient. (Kreijkamp-Kaspers et al. 2011) The most commonly used medicines

were antidepressants (41% of patients) and sedatives (27%). Another recent American study

reported similar numbers. (Boneva et al. 2009) The participating CFS patients took an average of 5.8

drugs or supplements with outliers of 19 drugs or supplements. In this study, 74% of CFS patients

took pain relievers, 41% took antidepressants and 20% took sedatives. The use of these three drugs

was significantly higher compared to the findings in a healthy control group (p>0.05). Beside 1

recent, positive result with coenzyme Q10 on fatigue that needs to be confirmed, to date not one

type of drugs or supplements has shown a significantly positive result in patients with CFS. (Castro-

Marrero et al. 2015;Kreijkamp-Kaspers, Brenu, Marshall, Staines, & Van Driel 2011)

With patients taking so many different drugs and supplements, side effects and drug interactions are

common. Avoiding unnecessary use of multiple drugs and supplements needs to be of great concern

to health-care workers.

Prognosis Percentages for recovery rates and improvement of CFS patients differ largely. (Cairns and Hotopf

2005) The spontaneous full recovery rate ranges from 0-12%. Spontaneous improvement during

follow-up ranges from 8-63%. Two studies investigated the effect of CBT on the prognosis of CFS.

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(Deale, Husain, Chalder, & Wessely 2001;Prins et al. 2001) Following CBT, 50%- 68% of patients

reported an improvement after 1-5 years. After 5 years the recovery rate was 24%.

Two factors were associated with a better outcome: a sense of control over the symptoms and not

attributing illness to a physical cause. Darbishire et al explored the role of baseline characteristics in

the prognosis of CFS after GET or CBT. (Darbishire et al. 2005) Only functional impairment and

greater perceived negative consequences were predictors for the final outcome.

Economic impact and employment Several case-control studies found a significant difference in employment rates between CFS patients

and healthy controls (Claypoole et al. 2001;Garcia-Borreguero et al. 1998;Vercoulen et al. 1997).

Employment rates ranged between 27% and 41% for CFS patients compared to 86-100% for healthy

controls. Recently, Collin et al. reported an employment rate of 40.7% among CFS patients; 34%

discontinued working permanently because of fatigue-related symptoms. (Collin et al. 2011) Those

who ceased working had significantly lower SF36 scores than those who had a job. Physical function

was a major factor in continuing or ceasing work. In 2004, Reynolds et al. showed an 27% overall

reduction in employment attributable to CFS (Reynolds et al. 2004). Overall, employment declined

from 72.3% to 54.8% for women and from 86.1% to 63.3% for men.

With regard to the economic impact of CFS, different aspects need to be considered: loss of

productivity of patients, health care expenditures and informal costs, including unpaid services

provided by friends and family because patients are unable to care for themselves.

The high rate of unemployment entails a huge loss of productivity. Reynolds et al. calculated an

annual loss of approximately $20,000 dollar per person with CFS, which totaled $9.1 billion in the US

in 2002; 75% of this sum was due to lost labor force productivity and 25% to lost household

productivity or informal care. (Reynolds, Vernon, Bouchery, & Reeves 2004) These calculations did

not include the health care expenses. The study by Lin et al only included loss in productivity and

direct medical costs.(Lin et al. 2011) The combined economic burden of CFS (direct and indirect

costs) was $11,780, 82% of which was caused by loss of productivity.

McCrone et al (2003) reported similar results. (McCrone et al. 2003) They calculated a total cost of

£3515 (standard deviation 4360) per person with CFS over a 3-month period, including loss of

productivity, health care expenditures and informal care.

Sabes-Figuera et al (2010) found a lower cost £3878 (standard deviation 4573) over a 6-month period

(Sabes-Figuera et al. 2010). In this British study, unpaid informal care accounted for as much as

26.4%, while productivity losses represented 60.6% and health care expenses only 13%.

Also in the UK, Collin et al (2011) investigated the total productivity cost for patients attending

specialized care facilities for CFS. (Collin, Crawley, May, Sterne, & Hollingworth 2011) They calculated

a total productivity cost of £49.2 million (£22,684 per patient) based on the available data.

Extrapolating this to the whole UK population would result in a total annual productivity cost of

£102.2 million for patients attending specialized medical care. Because Collin et al only used data

from patients in specialized care, the total productivity cost for all CFS patients might have been

underestimated.

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Since different countries have different health care systems, a thorough comparison of costs is

difficult.

Conclusion Chronic fatigue syndrome has a huge impact on a patient’s life. Several case definitions have been

proposed, each focusing on different aspects. In establishing the diagnosis of CFS it is important to

rule out other possible causes for the experienced symptoms. Recently it has been shown that only

23.3% of the patients with unexplained fatigue are diagnosed with CFS in a tertiary center.(Mariman,

Delesie, Tobback, Hanoulle, Sermijn, Vermeir, Pevernagie, & Vogelaers 2013a) Particularly sleeping

disorders and psychiatric disorders need to be ruled out.

Currently, a single, evidence-based etiopathogenetic mechanism for the syndrome is lacking,

although many different hypotheses have been advanced. Over the years, the biopsychosocial model

integrating many of the proposed hypotheses (psychological predisposing and persisting factors, and

psychological or physical precipitating factors) has been gaining popularity. (Harvey & Wessely 2009)

As long as the etiopathogenesis of CFS is not completely understood, therapy should be based on

these findings. The primary goal of CBT is to obtain control of the symptoms. (Stordeur S, Thiry N, &

Eyssen M 2013) The main principle of GET is avoidance of physical deconditioning from prolonged

rest and a gradual return to appropriate physical activities.(White, Goldsmith, Johnson, Potts,

Walwyn, DeCesare, Baber, Burgess, Clark, Cox, Bavinton, Angus, Murphy, Murphy, O'Dowd, Wilks,

McCrone, Chalder, & Sharpe 2011)

Two recent studies investigated functional capacity and post exertion fatigue in CFS patients and

healthy controls during two cardiopulmonary exercise tests with a 24-hour interval. (Snell, Stevens,

Davenport, & Van Ness 2013) Strikingly, CFS patients were unable to reproduce their initial

performance 24 hours later, while healthy controls did manage to do so. Whether this is due to

deconditioning or other underlying factors needs to be further investigated.

The high prevalence rates (0.2%-6.4%) and the low employment rates (27-41%) are responsible for

the huge burden imposed on society. (Claypoole, Mahurin, Fischer, Goldberg, Schmaling, Schoene,

Ashton, & Buchwald 2001;Garcia-Borreguero, Dale, Rosenthal, Chiara, O'Fallon, Bartko, & Straus

1998;Nacul, Lacerda, Pheby, Campion, Molokhia, Fayyaz, Leite, Poland, Howe, & Drachler

2011;Vercoulen, Bazelmans, Swanink, Fennis, Galama, Jongen, Hommes, van der Meer, & Bleijenberg

1997;Yiu & Qiu 2005) Exact numbers differ greatly between studies, depending on the country in

which the study was performed. However, all studies showed that the loss of productivity represents

the highest cost for society. Since CFS is a chronic condition, the costs become permanent.

Therefore, it is essential that specific actions be taken to encourage a return to work.

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Bewijs van publicatie

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Nederlandse samenvatting

Chronic fatigue syndrome – an update Steven Rimbaut, Céline Van Gutte, Lina Van Brabander, Luc Vanden Bossche

Het chronisch vermoeidheidssyndroom (CVS) is een wijdverspreide aandoening met een grote

impact zowel op het dagelijks leven van de patiënt als op de maatschappij. Dit wordt gekenmerkt

door een significant verlies aan productiviteit, hoge informele kosten en hoge medische uitgaven.

De hoge prevalentie (0.2%-6.4%) en de lage tewerkstellingsgraad (27-41%) zijn verantwoordelijk voor

de grote impact op de maatschappij, waarbij het verlies aan productiviteit de grootste kost

vertegenwoordigt.

Deze review brengt een systematisch literatuuroverzicht van de beschikbare, recente literatuur over

chronisch vermoeidheidssyndroom/myalgische encefalitis.

De gepubliceerde literatuur tussen 1 januari 1990 en 1 april 2015 werd gescreend naar relevante

artikels. Hierbij werd gebruik gemaakt van volgende databases: medline, cochrane library en web of

sciences. Daarnaast werden de referentielijsten van de geselecteerde artikels gescreend voor

overige, relevante artikels.

Verscheidene diagnostische criteria werden geopperd. Tot op heden zijn de meest gangbare, de

Fukuda-criteria (gepubliceerd in 1994):

Er is reeds uitgebreid onderzoek uitgevoerd naar de etiologie van CVS. Volgende hypothesen zijn

reeds uitgebreid geïnvestigeerd: infectieuze oorzaak, immuundysfunctie, slaapstoornis, endocriene-

metabole dysfunctie en neuropsychiatrische aandoeningen. Ondanks uitgebreid onderzoek, kon geen

enkel van de vooropgestelde etiologische factoren weerhouden worden. Er is tot op heden geen

sterk, reproduceerbaar bewijs geleverd.

De laatste jaren heeft het biopsychosociaal model aan populariteit gewonnen ten koste van het

biomedisch model waarbij de focus enkel ligt op fysische oorzaken. In het biopsychosociaal model

worden veel van de vooropgestelde hypothesen geïntegreerd.

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Aangezien de etiologie tot op heden niet ontrafeld is, is een eenduidige evidence-based behandeling

niet voorhanden. Enkel cognitieve gedragstherapie en graduele oefentherapie toonden een matige

effectiviteit aan.