The chronic fatigue syndrome (CFS) is fundamentally characterized by intense fatigue of unknown cause, which is permanent and limits the patient's functional capacity, producing various degrees of disability.
In medical terminology, fatigue is the early onset of tiredness after an activity has been started; it is a sensation of exhaustion or difficulty to carry out physical or intellectual activities, without recovery after a period of rest. Fatigue has been categorized as recent fatigue, prolonged fatigue and chronic fatigue, according to the time of evolution (less than one month, more than one month and more than six months, respectively) [1
It is advisable to differentiate fatigue from other medical concepts with which the symptom is often confused: first, from asthenia, defined as the lack of strength or feeling of inability to carry out daily tasks, which is more intense at the end of the day, and usually improves after a period of sleep; second, from weakness, which is the reduction or loss of muscular strength, and the key symptom in muscular diseases.
In addition to fatigue, CFS is associated to a wide spectrum of symptoms, including arthralgias, muscle pain, headaches, anxiety, depressive symptoms, cognitive disorders, sleep disorders, or intolerance to physical exertion, among the most frequent [2
The little understanding of CFS aetiopathogeny, together with the difficulties to achieve an objective and quantitative assessment of the symptoms that affected patients have, has prevented for a long time the establishment of a diagnosis [4
]. A consequence of such a problem is the variety of names CFS is known for, including allergic encephalomyelitis, immune dysfunction syndrome, neuroendocrine immune dysfunction syndrome, post viral syndrome, Iceland disease, neurasthenia, and Royal Free disease, among others [5
The various criteria established in recent years have allowed a more accurate delineation of CFS, and this has contributed to a better understanding of its clinical picture, and potential therapeutic interventions [1
CFS is, therefore, a complex, chronic disorder of unknown aetiology, characterized by the presence of intense and disabling fatigue (physical and mental), with a clinical course and without any apparent cause, which interferes with daily activities, does not decrease with rest, worsens with exercise, and is usually associated to systemic, physical and neuropsychological manifestations [6
The aetiology, diagnosis and therapeutic options for chronic fatigue syndrome in adults and pediatric patients are discussed below.
The aetiology and the pathogenic mechanisms of CFS
As the criteria for CFS diagnosis are not based on the understanding of aetiopathogenic mechanisms, some patients present similar clinical manifestations but are diagnosed with other conditions because fatigue is not the primary symptom. Some of those conditions are fibromyalgia, irritable bowel syndrome, and temporomandibular joint syndrome. Furthermore, in addition to sharing several symptoms with CFS, currently available evidence suggests that those diseases also share similar pathophysiologic mechanisms [8
Although the aetiology and the pathogenic mechanisms of CFS are not fully understood, several hypotheses have been postulated and described below, being the disorders of the central nervous system neuromodulator the one supported by more evidence to explain the possible pathogenic mechanisms involved in CFS [5
Epstein Barr virus, Candida albicans, Borrelia burgdorferi
, Enterovirus, Citomegalovirus, Human Herpesvirus, Espumavirus, Retrovirus, Borna virus, Coxsackie B virus, and hepatitis C virus (HCV) have been associated to CFS, but their pathogenic relationship with the syndrome has not been demonstrated [10
Although different disorders have been found in the immune system or its function, currently there is no scientific evidence to attribute the cause of this syndrome to a primary disorder of the immune system. There are a large number of studies on immune disorders in the CFS assessing identical parameters, but they frequently yield contradictory results [11
Several disorders in the hypothalamic-pituitary-adrenal axis (HPA) and in the production of related hormones have been found in CFS, as well as a disorder of the regulating mechanisms of the autonomic nervous system. It is currently known that the relationships between the different parts of the nervous system are mediated by neurotransmitters and that their disorders lead to unbalanced functioning of certain structures and to the development of well known diseases. Many of the clinical features in patients with CFS are similar to those found in patients with fibromyalgia, and it can therefore be postulated that the physiopathological mechanisms are probably similar in both conditions.
In patients with fibromyalgia, the research on neurotransmitter disorders has started to yield positive findings, and it is known that different clinical manifestations will appear according the type and the site of action of affected neurotransmitters [8
Prevalence and clinical features
It is difficult to establish the prevalence of CFS, since it depends on the diagnostic criteria used and the study population. Initial research suggested a prevalence between 0.002% and 0.04%. [16
]. However, latest epidemiological studies in the USA and in the United Kingdom show prevalence rates ranging from 0.007% to 2.5% of the general population. [18
] These rates increase up to 0.5-2.5% when the population assessed includes individuals seen in primary care facilities instead of the global population. [19
] In the United Kingdom, according the Oxford criteria [20
], the prevalence in the global population has been estimated in 0.6%. In Japan the prevalence has been found to be 1.5% in the general population[21
]. Thus, the prevalence in the general population appears to be much higher than previously indicated. Even with strict criteria for CFS, it is estimated that approximately 1% of the adult population experiences this condition. Interestingly, a large part of this group remains unrecognized by the general practitioner. A striking similarity in lifestyle pattern between SF, CF and CFS calls for further research. [23
CFS mainly affects young adults from 20 to 40 years, although the symptoms also exist in childhood, adolescence and in the elderly [10
]. It has a 2-3 times higher prevalence in women than in men. No evidence exists showing that any socio-economic group is more affected than others [5
The typical CFS case occurs acutely, and even suddenly, usually in a previously healthy person. Initially, fever, sore throat, cough, muscular pain and fatigue are the typically predominant symptoms; digestive symptoms such as diarrhoea are less common. This initial process resolves with intense tiredness as a sequel. The cardinal or key symptom is fatigue, essential for diagnosing the condition. Fatigue in CFS is characterised by not being secondary to excessive activity, with no improvement associated with rest and worsening with stress, and directly resulting in persistent disability (physical and mental) [7
The chronic symptoms develop later [24
], persisting for weeks or months. Predominant symptoms vary for the individual patient, and include fatigue, fever or intermittent dysthermia, migratory arthralgias, generalised musclar pain, pharyngitis or sore throat, headache, tender cervical or axillary lymph nodes, and other less common symptoms.
Fatigue is usually associated to neurocognitive and sleep disorders. Patients have difficulty in concentrating, insomnia or hypersomnia, and occasionally depression. Palpitations, thoracic pain, night sweating, or weight loss/increase are less common [10
In general, clinical evolution is characterized by regular and even seasonal recurrences. Each outbreak can be different from the previous one, and periods between each recurrence are rarely completely asymptomatic [1
]. CFS's symptomatology worsens with physical or emotional stress, interfering or limiting previous activities (including family, work, and social activities); in some cases, patients may need help for their basic daily activities.
The main co-morbidity is related with psychiatric disorders, such as depression or anxiety, with an approximate incidence of 28% in the Western population [25
As there is no pathognomonic sign or specific test for CFS, the diagnosis of the syndrome is clinical. Other causes of fatigue should be ruled out, through a complete and detailed medical history, focused on the characteristics of fatigue, delineating its form and time of onset, duration, triggering factors, relationship with rest and physical activity, and the degree of limitation of the patient's regular activities. Furthermore, targeted interrogation will collect the symptoms in the osteomuscular, neurovegetative and neuropsychological domains. Thus, chronic fatigue should be differentiated from debilitation, exercise intolerance, sleepiness, or loss of motivation and stamina.
The presence of psychiatric disorders (anxiety, depression) should be included in the personal history as well as possible non-infectious precipitating factors (organophosphorous insecticides, solvents, CO, multiple chemical hypersensitivity, sick building syndrome, situations that disturb sleep, etc.), and prior history of allergies. This information should be included to rule out other alternative diagnoses such as infections, neoplasias, depression or sleep disorder.
Specific exploration is required for the musculoskeletal system (strength, reflexes and muscular tone), the neurological system (looking for any neurological deficit), the cardiovascular and respiratory systems (anaemia and cardiac insufficiency), the endocrinological system (thyroid gland disorders), the immune system (tender cervical, axillary or inguinal lymph nodes) and the gastrointestinal system. Physical findings are usually unspecific, and a large variety of signs can be found, such as pharyngeal soreness, fever, tender posterior cervical or axillary lymph nodes, muscular tenderness on palpation, and, occasionally, rash.
Currently, there are no specific biological or morphological markers to establish per se the diagnosis of the CFS, and therefore none of the alterations that can be found are useful for diagnosis. Diagnostic criteria basically arise as a research requirement, but their limitations for actual clinical practice must be accepted.
The Centres for Disease Control and the CFS International Study Group proposed in 1994 an international diagnostic criteria (Table ) [27
]. Their main objectives were to increase the sensitivity of the previous classification, and to offer a more accurate definition of the condition, in order to achieve a more consistent clinical diagnosis and use it as a research tool. The international criteria are based on the fulfilment of two major criteria (chronic fatigue causing incapacity, lasting more than 6 months, and the exclusion of associated medical and psychiatric conditions), as well as the concurrence of a series of criteria, reducing the symptoms from 11 to 8: these criteria are based on symptoms, particularly rheumatological and neuropsychological symptomatology.
Diagnostic criteria for chronic fatigue syndrome
Diagnostic protocol for patients with suspected CFS
Figure details the algorithm for CFS diagnosis [28
]. Conditions that exclude the diagnosis of CFS are: psychiatric disorders, such as major depression, schizophrenia, eating disorders (anorexia, bulimia), bipolar disorder, alcohol or other substance abuse, in addition to morbid obesity, and active medical diseases, either non-treated or without a completely established resolution.
Diagnostic protocol for patients with suspected CFS.
There is an average time of 5 years from the beginning of the symptoms to the diagnosis of the syndrome, with total recovery rates between 0% and 37%, and improvement between 6% and 63% [29
]. Younger patients and those without concomitant psychiatric diseases show the best prognosis, although other studies have estimated that the rates for both groups are similar [30
There is no single tool for the assessment of patients with CFS that allows a global appraisal of the clinical manifestations and the impact of the disease on patients. There are specific questionnaires, according the feature to be measured, that can provide useful information on specific issues. A summary of them can be found in the systematic review by Bagnall et al [31
]. However, the most useful way of collecting information is with interviews and patient diaries. Interview can include patient self-records, questionnaires and scales for functional assessment, such as "Karnofsky Performance Scale, Medical Outcomes Study Short-Form General Health Survey" (SF-36®
] and Sickness Impact Profile (SIP) [33
]. Interviews should be repeated periodically in time.
Self-records and scales are excellent references and help the therapist to assess the patient's daily activities, general functioning and the degree of disability.
The scale is useful for the patient because they can fill in a hierarchy/severity scale their symptoms during the initial visit, and then, approximately every 6 months. This scale categorizes both the severity of the symptom and the aggravating factors.
Daily activity/functional capacity scale is also a useful tool. In this case the patient is asked to make a diary of all their daily activities and periods of rest for a week.
The easiest way to measure pain
in the locomotive apparatus is with an Analogical Visual Scale (AVS), especially when trying to assess the pain that a patient has experienced during a given period of time [34
To assess fatigue, one of the most used tools is the Multidimensional Fatigue Inventory [35
], a 20-item questionnaire that measures global, physical and mental fatigue, and decrease in activity and motivation.
When the patients have difficulties for carrying out physical exercise it is important to quantify the degree of impairment. The most objective methods are based on determining the aerobic capacity of patients, usually with spiro-ergometric tests, expired gases/heart rate are measured, and work load quantified. Other alternative methods that offer semi-quantitative measures, and are often used, are the 6-minute running test [36
], measuring the strength of certain muscular groups, and the degree of mobility of the column or the peripheral joints.
The assessment of disability is complex due to the fact that the clinical diagnostic criteria have not been validated in the medical-legal framework, to the lack of any objective proof of existence as well the lack or low medical-legal performance of validated instruments to quantify the disability associated with CFS. There is a big barrier for fulfilling two major conditions in the assessment of the disability, namely objective evidence of the impairment and the absence of data corroborating the severity of the pain [37