Category: Etiology

The chronic fatigue syndrome. A multifactorial approach and the treatment possibilities

Abstract:

The chronic fatigue syndrome is a poorly defined symptoms complex characterized primarily by chronic or recurrent debilitating fatigue and various combinations of other symptoms, including psychological symptoms, sore throat, lymph node pain, headache, myalgia, arthralgias. Psychological disturbances, ranging from mild depression or anxiety to severe behavioral abnormalities, are always present. Chronic fatigue syndrome is the name that more accurately describes this symptom complex of unknown cause.

A viral aetiology has long been hypothesized: many viruses are potential candidates, including any of the 23 Coxsackie A or 6 Coxsackie B viruses, herpes viruses, particularly Epstein-Barr virus and varicella. These studies, though interesting, remain unconvincing because of methodological flaws such as a poor case definition and inadequate control groups.

This syndrome may represent an infection by a yet unidentified virus. It is more likely due to an abnormal immune response toward different intracellular pathogens. There is no treatment to ameliorate the chronic fatigue syndrome. Epidemiological studies are essential with explicit operational case definition before progress can be made in the management of this distressing disorder.

 

Source: Pinardi G, Scarlato G. The chronic fatigue syndrome. A multifactorial approach and the treatment possibilities. Recenti Prog Med. 1990 Dec;81(12):773-7. [Article in Italian] http://www.ncbi.nlm.nih.gov/pubmed/2075278

 

Postviral fatigue syndrome

This is a syndrome that may or may not follow what appears to be an acute infectious illness, and may occur in epidemic or sporadic forms consisting of persisting or relapsing ‘fatigue’ or easy fatiguability of at least six months’ duration, for which no other cause is apparent. It is associated with a number of other variable features including mild fever, sore throat, painful lymph nodes, headaches, muscle pain, migratory arthralgia, photophobia, forgetfulness, irritability, concentration difficulties, depression, and sleep disturbance. It has been recognised since the early 1930s and known by a wide variety of names including Iceland disease, Royal Free disease, epidemic neuromyasthenia, myalgic encephalomyelitis, postviral syndrome, and more recently chronic fatigue syndrome.( 1 )

Although predominantly a disorder of young adults, it has been recognised in children with either an acute or insidious onset. At least 10-15 cases of the sporadic form are seen each year at the Hospital for Sick Children, Great Ormond Street, with lethargy, headache, abdominal pain, and subjective muscular weakness being the most common manifestations. Abnormal physical findings are usually conspicuous by their absence but occasionally pharyngeal injection, tender cervical lymph nodes, and muscle tenderness are present. A proportion of patients have an ‘atypical’ lymphocytosis, increased plasma creatine phosphokinase activity, circulating immune complexes, minor changes on electroencephalography and electromyelography, increased serum Epstein-Barr and Coxsackie B antibody titres, and VPI antigen in serum. Some workers have demonstrated enteroviral RNA in muscle biopsy material.(2 )Although an infective aetiology has been invoked, however, the full nature of the illness remains obscure and is probably a mixture of an initial infective insult followed by or associated with an important psychological component.

You can read the rest of this article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1792622/pdf/archdisch00656-0012.pdf

 

Source:  Lask B, Dillon MJ. Postviral fatigue syndrome. Arch Dis Child. 1990 Nov;65(11):1198. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1792622/

 

Myalgic encephalomyelitis: an alternative theory

Note: in this editorial published in the Journal of the Royal Society of Medicine ,Volume 83, August 1990, Dr. Wilson discusses the role allergy plays in the development of post-viral fatigue syndromes.

 

In his discussion paper on myalgic encephalomyelitis (April 1989 JRSM, p 215), Wessley drew attention to the destruction of body and mind, and subsequent suicidal despair, and torment, of patients suffering from myalgic encephalomyelitis (ME) or the postviral fatigue syndrome (PVFS). He referred to the reported relationship between identification of the VPI antigen and the presence of disease symptoms. He stated that more attention requires to be paid to methodological detail which he defined as population sample definition, and adoption of operational criteria. He suggested that a new term should be used to describe the observed symptoms: chronic fatigue syndrome (CFS), and enquired what constitutes the syndrome? Unfortunately he did not refer to the necessity for taking a complete clinical and family history in all patients. In his definition of CFS, he did not refer to any of the somatic symptoms which are always present. Yet, he stated that cases of this disease can only be selected by the (presumably holistic) clinical history. It appears that a new kind of approach based on absence of prejudice, more exhaustive and thorough clinical history taking, a wider approach to clinical examination of the patients, and a critical assessment of the origin of this psychosomatic disease would be of value in our investigations.

You can read the rest of the article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292769/pdf/jrsocmed00133-0005b.pdf

 

Source: Wilson CW. Myalgic encephalomyelitis: an alternative theory. J R Soc Med. 1990 Aug;83(8):481-483. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292769/

 

Chronic fatigue syndrome–a new disease picture?

Abstract:

The chronic fatigue syndrome has recently been more frequently diagnosed. Yet it is unknown if this syndrome represents a disease entity of its own or merely a diagnostic label for a miscellaneous group of disorders. Further investigations are needed to find out if the syndrome has an organic or psychosomatic aetiology, or a mixture of both. In the meantime it is the responsibility of the clinician to make this decision in each individual case.

 

Source:  Nix WA. Chronic fatigue syndrome–a new disease picture? Nervenarzt. 1990 Jul;61(7):390-6. [Article in German] http://www.ncbi.nlm.nih.gov/pubmed/2202912

 

Depression and myalgic encephalomyelitis

This comment, published in the Journal of the Royal Society of Medicine in May 1990, was written in response to a letter by Dr. Lev. You can read the letter here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292388/

 

We read the letter from Lev (November 1989 JRSM, p 693) with interest, but see a danger in using assumptions as to aetiology in definition of study groups. Operational definitions not making this assumption will produce replicable findings and progress towards better definitions and understanding of aetiology.

Definitions of depressed control groups are difficult, for example the following need to be controlled:

(1) Demographic variables

(2) Severity of depression symptoms: inappropriate control groups for ME patients would be severely depressed inpatients. Outpatient depressives are not too dissimilar in severity.

(3) Psychotropic medication: this is less likely to be given to ME patients where treatment is not agreed and could modify symptoms to be compared.

(4) Psychiatric history: in possible ME patients a previous significant psychiatric illness prior to fatigue symptoms leads to difficulty in studying this symptom and produces too much overlap with depressed controls.

(5) History of febrile illness: to minimize overlap, one must also control for preceding febrile illness in otherwise typical depressive illness.

Comparison of control groups should be serial, not cross-sectional as physical symptoms and markers may fluctuate, as may fatigue and depression.

Assessment of depressive symptoms is difficult, as Lev points out, due to non-specific ‘biological’ symptoms of depression. However, psychic ones such as pessimism should not overlap and could be assessed.

The concept of fatigue is poorly understood, as is its assessment. The paradigm of pain research has much to offer, where ‘dichotomization’ of physical and psychological components is not thought useful, but assessment emphasizes all components of the experience of pain. Thus, psychometric assessment of fatigue, for example, its severity, frequency, and pattern may be a future research area. Using such a paradigm, our initial findings of differences in fatigue in the two groups are because depressed patients are predominantly anergic, but ‘ME’ patients have more variability and unpredictable onset of fatigue relative to the severity of exercise attempted. Lack of motivation overlaps in both groups, explicable in Lev’s own terms as due to a reaction to a chronic illness.

~SEAN LYNCH Lecturer and Honorary Senior Registrar in Psychiatry

~RAM SETH Senior Registrar in Psychiatry St Charles Hospital, London

 

Source: S Lynch and R Seth. Depression and myalgic encephalomyelitis. J R Soc Med. 1990 May; 83(5): 341. PMCID: PMC1292666. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292666/pdf/jrsocmed00136-0073a.pdf

 

Old wine in new bottles: neurasthenia and ‘ME’

Abstract:

The history of  is discussed in the light of current interest in chronic fatigue, and in particular the illness called myalgic encephalomyelitis (‘ME’). A comparison is made of the symptoms, presumed aetiologies and treatment of both illnesses, as well as their social setting.

It is shown that neurasthenia remained popular as long as it was viewed as a non-psychiatric, neurological illness caused by environmental factors which affected successful people and for which the cure was rest. The decline in neurasthenia was related to the changes which occurred in each of these views. It is argued that similar factors are associated with the current interest in myalgic encephalomyelitis.

It is further argued that neither neurasthenia nor ‘ME’ can be fully understood within a single medical or psychiatric model. Instead both have arisen in the context of contemporary explanations and attitudes involving mental illness. Future understanding, treatment and prevention of these and related illnesses will depend upon both psychosocial and neurobiological explanations of physical and mental fatigability.

 

Source:  Wessely S. Old wine in new bottles: neurasthenia and ‘ME’. Psychol Med. 1990 Feb;20(1):35-53.  http://www.ncbi.nlm.nih.gov/pubmed/2181519

 

Chronic fatigue syndrome: review of the literature

Abstract:

Chronic fatigue syndrome, previously known as chronic mononucleosis or post-infectious fatigue, is a poorly understood illness characterized by chronic debilitating fatigue, recurrent flu-like symptoms, and few clinical or laboratory abnormalities. Attention was briefly focused on the Epstein-Barr virus (EBV) as a causal agent, but that hypothesis is now in serious doubt. While a significant incidence of psychiatric illness has been demonstrated among patients with the chronic fatigue syndrome, there is also evidence of subtle immune system abnormalities, leading some researchers to postulate a multi-factorial psycho-immune cause.

 

Source: Turgeon SA. Chronic fatigue syndrome: review of the literature. Can Fam Physician. 1989 Oct;35:2061-5. http://www.ncbi.nlm.nih.gov/pubmed/21249084

Note: You can read the full article here:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2280912/

 

Chronic fatigue syndrome

Note: This letter appeared in the February 15, 1989 edition of the Canadian Medical Association Journal in response to Dr. Ray Holland’s letter of August 1, 1988 . You can read Dr. Holland’s letter as well as Dr. Salit’s response here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268060/?page=1 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268061/

 

A useful supplement to the letters about chronic fatigue syndrome from Drs. Ray G.L. Holland (Can Med Assoc J 1988; 139: 198-199) and Irving E. Salit (ibid: 199) might be the working case definition of this syndrome proposed by Holmes and colleagues,(1) of the US Centers for Disease Control.

Holmes and colleagues have suggested that a case of chronic fatigue syndrome must fulfill two major criteria: that it consist of persistent or relapsing debilitating fatigue of new onset that has reduced the patient’s activity level to below 50% of normal for at least 6 months and that other clinical conditions that may produce similar symptoms have been excluded by thorough evaluation.

In addition, there must be 6 or more of 11 minor features (mild fever, sore throat, painful neck or axillary lymph nodes, generalized muscle weakness, myalgia, easy fatigability, headaches, migratory arthralgia, neuropsychologic complaints, sleep disturbances and rapid onset of the main symptom complex), along with 2 or more of 3 physical findings (low-grade fever, nonexudative pharyngitis, and palpable or tender neck or axillary lymph nodes).

We have found that many people with this clinical picture have concomitant food and chemical sensitivities and may have an intracellular magnesium deficiency in spite of normal serum levels.(2) This is probably the result of the inordinate amount of this essential mineral that they spill in their urine. The generalized aching and muscle tightness these patients experience can frequently be eased by appropriate magnesium (and calcium) supplementation, presumably because of the reduction of neuromuscular irritability.

We were therefore greatly surprised to learn in a later letter from Dr. Holland (ibid: 706) that “it would be nontherapeutic to offer such a patient empathy” and that we must not condone a belief in a “nonexistent disease”.

These statements are difficult to reconcile with the immunologic abnormalities,(3,5) disorders of muscle metabolism (5) and abnormal results of muscle biopsy (5) found in such patients. Specific flow cytometric measurements of lymphocyte dysfunction may prove to be a means of characterizing and diagnosing this syndrome.(6)

Holland, who reminds us of the dictum “Primum non nocere”, should take his own advice to heart. We are only beginning to unravel the secrets of this debilitating condition, which is very likely caused by a combination of triggering factors, including infective and environmental influences.

This condition, called myalgic encephalomyelitis in Britain, is most certainly not psychosomatic, in spite of the frequently associated emotional turmoil.

Most normal healthy people will react “emotionally” when their finances, lifestyle and health are shattered by a debilitating condition, and they may well respond to a sympathetic approach to their total well-being.

~Gerald H. Ross, MD, CCFP, Fellow in environmental medicine

~Jean A. Monro, MB, BS, LRCP, MRCS, Medical director Breakspear Hospital for Allergy and Environmental Medicine Abbots Langley, England

 

References

  1. Holmes GP, Kaplan JE, Gantz NM et al: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387-389
  2. Rea WJ, Johnson AR, Smiley RE et al: Magnesium deficiency in patients with chemical sensitivity. Clin Ecol 1986; 4:17-20
  3. Tosato G, Straus SE, Werner H et al: Characteristic T cell dysfunction in patients with chronic active EpsteinBarr virus infection (chronic infectious mononucleosis). J Immunol 1985; 134:3082-3088
  4. Kuis W, Roord JJ, Zegers BJM et al: Heterogeneity of immune defects in three children with a chronic active Epstein-Barr virus infection. J Clin Immunol 1985; 5: 377-385
  5. Behan PO, Behan WMH, Bell EJ: The postviral fatigue syndrome – an analysis of the findings in 50 cases. J Infect 1985; 10: 211-222
  6. Johnson TS, Gratzner HG, Steinbach T et al: Flow cytometric measurement of lymphocyte immune function in chronic fatigue syndrome patients. Presented at 22nd scientific session, American Academy of Environmental Medicine, Lake Tahoe, Nev, Oct 22-25, 1988

Source: Gerald H. Ross and Jean A. Monro. Chronic fatigue syndrome. CMAJ. 1989 Feb 15; 140(4): 361. PMCID: PMC1268650 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268650/?page=1

 

“Virus of the year”?

Note: This letter by Dr. Ray Holland, published in the Canadian Medical Association Journal on August 1, 1988, generated several responses. Dr. Salit’s response appears below. 

 

There appears to be a scarcity of information in medical and psychiatric journals (although not in the lay press) on what was initially termed the Epstein-Barr syndrome but was later renamed chronic fatigue syndrome because it can be caused by infective agents other than the Epstein-Barr virus (EBV). For example, the last article on the subject in CMAJ appeared in 1985.(1) There the syndrome, consisting of fatigue, depression, myalgia, muscle weakness, headaches and paresthesia, was named sporadic postinfectious neuromyasthenia (PIN), a term preferable to chronic fatigue syndrome because it is not ambiguous and because the condition can be of both infectious and psychologic origin.

Presumably the condition was named chronic fatigue syndrome because fatigue is the main presenting symptom, but in psychologic depression fatigue can also be the main manifestation. It is unfortunate, therefore, that the American Medical Association appears to have adopted such an ambiguous term while lamenting that the lack of a definitive diagnosis leaves both patients and health care providers frustrated.(2)

To confuse matters further, the media have labelled the condition chronic fatigue in overachievers or Yuppie flu. In fact, traditional psychiatrists have for some timed called chronic fatigue in overachievers anhedonia (inability to experience pleasure), which, if untreated, may lead to fatigue, depression and the other symptoms mentioned.

While the clinical picture may be ambiguous, the serologic findings may be more so, even when interpreted along with the clinical findings, because those exposed to EBV may have positive serologic results but no chronic sequelae, in much the same way as most people exposed to tuberculosis have subclinical infection. How high does the antibody titre have to be for a definite diagnosis of chronic fatigue syndrome in those who were apparently well before the acute viral attack, even if one excludes those with a previous psychiatric history, as Salit did? One must suspect that a high antibody titre that does not correlate with the clinical findings implies a psychologic origin, as does a low antibody titre. However, it appears that many patients who are told that they have positive but inconclusive serologic results of testing for EBV are choosing to believe that they have the disease. The local medical laboratory has informed me that there is not even a range of titres for EBV but that patients must find their own range by correlating values with how they feel! The media seem to infer that cases with negative results of EBV testing either have not been diagnosed because of lack of the necessary technology or have been misdiagnosed, because there is no mention that the cause may be psychologic.

Such a state of affairs is only too likely in today’s society, in which people are actually healthier than ever before but are more disease conscious and in which the media have a lively interest in medical matters. Rather than an epidemic of the disease, there appears to be an epidemic of the diagnosis, such that EBV should be named “virus of the year”.

May primum non nocere prevail as high-tech medicine continues to advance, at an alarming rate.

~Ray G.L. Holland, MD, FRCPC Box 458 Port Colbome, Ont.

References

  1. Salit IE: Sporadic postinfectious neuromyasthenia. Can Med Assoc J 1985; 133: 659-663
  2. Straus SE: EB or not EB – that is the question [E]. JAMA 1987; 257: 2335- 2336

 

[Dr. Salit responds:]

I too believe that the lack of information in medical journals on PIN [postinfectious neuromyasthenia] is a problem. There appears to be confusion about the condition among physicians, granting agencies and medical journals; they are unable to neatly classify the ailment into a nosologic category. The comment has been that the illness is “too vague” or “ill-defined”. This translates into an inability to have studies related to this subject published. Indeed, last year CMAJ rejected my article on immunologic aberrations in PIN, citing similar reasons.

The term chronic fatigue syndrome (1) was probably chosen by US investigators because it is a generic term. In 1985 these investigators thought that the illness was due to EBV; hence the common designation chronic EBV infection.(2) At that time I felt that the illness was induced by many etiologic agents, so I used the term PIN.(3) Most investigators in this area have come around to this way of thinking but have chosen not to use the term PIN.

Dr. Holland indicates that this disease has been acknowledged by psychiatrists in the past under other designations. Indeed, very similar illnesses have been known to different specialists by different names for decades. I have suggested a unifying hypothesis concerning a common pathophysiologic mechanism.(4)

EBV serologic findings have been the most confusing diagnostic aspect of this illness. Some patients after typical acute infectious mononucleosis have a form of chronic mononucleosis that symptomatically resembles PIN.(5) The serologic findings strongly suggest chronic active EBV infection. However, in most cases of PIN the illness probably did not start with acute infectious mononucleosis, and the patients probably do not have continuing active EBV infection. Using a sensitive DNA probe we found that PIN patients were not excreting EBV.(6) Furthermore, there is such extensive overlap between PIN patients and healthy controls that EBV serologic findings cannot be used to make the diagnosis.(7) It is also likely that such patients have moderately elevated titres of antibodies to a variety of other antigens. Most adults in Canada have EBV antibodies from a prior infection. Too often a diagnosis of chronic EBV infection is made on the basis of certain symptoms and the findings of any EBV antibody. This is inappropriate.

Holland says that “there appears to be an epidemic of the diagnosis”. What has become very apparent to me is that there are a large number of people in the community with illnesses that might be included under the rubric PIN. Physicians argue about the existence of this disease, but it is clear to me that PIN patients have an illness (or a deviation from a normal state of health). Despite the fact that we do not understand the disease process that results in this illness, the patients still require appropriate medical care, consisting of empathy, an acknowledgement that they are ill, reassurance that there is an absence of a more severe disease and, finally, guidelines on how best to manage the condition.(4’8’9)

I do not think that primum non nocere should prevail, although I can accept secundum non nocere. First we should show some understanding and compassion.

~ Irving E. Salit, MD, FRCPC Division of Infectious Diseases Toronto General Hospital Toronto, Ont.

References

  1. Holmes GP, Kaplan JE, Gantz NM et al: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387-389
  2. Jones JF, Ray CG, Minnich LL et al: Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated antiearly antigen antibodies. Ann Intern Med 1985; 102: 1-7 3. Salit IE: Sporadic postinfectious neuromyasthenia. Can Med Assoc J 1985; 133: 659-663
  3. Idem: Chronic EBV infections (postinfectious neuromyasthenia). Med North Am 1987; 10: 1944-1950
  4. Straus SE: The chronic mononucleosis syndrome. J Infect Dis 1988; 157: 405- 412
  5. Salit IE, Diaz-Mitoma F, Walmsley S et al: Absence of Epstein-Barr virus excretion in post-infectious neuromyopathies. Presented at the American Society for Microbiology annual meeting, Miami Beach, May 9, 1988
  6. Buchwald D, Sullivan JL, Komaroff AL: Frequency of “chronic active Epstein-Barr virus infection” in a general medical practice. JAMA 1987; 257: 2303-2307
  7. Salit IE: Post-infectious fatigue. Can Fam Physician 1987; 133: 1217-1219 9. Taerk GS, Toner B, Salit IE et al: Depression in patients with neuromyasthemia. Int J Psychiatry Med 1987; 17: 49-56

 

Source: R G Holland. “Virus of the year”? CMAJ. 1988 Aug 1; 139(3): 198–199. PMCID: PMC1268060 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268060/?page=1 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268061/

 

Chronic fatigue syndrome associated with Epstein-Barr virus infection

Abstract:

Epstein-Barr virus (EBV) infection is ubiquitous and may result in multiple and widely different clinical features; the most common of these is infectious mononucleosis (IM). Recently, a group of patients has been included in the chronic EBV infection syndrome (EBVIS), with a sustained nonspecific syndrome consisting of asthenia, anorexia, low grade fever and changes in mood, associated with a viral infection not necessarily caused by EBV; this has been called chronic fatigue syndrome (CFS). We report a patient who fulfilled the criteria for CFS associated with EBV after an acute, well documented EBV infection. We discuss its etiological and pathophysiological implications, emphasizing the need for extreme caution in the diagnosis of CFS. A merely clinical diagnosis may hide severe mistakes.

 

Source: Parras F, Salvá F, Reina J, Gil J, Portela D, Alomar P. Chronic fatigue syndrome associated with Epstein-Barr virus infection. Med Clin (Barc). 1989 Apr 29;92(16):619-22. [Article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/2545980