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Edwards syndrome

Trisomy 18 or Edwards Syndrome (named after John H. Edwards) is a genetic disorder. It is the second most common trisomy after Down's Syndrome. It is caused by the presence of three - instead of two - chromosomes 18 in a fetus or baby's cells. more...

Ebola hemorrhagic fever
Ebstein's anomaly
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Edwards syndrome
Ehlers-Danlos syndrome
Elective mutism
Ellis-Van Creveld syndrome
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The additional chromosome usually occurs before conception, when egg and sperm cells are made. A healthy egg or sperm cell contains 23 individual chromosomes - one to contribute to each of the 23 pairs of chromosomes needed to form a normal cell with 46 chromosomes. Numerical errors arise at either of the two meiotic divisions and cause the failure of segregation of a chromosome into the daughter cells (non-disjunction). This results in an extra chromosome making the haploid number 24 rather than 23. Fertilization of these eggs or sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two. It is this extra genetic information that causes all the abnormalities characteristic of individuals with Edwards Syndrome. As each and every cell in their body contains extra information, the ability to grow and develop appropriately is delayed or impaired. This results in characteristic physical abnormalities such as low birth weight; a small, abnormally shaped head; small jaw; small mouth; low-set ears; and clenched fists with overlapping fingers. Babies with Edwards syndrome also have heart defects, and other organ malformations such that most systems of the body are affected.

Edwards Syndrome also results in significant developmental delays. For this reason a full-term Edwards syndrome baby may well exhibit the breathing and feeding difficulties of a premature baby. Given the assistance offered to premature babies, some of these infants are able to overcome these initial difficulties, but eventually succumb.

The survival rate for Edwards Syndrome is very low. About half die in utero. Of liveborn infants, only 50% live to 2 months, and only 5 - 10% will survive their first year of life. Major causes of death include apnea and heart abnormalities. It is impossible to predict the exact prognosis of an Edwards Syndrome child during pregnancy or the neonatal period. As major medical interventions are routinely withheld from these children, it is also difficult to determine what the survival rate or prognosis would be for the condition if they were treated with the same aggressiveness as their genetically normal peers. They are typically severely to profoundly developmentally delayed.

The rate of occurrence for Edwards Syndrome is ~ 1:3000 conceptions and 1:6000 livebirths, as 50% of those diagnosed prenatally with the condition will not survive the prenatal period. Although there is an increased risk of conceiving a child with Edwards Syndrome as a woman's age increases, women in their 20's and 30's still conceive Edwards Syndrome babies.

A small percentage of cases occur when only some of the body's cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected people have two copies of chromosome 18, plus extra material from chromosome 18 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 18 and the abnormalities are often less than for the typical Edwards syndrome.


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Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome
From British Medical Journal, 2/17/01 by Pauline Powell


Objective To assess the efficacy of an educational intervention explaining symptoms to encourage graded exercise in patients with chronic fatigue syndrome

Design Randomised controlled trial.

Setting Chronic fatigue clinic and infectious diseases outpatient clinic.

Subjects 148 consecutively referred patients fulfilling Oxford criteria for chronic fatigue syndrome.

Interventions Patients randomised to the control group received standardised medical care. Patients randomised to intervention received two individual treatment sessions and two telephone follow up calls, supported by a comprehensive educational pack, describing the role of disrupted physiological regulation in fatigue symptoms and encouraging home based graded exercise. The minimum intervention group had no further treatment, but the telephone intervention group received an additional seven follow up calls and the maximum intervention group an additional seven face to face sessions over four months.

Main outcome measure A score of [is greater than or equal to] 25 or an increase of [is greater than or equal to] 10 on the SF-36 physical functioning subscale (range 10 to 30) 12 months after randomisation.

Results 21 patients dropped out, mainly from the intervention groups. Intention to treat analysis showed 79 (69%) of patients in the intervention groups achieved a satisfactory outcome in physical functioning compared with two (6%) of controls, who received standardised medical care (P [is less than] 0.0001). Similar improvements were observed in fatigue, sleep, disability, and mood. No significant differences were found between the three intervention groups.

Conclusions Treatment incorporating evidence based physiological explanations for symptoms was effective in encouraging self managed graded exercise. This resulted in substantial improvement compared with standardised medical care.


Patients' beliefs are based on evidence they find convincing.[1] As most of the symptoms of chronic fatigue syndrome are physical, patients develop a strong physical perception of the condition. In the absence of medical explanation, many attribute intense and unpleasant symptoms to an underlying disease and are disinclined to accept that psychological factors may have a role. Attributing symptoms to ongoing physical disease is an important predictor of poor prognosis.[2]

The aetiology of chronic fatigue syndrome is controversial, and extensive research has failed to identify any serious underlying pathology. However, many patients show signs of disrupted physiological regulation. Chronic fatigue syndrome may be associated with desynchronisation of circadian rhythms, which may be a consequence of disruption of the daily cues needed to reset the biological clock--for example, by a viral infection or stressful life events.[3] Evidence of sleep abnormalities[4] and cortisol deficiency[5 6] are consistent with this hypothesis. The subsequent reduction in activity results in cardiovascular and muscular deconditioning, which exacerbates symptoms.[7 8] Inaccurate illness beliefs that encourage avoidance of activity and chaotic sleep patterns may perpetuate the condition.[9] This model suggests that providing patients with evidence based illness beliefs may facilitate activity and bring about therapeutic change.

Two randomised clinical trials of cognitive behaviour therapy and grade exercise that are compatible with this model have produced positive results.[10 11] However, cognitive behaviour therapy is expensive and carries the risk of deterring patients who are fearful of contact with mental health workers. We have developed a treatment for chronic fatigue syndrome that is briefer. It involves educating patients about the medical evidence of the physical and psychological effects of physical deconditioning and circadian dysrhythmia, with the intention of encouraging a self managed graded exercise programme. A more detailed account of the intervention approach has been published.[12]

Participants and methods

Patients were recruited from consecutive referrals to a dedicated chronic fatigue clinic at the Royal Liverpool University Hospital and from an infectious diseases outpatient clinic at University Hospital, Aintree.

Inclusion criteria specified that patients fulfilled the Oxford criteria for chronic fatigue syndrome[13] and scored [is less than] 25 on the physical functioning subscale of the SF-36 questionnaire (10 indicates maximum physical limitation in self care and 30 indicates ability to do vigorous sports).[14] Patients were excluded if they were having further physical investigations or taking other treatments, including antidepressants for less than 3 months; had a psychotic illness, somatisation disorder, eating disorder, or history of substance misuse; or were confined to a wheelchair or bed. The study was approved by the district research ethics committee, and all participants gave written informed consent.


Immediately after medical assessment, eligible patients were randomised into four groups by means of a sequence of computer generated random numbers in sealed numbered envelopes. We used a simple randomisation with stratification for scores on the hospital anxiety and depression scale,[15] using a cut off of 11 to indicate clinical depression.

Treatment conditions

Patients in the control group received standardised medical care. This comprised a medical assessment, advice, and an information booklet that encouraged graded activity and positive thinking but gave no explanations for file symptoms.

The intervention groups all received a medical assessment followed by evidence based explanations of symptoms that encouraged graded activity. Explanation of symptoms focused on circadian dysrhythmia, physical deconditioning, and sleep abnormalities. A graded exercise programme was designed in collaboration with each patient and tailored to his or her functional abilities. Once patients were successfully engaged in treatment, the role of predisposing and perpetuating psychosocial factors was discussed. Treatment was supported by an educational information pack that reiterated the verbal explanations. The intervention groups differed in the method and number of treatment sessions.

Minimum intervention group--Patients received two face to face sessions totalling three hours in which symptoms were explained and the graded exercise programme was designed.

Telephone intervention group--In addition to the minimum intervention patients received seven planned telephone contacts, each of about 30 minutes over three months. During these calls explanations for symptoms and the treatment rationale were reiterated and problems associated with graded exercise were discussed with the use of motivational interviewing techniques.[16]

Maximum intervention group--In addition to the minimum intervention, patients received seven one hour face to face treatment sessions over three months. These had the same function as the telephone sessions in the telephone intervention group.

Outcome measures

Patients were sent questionnaires containing validated measures of outcome by post before randomisation and at three, six, and 12 months. Primary outcomes were scores on the physical functioning subscale of the SF-36 questionnaire and on the fatigue scale (range 1-11, scores [is greater than] 3 indicate excessive fatigue).[17] The predetermined criterion for clinically important improvement at one year was a score of [is greater than or equal to] 25 or more or an increase of [is greater than or equal to] 10 from baseline on the physical functioning scale (range 10 to 30). This is similar to normal daily functioning for the UK general population.[18]

Secondary outcome measures included scores on the hospital anxiety and depression scales,[15] a sleep problem questionnaire,[19] and a global impression of change score one year after trial entry.[20] A simple questionnaire was used to assess illness beliefs and experience of treatment at one year.

Statistical analysis

We used an intention to treat analysis. For patients who dropped out of treatment, the last values obtained were carried forward.

We tested the significance of changes in primary outcomes by analysing scores at one year with baseline scores and depression scores as covariates; this strategy reduced the problems associated with multiple testing. The clinical importance of improvement at one year was tested with the [chi square] statistic.


Of the 312 patients assessed, 152 did not meet the trial criterial and 12 declined to participate (see BMJ's website for details). A total of 148 patients entered the trial. Table 1 shows patients' characteristics on admission to the trial.


Treatment effects

Table 2 gives the scores for the primary outcome measures at baseline and follow up. At one year, significantly more patients had improved on the SF-36 physical functioning scale than in the control group. The mean score in all three intervention groups was higher than in the control group. Similarly, on the fatigue scale, improvement at one year follow up was greater in each of the intervention groups than in the control group.


Only two of the 34 patients in the control group met our criteria for a clinically important improvement compared with 26/37 in the minimal intervention group, 27/39 in the telephone group, and 26/38 in the maximum intervention group ([chi square]=42.54, df=3, P [is less than] 0.001). These proportions equated to numbers needed to treat of 1.6 in each group. Fatigue, sleep, disability, and mood also improved in the intervention groups but not in the control group (further details are available on the BMJ's website).

Changes in beliefs

Seventy seven patients in the intervention groups completed questionnaires about their illness beliefs. Only 15% (11/75) reported that they had believed that their condition was related to physical deconditioning at baseline whereas 81% (61/75) believed this after treatment. The explanations of their symptoms convinced 94% (72/77) of the patients to carry out graded activity.


The interventions were more effective in improving fatigue and physical functioning than standardised medical care. Mood, sleep, and disability scores also improved (see These gains were maintained at one year follow up. Improvement in the control group was similar to that observed elsewhere.[21]

Of the patients who completed treatment, 81% met our improvement criterion. Although the intervention was generally beneficial, an intention to treat analysis showed that 32% of patients still complained of fatigue at one year despite a substantial improvement in physical functioning.

We found no significant differences between the three intervention groups. For many of the patients, the minimum intervention of two lace to face sessions and up to four follow up telephone contacts was sufficient to bring about clinical gains. There was no evidence that further face to face or telephone contacts facilitated further improvement, although differences may emerge when longer term follow up data are collected.

Other trials in chronic fatigue syndrome reported encouraging results with cognitive behaviour therapy,[10 11] and graded exercise.[21 22] In those trials, 60-74% of patients who completed treatment rated themselves as better or much better compared with 84% of patients who completed the interventions in the present trial. A recent review found that, "Cognitive behavioural therapy administered by highly skilled therapists in specialist centres is an effective intervention for people with chronic fatigue syndrome, with a number needed to treat (NNT) of 2."[23] Our findings compare favourably with this outcome. Our intervention requires fewer sessions than cognitive behaviour therapy and could be carried out by a clinician without advanced training in psychological therapies.


Our current study has several limitations, including the lack of a placebo control group that received equivalent therapist time and attention. However, other investigators have found that therapist time alone does not result in positive outcomes.[11 21 22] After treatment, most patients attributed their improvement to changes of behaviour brought about by the physiological explanations they were given for their symptoms.

What is already known on this topic

No serious underlying pathology has been identified in patients with chronic fatigue syndrome

Patients with chronic fatigue syndrome show evidence of disrupted physiological regulation, including physical deconditioning, sleep disturbance, and circadian dysrhythmia

Cognitive behaviour therapy targeted at changing illness beliefs and graded exercise helps some patients

What this study adds

Patients given evidence based physiological explanations for their symptoms and encouraged to do graded exercise were significantly better than those who received standardised care at one year

The approach may be as effective as cognitive behaviour therapy but is shorter and requires less therapist skill

Contributors: PP conceived the study. PP and RPB jointly designed the study in collaboration with RHTE and FJN. PP carried out the therapy. FJN and RHTE clinically assessed patients. RPB analysed the data and interpreted the results. PP and RPB wrote the paper, guided by the comments of the other authors. RPB and PP are the guarantors.

Funding: Linbury Trust.

Competing interests: None declared.

[1] Wessely S. Edwards RHT. Chronic fatigue. In: Greenwood R, Barnes M, McMillan T, Ward C. eds. Neurological rehabilitation. Edinburgh: Churchill Livingstone. 1993:311-25.

[2] Wilson A, Hickie I, Lloyd A, Hadzi-Pavlovic D, Boughton C, Dwyer J, et al. Longitudinal study of outcome of chronic fatigue syndrome. BMJ 1994;308:756-9.

[3] Williams G, Piromohamed J, Minors D, Waterhouse J, Arendt J, Edwards RHT. Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome. Clin Physiol 1996;16:327-33.

[4] Morriss R, Wearden A, Battersby L. The relation of sleep difficulties to fatigue, mood and disability in chronic fatigue syndrome. J Psychosom Res 1997;42:597-605.

[5] Demitrack M, Dale J, Stratus S, Laue L, Listwak S, Kruesi M, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endcrinol Metab 1991;73:1224-34.

[6] Cleare A, Bearn J, Allain T, McGregor A, Wessely S, Murray R, et al. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Disord 1995;35:293-89.

[7] Edwards R, Clague J, Gibson H, Helliwell T. Muscle metabolism, histopathology, and physiology in chronic fatigue syndrome. In: Straus S, ed. Chronic fatigue syndrome. New York: Marcel Dekker, 1994:241-61.

[8] De Lorenzo F, Xiao H, Mukherjee M, Harcup J, Suleiman S, Kadziola Z, et al. Chronic fatigue syndrome: physical and cardiovascular deconditioning. QJ Med 1998;91:475-81.

[9] Wessely S, Hotopf M, Sharpe M. Chronic fatigue and its syndromes. Oxford: Oxford University Press, 1998.

[10] Sharpe M, Hawton K, Simkin S, Surway C, Hackmann A, Klimes I, et al. Cognitive behaviour therapy for the chronic fatigue syndrome: randomised controlled trial. BMJ 1996;312:22-6.

[11] Deale A, Chalder T, Marks I, Wessely S. Cognitive behavioural therapy for chronic fatigue syndrome: a randomised controlled trial Am J Psychiatry 1997;154:408-14.

[12] Powell P, Edwards R, Bentall R. The treatment of wheelchairbound chronic fatigue syndrome patients: Two case studies of a pragmatic treatment approach. Behavioural and Cognitive Psychotherapy 1999;27:249-60.

[13] Sharpe M, Archard L, Banarvala J, Borysiewicz L, Clare A, David A, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med 1991;84:118-21.

[14] Ware J, Sherbourne C. The MOS 36-item short form health survey (SF36). Med Care 1992;30:473-83.

[15] Zigmond A, Snaith R. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361-70.

[16] Miller W, Rollnick S. Motivational interviewing. New York: Guilford Press, 1991.

[17] Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, et al. Development of a fatigue scale. J Psychosom Res 1993;37:147-53.

[18] Garratt A, Ruta D, Abdalla M, Buckingham J, Russell I. The SF36 health survey questionnaire: an outcome measure suitable tot use within the NHS? BMJ 1993;306:1440-4.

[19] Jenkins D, Stanton B, Niemcryk S, Rose R. A scale for the estimation of sleep problems in clinical research. J Clin Epidemiol 1988;41:313-21.

[20] Guy W. Clinical global impressions. In: ECDEU assessment manual for psychopharmacology. Rockville, MD: National Institute of Medical Health, 1976:218-22.

[21] Wearden A, Morriss R, Mullis R, Strickland P, Pearson D, Appleby L, et al. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome. Br J Psychiatry 1998;172:485-96.

[22] Fulcher K, White P. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ 1997;314:1647-52.

[23] Reid S, Chalder 2, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. BMJ 2000;320:292-6.

(Accepted 17 November 2000)

Regional Infectious Diseases Unit, University Hospital Aintree, Liverpool L9 7AL

Pauline Powell senior clinical therapist Fred J Nye consultant physician

Department of Psychology, Coupland 1 Building, University of Manchester, Manchester M13 9PL

Richard P Bentall professor of experimental clinical psychology

Department of Medicine, University of Liverpool, Liverpool L69 3GA

Richard H T Edwards professor of medicine

Correspondence to: R P Bentall bentall@

BMJ 2001;322:387-90

COPYRIGHT 2001 British Medical Association
COPYRIGHT 2001 Gale Group

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