Chronic Fatigue Syndrome Electronic Newsletter : No. 102 March 1, 2001 Washington DC
Seattle, Washington, USA
Reprinted with Permission of Dr. Vallings.
The American Association for Chronic Fatigue Syndrome (AACFS) held its 5th biannual conference in Seattle during January 25-29, 2001. Below is a report by Dr. Rosamund Vallings on that conference. Dr. Vallings is a general practitioner from Bucklands Beach Auckland, New Zealand. Her practice is mostly CFS patients and she has seen about 2,000 patients with the illness.
TREATMENT
The first presentation in this session was by D Williams (Washington DC). He had done a randomised controlled trial of CBT in fibromyalgia (FM). 2 groups were assigned: standard medical treatment coupled with aerobic fitness instruction or CBT plus standard medical care. CBT was given over 6 sessions. Of the CBT group, 25% achieved improvement in physical functioning at 12-month follow up, while 12% of those in the standard medical group achieved the same level of improvement. This represents a 48% improvement with the addition of CBT, and this finding supports the inclusion of CBT as an essential component in standard treatment procedures for FM.
The efficacy and safety of modafinil for the treatment of fatigue in Multiple Sclerosis (MS) was discussed by K Rammohan (Ohio). Modafinil is described as a wake-promoting agent shown to be effective in narcolepsy. 200mg daily was found to significantly improve fatigue and daytime sleepiness in a study of 72 MS patients. It was well tolerated, though side effects were more common at 400mg, and at this higher dose there was no extra improvement noted. This drug may be a useful addition to the pharmacological options available to treat fatigue associated with MS and other fatiguing conditions.
K Rowe (Melbourne) presented a 7-year follow up of 58 young people with CFS who were involved in an IV gammaglobulin trial. There was continued improvement in functioning with 75% able to work or study full-time. 17% still described themselves as disabled. A small percentage had relapsed or experienced exacerbation of symptoms, and the occurrence of other serious illnesses was not greater than could be expected by chance.
D Cox (London) described the inpatient occupational therapy intervention for CFS at Romford, Essex. The principles of CBT and graded activity were applied to this very ill group of patients. At 6 months there was no significant change in symptoms or ability level, but there was a significant effect on the patients' perceived health, length of time tired and management of the illness, with 72% of the inpatient group, compared to 44% of the comparison group, stating that they felt better and felt the illness was being managed better. It was found wise to limit the hospital stay to no more than 6 weeks, as transition back to home would then prove more difficult. Age had no significant effects on outcome, although those who had been ill for less than 5 years did better.
A pilot study of tumour necrosis factor fusion protein, etanercept (a substance which blocks the interaction of TNF with its cell surface receptors) was done by K Lambrecht et al (Minneapolis). 6 CFS patients were given an 8 week trial of etanercept injections. Significant reductions were observed in the severity of fatigue, muscle pain, headache and lymphodynia. Exercise tolerance was improved. This lends support to the theory that proinflammatory cytokines maybe involved in the pathogenesis of CFS, and this should be further studied in a placebo-controlled trial.
A safety and feasibility study of immunomodulation using lymph node extraction, ex vivo cell culture and autologous cell reinfusion by N Klimas et al (Miami) found a lack of adverse effects, coupled with favourable clinical results. 13 patients were studied of which 2 had unsuitable nodes. The remaining 11 all underwent the procedure successfully with significant positive clinical outcome over 24 weeks. An improved cytokine shift correlated with clinical improvement, and this holds weight to the idea that increases in cytokines lead to symptoms. At 18 months, improvement is sustained. Further clinical trials seem warranted.
TREATMENT POSTERS
T Emms (Newcastle NSW) presented data suggesting that food intolerance as opposed to allergy may represent co-morbidity in a subgroup of CFS patients, and this could have implications for development of gastro-intestinal dysfunction. It was suggested that clinicians should trial a treatment protocol involving dietary history coupled with elimination diets.
Longterm nutritional supplementation was shown by K Dykman (Texas) to have some positive effect on the general functioning in FM/CFS
patients. Glyconutritional products and phytogenins were used. Polynutrient supplements were also trialled by F Brouwers et al (Nijmegen) and no significant differences were found between placebo and experimental condition.
Downregulation of Th2 cytokine production with a shift to Th1 cytokine expression was suggested as a useful intervention in CFS by R Partarco (Miami). Past approaches have been based on the use of Staphylococcus vaccine, influenza and/or rubella vaccines and autologous reinfusion of expanded lymph cells. Further studies are needed to allow elucidation of factors that mediate Th2-type cytokine expression predominance and maintenance.
G Whalen (Washington DC) considered the issue of autonomic dysfunction in CFS, and compared immune and cardiac responsiveness to beta-adrenergic agonist infusion (using isoproterenol) in CFS patients and controls. No differences were found, suggesting that there are no differences in afferent sensitivity to beta-adrenergic receptor occupation in this illness.
C Van der Eb (Illinois) designed a college course experience for students and their partners with CFS. Field work involved one-to-one support by the student with a person with CFS (a buddy system). The students were involved in a community-based learning programme educating them about the realities and personal costs of such an illness. This provided much needed, individualised support for those with CFS.
The use of ampligen in CFS by C Snell (Philadelphia) in 2 women with CFS led to some improvement in quality of life , decreased pain, enhanced energy levels and improved cognition. Ampligen intervention was also looked at from the economic point of view by A Shillington (Illinois). A pharmacoeconomic analysis was performed on data collected from 92 patients with severe CFS, who were randomised to a double blind, placebo-controlled trial of ampligen. A twice weekly infusion of 400mg ampligen over 24 weeks was found to significantly reduce the consumption of valuable health resources, and thereby reduce the costs of treating CFS. The therapy was well tolerated. A poster by D Strayer (Philadelphia) also showed considerable benefit from the use of ampligen as measured by Karnofsky scores and cognitive function data. 41 severely debilitated CFS patients were treated with the majority continuing treatment beyond 24 weeks. In his 2nd poster, he compared twice weekly with thrice weekly dosing with ampligen , and found that the thrice weekly dosing offered no advantages.
Midodrine (a peripheral alpha-antagonist) was used with some improvement in adolescents with orthostatic intolerance and CFS by M Alexander (Boston). Serious side effects seem uncommon and this drug can be a useful adjunct for management. If fludrocortisone is used concurrently, there is a small risk of hypertension.
Group CBT for 31 patients with CFS was compared to a waiting list control group of 35 CFS patients by G Bleijenberg (Nijmegen). It was found that CBT had a positive effect on fatigue when compared to the control group, but differences on outcomes concerning functional impairment were opposite to what was expected, in that those in the control group improved while those on CBT remained the same.
On the final afternoon of the conference, the current state of our knowledge and various aspects of underlying pathology, diagnosis and
management were summarised:
BIOLOGICAL ASPECTS OF CFS AND FIBROMYALGIA (A Komaroff, D Clauw)
The issue of pain in fibromyalgia (FM) was considered. Many syndromes are associated with FM such as irritable bowel syndrome, and the generalised pain threshold is low. Patients have an increased sensitivity to noxious stimuli, but normal detection threshold to touch. Likely mechanisms are: expectancy, hypervigilance or central changes in nociceptive processing, which is more physiological. Physiological mechanisms seem to be more prominent than psychological. The problem seems to be at the level of the cord or brain and not at the skin. Levels of substance P are 3-4 times higher in the spinal fluid in FM, and MRI studies show changes when the patient is experiencing pain. i.e. we are looking at a sensory processing defect.
Various types of brainscanning were reviewed. On MRI there are small areas of high signal in the white matter, and although many of these are seen in healthy controls, all studies have shown an increased number in those with CFS/FM. (80% in patients, 20% in controls). SPECT scans are more physiologic and show a "tattered" signal in CFS. A functional MRI gives a better picture of the physiology. The brain appears to be working harder than in a healthy person doing the same task. Other parts of the brain seem to be brought in to "help".
Abnormalities have been found in both the parasympathetic and sympathetic nervous systems. In the neuro-endocrine system, the hypothalamus is disordered, with disruption of ACTH stimulation and abnormalities in prolactin and growth hormone.
DIAGNOSTIC STRATEGIES IN CFS (K de Meirleir)
History taking is an important part of making a diagnosis of these disorders. One needs to consider whether the illness occurred as a result of an infectious on non-infectious event. History of all the following need to be considered: blood transfusion, surgery, febrile illness, toxic exposure, bites or stings, stress, trauma, foreign travel, STDs, sleep patterns, dental problems, ownership of pets or birds, immunisations, pregnancy, bleeding gums, sinus and respiratory infections, TM joint dysfunction etc.
First level of testing should include: full blood picture, IgE, intracellular RBC magnesium and serology, ECG including an exercise test. (The U+T wave is often big, and may look like a prolonged UT segment), chest Xray, abdominal ultrasound and further tests depending on specific symptoms e.g. panoramic Xray of dental roots, pulmonary function testing.
Second level of testing, much of which could only be done in a specialised laboratories (such as in Brussels) would include: LMW RnaseL/actin fragments, swabs to check for toxin producing coag uve staph aureus, immunophenotyping (total lymphocytes, activated T cells, CD4/CD8 ratio, NK subsets etc), antithyroid antibodies, immunoglobulins, Th1/Th2 profile, TNFalpha, interleukin 1, PCR for mycoplasma, chlamydia etc., hypoglycaemia test ( looking at ACTH, GH, cortisol, prolactin after injection of insulin), polysomnography in males over 35 (for sleep apnoea), neuropsychiatric evaluation.
It was pointed out that many physicians would not have access to these specialised tests, and also much time would be needed, particularly for tests such as a full neuropsychological investigation, which could take 3 hours.
DIAGNOSIS OF FIBROMYALGIA (L Calabrese)
10% of the population have widespread pain, females more so than males. The prevalence of FM is 2%. There is no diagnostic test. The more tender points, the greater the distress. The more constant the pain, the more likely the diagnosis is to be FM. The pain is achy and generalised, and waxes and wanes. 30% patients reviewed recently had an active mood disorder. Patients usually feel drained with a poor sleep pattern, headaches and concurrent irritable bowel is common.
Examination reveals the typical tender points, with no evidence of muscle or joint disease. (NB if the thumb nail blanches, one is applying adequate pressure). Lab investigations show normal acute phase reactants (ESR,CRP), muscle enzymes and thyroid function. Treatable disease must be excluded, such as sleep disorder, subclinical hypothyroidism, ankylosing spondylitis. One cannot rely solely on the tenderpoint examination and FM can co-exist with other conditions. FM does not respond to prednisone, so benefit from this may indicate a condition such as polymyalgia.
REVIEW OF TREATMENT OF CFS
We are looking at a heterogeneous population with lack of objective diagnosis. Few treatment trials have been done, and there is an absence of objective response markers. Newly diagnosed cases may be quite different from long-standing cases. For correct management a diagnosis is vital. Many hypotheses for therapeutic intervention exist, and a wide range of drugs have been tried such as: calcium channel blockers, psychoactive agents, opium antagonists, immune modifiers, antidepressants, stimulants etc.
Various treatments were reviewed:
Sleep impairment is an important area of treatment and may respond to tricyclics or clonazepam. Antidepressants do appear generally beneficial. Cortisol has been shown to have no benefit and may cause adrenal suppression. A trial with low dose hydrocortisone showed some mild benefit, but this is not generally recommended. For those suffering neurally mediated hypotension, treatment maybe helpful. In a study using of galantamine, an acetylcholinesterase inhibitor, there was no significant benefit. Growth hormone showed minimal help. CBT has been found to be better than just standard practice. Most people who have tried NADH have not been helped, though a small percentage did improve in one study. Neither treatment for allergies or use of antifungals have been found to be helpful. Some studies have shown evening primrose oil to be useful, but echinacea is of no help. Surgery for Chiari syndrome is rarely of use. There is some evidence that some antivirals can be of use, when viral pathology is implicated.
REVIEW OF TREATMENT OF FIBROMYALGIA (D Clauw)
There is often maladaptive illness behaviour with psychiatric co-morbidity, issues of secondary gain, general distress etc. as opposed to physiologic factors, but the greater the physiologic factors, the more likely the behavioural problems will develop.
Some drugs will raise the concentration of anti-nociceptive compounds.
a) descending pathways: tricyclics, SSRIs, new MAOs.
b) opioids
c) GABA
d) cytokines (no suitable drug)
e) CRH. We know of no drugs to lower the concentration of pro-nociceptors, except possibly dextromethorphan.
Treatment approaches should include: education, pharmacology (tricyclics for sleep, symptom based therapy such as tramadol for pain etc.), aerobic exercise (which should begin after pharmacological approach to reduce pain), CBT to reduce maladaptive behaviours in a stepped approach and some complementary therapies (acupuncture, biofeedback/relaxation, physical modalities).
RESEARCH and REHABILITATION PANEL DISCUSSION (Chair: P Levine)
A 4 phase model of CFS was outlined by P Fennell using the Fennell Phase Inventory: crisis, stabilisation, resolution and integration. During each phase, 3 domains were important: physical/behavioural, psychological and social/interactive. For each domain in each phase, medical assessment and intervention and phase assessment and intervention were discussed. A very useful protocol was provided in a handout, which would be important for physicians, psychologists, social workers and other professionals dealing with CFS. D Uslan enlarged on some of the detail, and much discussion ensued regarding this important multi-dimensional approach to management.
Education of physicians was considered really important for the benefit of all CFS patients and a co-ordinated team approach seems the ideal.
CASE DEFINITION -- considerations for revising the 1994 criteria (Chair: W Reeves)
(CDC and prevention planning session)
An open forum discussed this issue before the conference officially began. The actual definition of fatigue was covered. There are many parameters of fatigue (e.g. the fatigue in cancer is quite different to that in CFS) and the question was asked "Is fatigue the right way to identify these atients?". One needs to be able to qualify and quantify fatigue. As yet there is no "perfect" definition of fatigue.
N Klimas pointed out that we should not refer to the definition as the CDC definition but the International Consensus definition. There is confusion between the research and clinical definition, and the current definition refers to the research case definition. She went on to say that fatigue has much ambiguity, such as physical and mental, frequency, duration and level etc., and the exclusion criteria are vague, e.g. obesity, depression.
L Jason talked of the standardisation/operation of the classification instruments. CFS patients are more functionally impaired than, for example those with diabetes. One needs questionnaires on various aspects of the illness. There are also a number of overlapping syndromes. Useful measures are the sickness impact scale, medical outcome scale, sleep assessment questionnaire, fatigue severity scale, Beck depression inventory, scale of fatigue (Australia) and SCID and DIS for assessment of psychiatric co-morbidity. Onset, severity and phases of illness need to be established.
Study design was discussed by S Vernon (CDC). There is often a lack of the number of symptoms at particular times in the illness, and this may relate to its waxing and waning character. There are problems in the absence of a specific lesion. Systemic blood needs to be used in the hope to find molecular markers.
W Reeves said that as the current definition was developed by consensus we need to empirically define CFS, The 1994 guidelines are driven by "fatigue". There is no single marker for CFS, so it is necessary to decide which symptom complex best defines CFS.
Data was collected in a population based study in Wichita looking at the whole community of 27,000. 3500 were found to be fatigued for more than one month, and 46 had CFS. A dichotomous factor analysis of the symptom complexes was performed. Chronic fatigue, weakness and non-refreshing sleep were the factors not differentiating patients and controls. There was some overlap between those who were chronically unwell and those with CFS. These findings were similar to what was found in Gulf War Illness. Very few minority groups were seen.
In summary important conclusions were that patients with symptoms of fatigue need an intensive medical workup, and we cannot do research
properly until we have a workable case definition.
NAME CHANGE WORKGROUP OPEN FORUM (N Klimas, C Lapp, L Jason)
This was a lively discussion in which the possibility of name change was addressed by a number of health professionals and CFS patients looking at the issue from many points of view. Names describing underlying pathology such as myalgic neuro-asthenia, neuro-endocrine immune disorder and myo-encephalopathy were suggested, as were names of people who had suffered the illness or researched it, such as Nightingale disease or Shelokov syndrome. Incorporation of place names seemed too specific to particular epidemics: Royal Free disease, Incline village syndrome, Icelandic disease.
General consensus seemed to come down in favour of getting away from Chronic Fatigue Syndrome, and concentrating on the underlying pathogenesis, while retaining something familiar, such as the term ME, which is still widely used in a number of countries. Myo-encephalopathy did fit the bill, but obviously any decision for name change needs to be international and taken with great care to avoid need for further change, which eventually only confuses the issue further and does not work in patients' best interests.
[This concludes Dr. Vallings' three-part report on the Seattle AACFS conference. Please remember, regardless of what you may read in these reports, be sure to consult your licensed health care practitioner about your own health care.]
CFS-NEWS (ISSN 1066-8152) is an international newsletter published and edited by Roger Burns in Washington D.C. Suggestions and contributions of news may be sent to Roger Burns by Internet e-mail to CFS-NEWS@MAELSTROM.STJOHNS.EDU or leave a voicemail message by telephone at 1-202-966-8738, or send to postal address 2800 Quebec St NW, no. 1242, Washington DC 20008 USA. Copyright (c) 2001 by Roger Burns.
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