IN
CHRONIC FATIGUE SYNDROME
NATIONAL CONSENSUS CONFERENCE
CHRONIC FATIGUE SYNDROME RESOURCE DOCUMENTS
Presented by
The Australian Comprehensive Medicine Association (ACMA)
The Institute of Functional Medicine
Major Sponsor
Blackmores Professional Services
This document represents the presentations given by Dr Paul Cheney, keynote speaker at the Complementary Medicine in CFS National Consensus Conference held at the Convention Centre, Darling Harbour, Sydney Australia on the weekend of February 19 and 20, 1995.
The Conference was presented by the Australian Comprehensive Medicine Association (ACMA) and the Institute of Functional Medicine, and was attended by one hundred and fifty medical scientists and medical practitioners from around Australia. These included university researchers, consultant physicians, and general practitioners. Over thirty presentations were made during the two days, covering all aspects of Chronic Fatigue Syndrome, from preliminary research findings through to the results of intervention outcome studies.
Following the Conference, Dr Cheney returned to Australia in August, 1995, to provide a three day intensive workshop for practitioners treating mainly Chronic Fatigue Syndrome patients. The workshop provided in depth understanding of the causes of CFS, and the biological processes involved. A diagnostic program has evolved from the workshop, allowing for better categorisation and management of CFS sufferers. The doctors at the workshop have adopted this as a common diagnostic standard, and will be implementing the therapeutic practices which have proven benefit in this disease. The names and contact numbers of the practitioners attending the Cheney Clinic Protocols Workshop are available by phoning the Institute of Functional Medicine (1 300 650 455), or by contacting the Australian Comprehensive Medicine Association (+61 2 968-4422).
The full proceedings, including the consensus statement, are available from:
The cost of the proceedings is $A90 (plus postage and packaging), and comprises 200 pages of conference transcripts and summaries, as well as approximately 200 pages of articles, references, resources and information on CFS fro physicians, patients, carers and the interested public.
The Australian Comprehensive Medicine Association is a medical organisation representing medical practitioners who provide additional skills, drawn from the various fields of Complementary Medicine and Alternative Medicine, in their medical practices. Its mission is to promote and foster safe and effective Complementary Medical practice within a framework of Total Health Care. ACMA is involved in setting uniform and high educational and practice standards within Complementary Medicine, and to initiating and supporting quality education and research in the field. This will result in improved practice standards, and better outcomes for those who wish to look at complementary practices for optimising their health or managing their illnesses.
ACMA can be contacted at:
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Session 1 Presentation 3 Tape 2
The history of medicine is a story of
amazing foolishness and amazing intelligence
Jerome Tarshis
Paul R. Cheney, MD, PhD
Director, The Cheney Clinic, P.A.
10620 Park Road, Suite 234 Charlotte NC 28210 USA
phone (704) 542-7444 fax (704) 542-0720
In recent years it has become ever more apparent that a difficulty to diagnose but clinically recognisable disorder characterised by unexplained debilitating fatigue and other systems exists in large numbers in communities across the developed world. Recent studies using defined case definitions 1, for 'Chronic Fatigue Syndrome' have revealed that community prevalence rates range from 40 2 to 267 3 cases per 100,000. Much larger prevalences can be seen in certain medical professions (680 cases per 100,000 nurses) 4 or primary care setting (1,000 cases per 100,000 visits) 5.
There is also a sense that the numbers of such patients may be increasing. In April 1994, one of the largest disability insures in the United States, UNUM Corp of Portland, Maine, reported that in the five years from 1989 through 1993, men's disability claims for CFS increased 360%; women's claims increased 557%. No other disease category surpassed these rates of increase. We will present evidence that there may have been a sharp rise in the case production rate of CFS beginning in the late 1970s and peaking in 1987 followed by a slow decline since that time.
In our view, the clinical coherence of these patients surpasses the sometimes differing clinical description of similar fatiguing illness reported over the past several centuries, both sporadic 6,7,8 and epidemic 9,10,11. We will present evidence of this clinical coherence in a case-control study of physical findings. It is likely that the syndrome we call chronic fatigue syndrome is both very old and also very new. What is old is the pathophysiology of post-infectious or post-stressor syndrome which results in a self-maintaining cycle of dysfunction with the most important locus of injury within the central nervous system. While there are many ways to get sick, there are only a few ways to feel sick, and fewer ways still to remain sick. On the other hand, the coherence of these patients and the rather remarkable rise and fall in case production which is fixed in time suggests the distinct possibility that a novel agent or process exits.
There are therefore two challenges before us; one is to elucidate the common pathophysiology of long term fatiguing illness of variable aetiologies or triggers and the other is the remarkable challenge of reducing some and possibly most cases of CFS to a single aetiology evident since the late 1970s
References
1. Holmes, GP., Kaplan, JE., Gantz, NM., Komaroff, AL., Schonberger, LB., Straus, SE., Jones, JF., Dubois, RE., Cunningham - Rundles, C., Pahwa, S. Tosato, G., Zegans, LS., Purtilo, DT., Brown, N., Schooley, RT. and Brus, I. "Chronic Fatigue Syndrome, a Working Case Definition." Annals of Internal Medicine (1988):108, 387-389
2. Lloyd, AR. et al "Prevalence of chronic fatigue syndrome in an Australian population." Med J Aust. (1990): 153,522-528.
3. Buchwald, D. et al "Prevalence of chronic fatigue and chronic fatigue syndrome in a large community based HMO." AACFs Research Conference presentation : Ft. Lauderdale, FL., October (1994):pg 9.
4. Jason, L.: Pilot study results reported in The CFIDS Chronicle., Winter (1995): Vol 8 No 1: pg 6.
5. Bates, DW. et al. (Prevalence of chronic fatigue and chronic fatigue syndrome in a primary care practice." Arch Int. Med. (1993): 153,2759-2765.
6. Manningham, R. "The symptoms, nature, causes and cure of the febricula, or little fever; commonly called the nervous fever or hysteric fever, the fever on the spirits, vapous, hypo or spleen." 2nd Edition. London: J Robinson 1750:52 -3.
7. Beard, G. "Neurasthenia, or nervous exhaustion." Boston Medical and Surgical Journal. 1896; 3 (new series):217-220.
8. Da Costa, JM. "On irritable heart, a clinical study on a form of functional cardiac disorder and its consequence." Am. J. Med. Sci. 1871; 121, 17-52.
9. Poskanzer, DC., Henderson, DA., et al."Epidemic neuromyasthenia: Outbreak in Punta Gorda Florida." NEJM (1957) :257, 356-364
10. Gilliam, AG. "Epidemiological study of an epidemic, diagnosed as poliomyetis, occuring among the personnel of the Los Angeles County Hospital during the summer of 1934" Public Health Bulliten No. 240, April (1938).
11. Sigurdsson, B., Sigurjonsson, J., Sigurdsson, JH.,
Thorkelsson, J., and Gudmundsson, K. "A disease epidemic in Iceland
simulating poliomyelitis." American Journal of Hygiene.(1950):
52,222-38.
There is an appropriate quote from the philosopher, William
James.
When a thing was new, people said 'It's not true'.Later when the truth became obvious, people said 'It's not important'.
And when its importance could not be denied, people said 'Anyway, it's not new.'
Chronic Fatigue Syndrome has features of autoimmune disorders (eg lupus), features of allergy and Multiple Chemical Sensitivities (MCS), features of neurological disease (like MS), and features of psychiatric disease. The syndrome shares many features of infectious disorders (like HIV), and features of tempero-limbic encephalopathies. The disorder does not fit the definitions of other diseases, and probably is a distinct entity.
The Centre for Disease Control has recently revised the case definition of CFS in the Annals of Internal medicine (Dec 15, 1994;121:953-959 - see appendix). The definition now includes a separate diagnostic category for prolonged fatigue which does not meet the necessary criteria for CFS. This is termed Idiopathic Chronic Fatigue (ICF).
The critical issues in the proposed diagnostic criteria is that prolonged, unexplained fatigue must have been present for more than 6 months, and four or more of the seven symptoms listed must have been present for at least six months following the onset of the fatigue. In addition, certain factors must be excluded, including:
There is a major problem with the case definition in my opinion, and that is that five of the eight symptoms relate to pain. So a patient without pain cannot, by definition, fulfil the diagnostic criteria for CFS. This seems to me incorrect.
As well, the diagnostic criteria do not include symptoms of environmental sensitivities and balance problems, which I believe are common in CFS.
The case definition does define certain data which should be collected, and testing required to exclude other illness. These include:
The case definition goes on to describe the information required in addition, termed "essential subgrouping variables". The majority are questionnaires, and include:
In summary, conforming to the requirements of the case definition is an ONEROUS task, and not likely to be able to be performed in clinical practice.
The disease seems to have been around for some time, under various names. CFS, or something like CFS, has been variously termed:
There have been many published studies of epidemics over past 100 years. However, original articles from 1700s and after show one striking issue - that the syndrome described often results in death. This is not what we see today, and it makes me wonder if we really are talking about the same illness.
There are certain hallmarks of the illness we currently term CFS. These include:
The signs of CFS are usually not considered, but can include the following abnormalities on formal testing:
We performed a study looking at CFS and signs and symptoms. Controls were selected by Random Digit Dialling method.
|
Cases |
Control |
Sign |
|
80% |
20% |
Hyperreflexia without clonus |
|
80% |
20% |
Crimson crescent in oropharynx |
|
44% |
16% |
Loss of fingerprints |
|
32% |
0% |
Fever > 99.2° F |
|
88% |
0% |
Tender posterior cervical nodes |
|
92% |
0% |
Supraclavicular tenderness |
|
84% |
4% |
Rhomberg mild positive |
|
92% |
4% |
Augmented Tandem Stance positive |
Prevalence and incidence have been reported over a very broad range, depending greatly on the selection criteria & the type of study undertaken. The following shows the "range" of the data.
|
Author/Institution (country) |
Reported Incidence/Prevalence |
Type of study/criteria |
|
CDC (USA) |
10 cases/100,000 of pop/yr |
(referral by doctors) |
|
Lloyd (Australia) |
40 cases/100,000 of pop/yr |
(referral by doctors) |
|
Bates (Boston) |
300 cases/100,000 visits |
(on old CDC definition) |
|
Harvard Primary Care Clinic |
1,000 cases/100,000 visits |
(on Australian definition) |
|
Buckwald (Seattle) |
267 cases/100,000 visits |
(on old CDC definition) |
|
Jason (Chicago) |
200 cases/100,000 visits |
(on old CDC definition) |
|
Jason (Chicago) (est) |
600 cases/100,000 visits (est) |
(on new CDC definition) |
It is also noted that CFS has the highest rate of increase in claims among insurers over the past five years of any illness.
Note that the community- based studies do not suggest significant sex ratio differences. The preponderance of women among CFS cases presenting to doctors may well be an artifact, and due to factors related to doctor visits.
Session 3 Presentation 1 Tape 5
We must turn to nature itself, to the observations of the
body
in health and disease, to learn the truth.
Hippocrates (c. 460 BC &endash; 377 BC)
of Chronic Fatigue Syndrome
Paul R. Cheney, M.D., Ph.D.,
Director, The Cheney Clinic
PA. 10620 Park Rd, Suite #223,Charlotte NC 28210 USA
Phone (704) 542-7444. Fax (704) 542-0722
Conceptualising this complex disorder is a first step in the process of understanding and successfully treating Chronic Fatigue Syndrome (CFS)
Chronic fatigue syndrome represents a chronic, debilitating and prolonged illness characterized by numerous symptoms but most especially fatigue, cognitive dysfunction and pain. Frequent but subtle physical findings support laboratory evidence 1,2,3 involving excessive alpha-interferon production 4 and functional brain scan evidence 5,6,7 of central nervous system injury which is likely metabolic and possibly due to alpha-interferon itself. Immune activation with excess lymph production may produce peripheral pain 8 in certain tissues which is then amplified centrally by injury to key central nervous system structures 9 and mediated by opioid receptor linked alpha-interferon induced neurotoxicity 10, Fatigue itself may ultimately have cellular basis at a level of mitochondrial dysfunction 11,12,13. Organ systems may be differentially affected and within organ systems there may be a mosaic of affected and unaffected cells, the sum of which defines the degree of organ dysfunction immune activation and its effects on the CNS may set up a vicious cycle which is independent of an initial triggering agent or event which may no longer be present. It is also possible that a persistent causative agent(s) exists and plays an active role in the maintenance of this pathophysiology. The exact nature of this putative agent remains unknown but the clinical presentation and the presence of high levels of alpha-interferon or its sub-cellular effects 14 favours a viral etiology.
References
1. Kilmas, N., Salvato, F., Morgan, R. and Fletcher, M. "Immunologic Abnormalities in Chronic Fatigue Syndrome." J. of Clinical Microbiology. (1990): 28,1403-1410.
2. Lloyd, AR., Wakefield, D., Boughton, CR., Dwyer, JM., "Immunologic Abnormalities in The Chronic Fatigue Syndrome." Medical Journal of Australia (1989): 151(3), 122-124.
3. Landay, AL., Jessop, C., Lennette, ET., & Levy, JA. "Chronic Fatigue Syndrome : Clinical Condition Associated with Immune Activation" The Lancet (1991): Vol. 338, No. 8769.
4. Suhaldonik, RJ., Reichenbach, NL., Hitzges, P., Sobol, RW., Peterson, DL., Henry, B., Ablashi, D., Muueller, WEG., Schroeder, HC., Carter, WA., and Strayer, DR., "Up-regulation of the 2-5 A RNaseL Pathway associated with Chronic Fatigue Syndrome." Clin. Inf. Dis. (1994): Vol. 18, Suppl. 1 : S96 - 104.
5. Schwartz, RB., Komaroff, AL., Garada, BM., Gleit, M., Dolittle, TH., Bates, DW., Vasile, Rg., Holman, BL. "SPECT Imaging of the Brain: Comparison of Findings in patients with Chronic Fatigue Syndrome, AIDS Dementia Complex, and Major Unipolar Depression." American Journal of Radiology. (1994): 162, 943-951.
6. Buchwald, D., Cheney, PR., Peterson, DL., Henry, B., Wormsley, SB., Geiger, A., Abalashi, DV., Salahuddin, Z., Saxinger, C., Biddle, R., Kikines, R., Jolesz, FA., Folks, T., Balachandran, N., Peter, Jb., Gallo, RC., and Komaroff, AL., " A Chronic Illness Characterised by Fatigue, Neurologic and Immunologic Disorders, and Active Human Herpesvirus - 6" Annals of Internal Medicine (1992): Vol. 116 (2): 103-113.
7. Cheney, PR., & Gallen, C. "CFS; A Clinical Perspective on the use of MEG and EEG brain mapping" The Third Annal Conference - Chronic Fatigue Syndrome and the Brain., Bel-Air, California, April (1992)
8. Straus, SE., Fritz, S., Dale, JK., Gould, B., Stober, W. "Lymphocyte phenotype and function in the chronic fatigue syndrome" J. Clin. Immunol. (1993): 13(1), 30-40.
9. Demitrck, Mark A., Dale, Janet K., Straus, Stephen E., Laue, Louisa., Listwak, Sam J., Kruesi, Markus JP., Chrousos, George P., and Gold, Philip W. " Evidence for Impaired Activation of the Hypothalamic - pituatary - adrenal Axis in Patients With Chronic Fatigue Syndrome." J. Clin. Endocrinology and Metabolism (1991): vol. 73, No. 4.
10. Saphier, D., Welch, JE., CHuluyan, HE., "Alpha- Interferon Inhibits Adrenocortical Secretion via u-opioid Receptors in the Rat.", European Journal Of Pharmacology. (1993): 236, 183-191.
11. Cheney, PR., Lapp, CW., Davidson, M., Naegele, C.," Bicycle Ergometry with Gas Analysis and Neuroendocrine Responses to Exercise in Chronic Fatigue Syndrome." 4th Annual Conference of Medical Neurobiology of Chronic Fatigue Syndrome and Fibromyalgia, Los Angeles, CA.,May (1993)
12. Kuratsune, H., Yamaguti, K., Takashi, S., and Kitani, T., "Acylcarnitine Deficiency in Chronic Fatigue Syndrome." Clin. Inf. Dis. (1994) Vol. 18, Suppl. 1: S62-67.
13. Eisinger, J.,MD., Plantamura, A.,MD., and Ayavou, T.,MD., " Glycolysis Abnormalities in Fibromyalgia." Journal of The American College of Nutrition. Vol. 13, No.2 (1994): 144-148.
14. Suhadolnik, RJ., Reichenbach, NL., Hitzges, P., Adelson, ME., Peterson, Dl., Cheney, PR., Salvato, P., Thompson, C., Loveless, M., Muller, WG., Schroder, HC., Strayer, DR., and Carter, WA., "Changes in the 2-5A Synthetase/RNase L Antiviral Pathway in a Controlled Clinical Trial with Poly(1)-Poly(C12U) in Chronic Fatigue Syndrome." In Vivo 8 (1994): 599-604.
Proposed Pathophysiological Mechanism of CFS
Dr Paul Cheney
From Notes & References kindly provided by Dr Cheney
Chronic Fatigue Syndrome ( CFS) , also known as Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS), represents an emerging clinical disorder of unknown cause marked by chronic disability and multiple, somatic complaints. Although typically a chronic illness without remission, cycles of severe relapses are common as well as a characteristic evolution of symptoms over time.
In its classic form, CFIDS begins abruptly with a mono-like or flu-like illness and then rapidly evolves into a sever and debilitating fatigue state with a dramatic loss of functional capacity. Over time there are increasingly severe neurocognitive problems which often become the primary reasons for disability. Different patients have different symptoms, but the general pattern or constellation of symptoms, their evolution and the major symptoms are remarkably coherent when patients are viewed as a group and over time.
The top three complaints which form the basis for the clinical coherence of the syndrome are;
- debilitating fatigue,
- characteristic cognitive complaints, and
- pain.
The view that these patients usually turn out to have other more
definable disorders, while the true for fatigue in general, is
certainly not the case for meeting the CDC case definition for CFS
.
Among the most common symptoms are:
|
low grade fever or subnormal temperatures |
dizziness or balance problems |
|
myalgias (esp axial skeletal muscles) |
migrating sensory dysesthesias |
|
deep bone pain in the extremities |
sensitivity to heat, cold, light, sound, chemicals |
|
arthralgias |
decreased alcohol tolerance |
|
pressure headaches |
food and drug intolerance |
|
sleep disorders |
visual disturbances |
|
enlarged and/or painful lymph nodes |
disabling cognitive impairments |
|
night sweats |
acneform, herpetiform, morbilliform skin eruptions |
|
recurring upper respiratory tract infections (sinus, pharynx, & bronchi) |
an assortment of respiratory, cardiac, gastrointestinal and genitourinary complaints. |
|
new onset of worsening of allergies |
|
Among the most common physical findings in CFS are palpable, slightly enlarged, discoid shaped (as opposed to shotty or spherical) and tender posterior cervical chain lymph nodes, which are almost always left predominant and extend into the supraclavicular node area. This left-sided predominance and lymphatic channel tenderness extending into the medical supraclavicular node area strongly suggests increased lymph production and clinically supports the published reports of immune activation in CFIDS (see 1 in diagram).
Lymphatic fluid carries the protein messages, or cytokines, released by antigen-processing cells. in an immune activation state, lymphatic fluid flow increases. An acceleration of lymph production would cause fluid retention and tissues edema, which is common pathways of the lymphatic system, such as the left supraclavicular area. Anatomically, over 90 percent of lymph flows back into the blood stream just below the left collarbone: 10 percent or less to the right. therefor, with increased flow, congestion will occur prominently within node chains closest to the juncture; hence... left-sided dominance of lymph nodes tenderness in the supraclavicular are.
These abnormalities clinically support the evidence of central nervous system (CNS) injury observed on functional and structural brain scans . and suggested by neuropsychometic testing (see 4 in diagram) , the link between immune activation and CNS injury may be in the intense activation of alpha interferon induced 2'-5' A antiviral pathway seen in the great majority of CFIDS patients (see 2 in diagram) . Alpha interferon is known to induce neurotoxic injury to limbic structures and serotonergic pathways via opioid receptors (see 5 in diagram) agonist/antagonist.
Deleterious effects on CRH (corticotrophin releasing hormone) the TRH (thyrotropin releasing hormone) production in the hypothalamus (a key limbic structure) are known to exist in CFS patients (see 6,7 in the diagram ) . The CRH deficiencies could then set up a positive feedback loops (see 6 in the diagram) which maintains immune activation and thus creates a vicious cycle.
Recent studies on CFS patients have also demonstrated evidence of a metabolic disorder involving cellular energy production (see 3 in the diagram). Studies at UCLA and elsewhere have demonstrated reduced oxygen consumption at maximal exercise consistent with defect in mitochondrial function . Additional indicators of defects in trans-membrane mitochondrial transport mechanisms have been reported in CFS and CFS-related disorders .
Finally, most patients with CFS show evidence of abnormalities in citric acid cycle intermediated on overnight urine using gas chromatography technology. Taken together this evidence supports a defect in cellular energy production at the level of the mitochondria. We may ultimately view this defect in cellular energy production as cellular basis of fatigue in Chronic Fatigue Syndrome, as well as the basis in related and unrelated disorders.
Chronic Fatigue Syndrome represents a chronic, debilitating and prolonged illness characterized by numerous symptoms but especially fatigue, cognitive dysfunction and pain. Frequent but subtle physical findings support laboratory evidence of central nervous system injury which is likely metabolic and possibly due to alpha interferon itself. Immune activation with excess lymph production may produce peripheral pain in certain tissues, which is then amplified centrally by injury to key central nervous system structures, and mediated by opioid receptor-linked. alpha-interferon induced neurotoxicity. Fatigue itself may ultimately have a cellular basis at the level of mitochondrial dysfunction.
Organ systems may be differentially affected, and within organ systems there may be a mosaic of affected and unaffected cells, the sum of which defines the degree of dysfunction. Immune activation and its effects on the CNS may set up a vicious cycle which is independent of an initial triggering agent or event, which may no longer be present. It is also possible that a persistent causative agent exists, and plays an active role in the maintenance of this pathophysiology. The identity of this putative agent (or agents) remains unknown, but the clinical presentation, and the presence of high levels of alpha-interferon, or its subcellular effects, favour a viral etiology.
Session 5 Presentation 2 Tape 8
When a lot of remedies are suggested for a disease,
That means it can't be cured.
Anton Chekhov (1860 &endash; 1904)
Russian dramatist
Paul R. Cheney, M.D., Ph.D.
DirectorThe Cheney Clinic,
PA 10620 Park Road, Suit 234, Charlotte NC . USA
phone AC (704) 542-744 fax Ac (704) 542-0720
The diagnosis of chronic fatigue syndrome is made on clinical grounds. This method includes a careful history which details the major and minor symptoms common to this syndrome of debilitating fatigue characteristic cognitive complaints and typical pain are the striking hallmarks of the disorder. The Post exertional relapses, balance disorder, alcohol intolerance, pressure-like headaches and unrefreshing sleep add to its recognition. Physical findings of tender, left predominant lymphodynia in the supraclavicular and posterior cervical node chains and an abnormal vestibular function exam add more weight to the clinical impression. Finally, essentially normal routine blood work which nevertheless yields some clues to this disorder helps to confirm that no other defined illness is likely to explain this syndrome.
There are many other tests which can help confirm the conceptual view of this disorder as an immune activation state with neuroendocrine sequelae and a variety of metabolic problems centred on the mitochondria. Various functional tests to the liver, gut, brain autonomic nervous system and aerobic exercise potential can confirm functional impairments and support rational treatment. There are no tests, however, that can diagnose the disorder and the tests lack specificity or their specificity for CFS is unknown when compared to other clinically similar diseases. it should be noted, however, that CFS is not unique on the issue of tests that support but do not diagnose. The diagnoses of multiple sclerosis, lupus erythematosus and mononucleosis are often supported by non-diagnostic tests. In addition, in CFS, there are some test that support rational treatment that appears to improve symptoms. There are also tests that appear necessary to document functional impairments for successful disability application. Some of these tests will be discussed in this talk.
The traditional treatment of chronic fatigue syndrome has been largely symptomatic and driven by anecdote or ones conceptual view of the disorder. The problem with symptomatic treatment is that what makes one feel better may not be better, such as suppressing cough in pneumonia or steroid therapy in AIDS. The better approach is to conceptualize the illness so that you can target the critical link in the pathophysiology and to confirm in the individual patient whether by tests or clinical instinct and experience that they conform to your conceptual view of model. Treatment should be monitored and ideally, multi-dimensional, patient outcome assessment tools used to document functional and/or symptom improvement. In our opinion, there is no one best way to manage these patient but a broad based, comprehensive approach seems to work best. Elements should include basic nutritional support such as diet adjustments, vitamin and mineral recommendations and specially configured nutrition; lifestyle adjustment and exercise prescriptions; psychological counselling if appropriate; immune modulatory techniques; antiviral approaches in some patients; various metabolic and functional resuscitation therapies, especially liver-gut function and broad--spectrum anti-oxidant protection. finally, the single most important therapy should be steps to address an as yet ill-defined neurotoxicity present in these patients using generic concepts such as blocking NMDA receptor mediated amplification of non-specific brain injury. The most important symptoms to address are sleep disturbance and pain. The approach to pain relief in certain very ill patients in severe pain can easily be the most challenging problem in CFS management.
This is a talk on useful diagnostic procedures, concentrating
particularly on routine blood work. Just as there are a lot of
interesting, observable, and subtle abnormalities on physical exam,
there are also subtle abnormalities on routine tests. There was an
excellent paper recently published by Komeroff and company produced
by Harvard that I'll organize my talk around, and then I'll try to
fly through useful management techniques that I've found helpful and
a couple of more novel approaches that I've found useful.
There are a range of tests that I have found useful, although I find
myself doing (sometimes) less and less testing as I go along. I
tended to do more tests years ago than I do now. A lot more attention
to routine testing, certain immunologic tests, looking for a pattern
of immune activation, combined with discrete defects is helpful. We
are trying to look for one or two tests which seem to be the
most sensitive and least expensive, to look at this
pattern of immune activation and discrete defects.
I've tended not to do as much testing in this area. It's just too much of a swamp at times. There are some interesting things coming along in terms of antigen capture assays, particularly for HHV-6, that might be most appropriate to perhaps identify a subgroup of patients that really do have significant viral replication using antigen capture techniques.
DHEAS seem to identify at least 14% of the patients with very low,
even absent DHEAS. I've found that DHEAS tends to mark a subgroup of
patients that do not do well over time.
I look at the combination of T4/TSH trying to assess tertiary
hypothyroidism, in which both of these are low and going down
together.
Urinary free cortisols have been useful in the very ill or
hospitalised patient. I've seen significant reductions in cortisol
production in the seriously ill patient, sometimes requiring
intervention.
One test I have found increasingly useful is the urinary organic acid
analysis as a fingerprint of metabolism.
Some people I assess for possible multiple sclerosis using MRIs. I do lumbar punctures on seriously ill individuals and EEGs can also be useful. These are not applied across the board and are generally limited to very ill individuals.
Neuropsychological testing is useful for documenting a disability.
Routine Tests in the Chemical Panel
Complete Blood Counts (CBC)
Immunologic Testing
What Distinguishes CFS?
I will present here work published in the Archives of Internal Medicine by Bates and Kormaroff at Harvard (see Appendix). They looked at literally hundreds of chemistry panels and routine tests in CFS patients at Harvard in Boston and University of Washington in Seattle. Hundreds of cases were analyzed against quite a number of controls in both settings.
In terms of treatment, I will provide a quick overview of various treatment areas:
NUITS (New, Unusual, or Investigative Treatments)
Put them on polyphasic digestive enzymes with particular emphasis on proteolytic digestive enzymes as opposed to lipolytic can be most helpful and is very cheap therapy
The modified elimination diet is low fat and eliminates red meat, processed sugar, aspartame, optionally gluten, and optionally low fat. We tend to eliminate these in the sicker patient and allow it in the less sick if they tolerate it. We have them go on/off/on in a 3 week cycle to see if it influences symptoms, especially GI symptoms, but other symptoms as well. We tend to restrict fruits and fruit juices to be taken with food as opposed to an empty stomach, and obviously restrict foods to which they are sensitive or allergic. A four day rotation has been optionally useful in some patients.
We put them on a soy- based branched-chain amino acid rich nutrient supplement to take advantage of a particular pathway. I think they use this compensatory pathway to block higher mitochondrial transport regions, of which several defects have now been published.
Pacing, avoid overheating and no hot bathing. In a direct analogy to MS, there used to be a test for MS called the MS hot tub test - if you thought someone had MS, you put then in a jacuzzi at 104 degrees and activate their MS. Likewise with CFS patients, you put them in a jacuzzi at 104 degrees and it will activate their CFS symptoms. I think the concept is that in an immune activation state, if you raise the body temperature you activate it more.
We have reason to believe their anaerobic systems are still working okay, so we emphasis anaerobic training (primarily light weights - lifting for 30 seconds, resting for 60 seconds) about 20 minutes 3 times a week. On the other hand, aerobic training is a problem and we think there is a mitochondrial problem in these patients so if they exceed certain aerobic boundaries they'll get sick. So we have them go to their limit and not exceed it, and the limit is defined by the patients; for some it's walking around the bed, for some it's walking around the house, for others it's walking around the block and for some it's walking around the neighbourhood, but there is a limit beyond which they can't exceed or they get worse. Aerobic exercise that seems to be tolerated are walking, swimming or cycling, I think because it can be done without overheating, and they can be titrated to that limit.
I had 10 consecutive CFS patients presenting at my clinic, and I intervened relatively conservatively, not a lot of drugs. 6 weeks after intervention the percent reduction in the initial MSQ score in one group of them was 30 - 60% lower. There was another group who got on average 8% worse, who had the exact same intervention. It's as if to say - if you get below 200 on the MSQ, I can help you, with fairly conservative intervention, yet if you score 200 or higher what I was doing to make other people better was almost guaranteed to make you worse.
Firstly we thought that this was the effect of the act of getting to the clinic, eating strange food, being talked at for 3 hours, etc for the sicker individuals. At about 9 - 20 weeks, on average, the ones getting better continued to get better and the ones getting worse continued to get worse. Treating the disease symptomatically seems to backfire in the sicker patients.
In an article in Scientific American on stroke therapy showed how brain injury of almost any kind can be amplified by the NMDA receptor (primary excitatory receptor present on most if not all neurons). This excitation of the NMDA receptor amplifies the original injury and if sufficiently amplified, will kill the cell. So you might not be able to do anything about the primary damage, but you are able to do something about the injuring amplification induced by this receptor by either inhibiting this receptor or inhibiting the downstream effects of the firing of this receptor. You can inhibit this receptor with magnesium, Klonopin and possibly other drugs that change the balance between NMDA and GABA firing. Another way to look at it is that GABA and NMDA are balancing each other out, and in a balanced form they set the threshold potential for neuronal polarisation within the normal range.
Under conditions of brain injury, of whatever kind, NMDA fires in excess over GABA which has the effect of lowering the threshold potential. The neuron now tends to fire inappropriately, scrambling information, processing in the area in which this is occurring. If NMDA is in even greater excess, you further lower the threshold potential and the neuron fires all the time. Going the other way, GABA firing over NMDA, increases the threshold potential, which if appropriate is good (if you're sleeping). If you continue to raise GABA, the neuron shuts down, it doesn't fire at all.
What we're attempting to do with these patients then, by using Klonopin and magnesium is to shift them to be reset at a different firing ratio so they process better.
The rationale for using high doses of B12 is not because the patient is deficient in the vitamin, they are deficient in an enzyme to which the vitamin is a co-enzyme. We think there is way too much attention payed to the antioxidants themselves and not nearly enough attention payed to the bioflavonoids which resuscitate the anti-oxidants. A recent article in the New England Journal of Medicine on smokers - just beta-carotene in very high doses tended to accelerate their cancer production over placebo and that acceleration was not seen when vitamin E was added. The antioxidant system is a cascade system. It's very important that at the bottom, you recycle the antioxidants, and the bioflavonoids are recyclers - and it may be dangerous to treat with high doses of an antioxidant without attention to the recycler.
Magnesium and antioxidants are capable of protecting the central nervous system against the potentially neurotoxic effects of certain compounds, and are useful in the overall management for this reason.
Specially configured nutrition is important. There seems to be a problem in transporting food across the mitochondrial membrane. In the case of Acyl carnitine, not only is it important in transporting fat, it's very important in transporting toxins out of the mitochondria. A defect in acyl carnitine can not only create problems in terms of energy generation, but the mitochondria can literally be poisoned. There may be a problem with pyruvate decarboxylase.
The low fat EFA supplemented modified elimination diet with organic foods, intervening with soy based which is 50% branch chain amino acids (eg vegetables). We tried to fill these patients with calories that we think they can utilize better given the particular problems of mitochondrial dysfunction These people tend to eat empty calories in the food chain. They have nutritional utilisation blocks, mitochondrial transport blocks, enzyme deficiencies and cell homeostasis problems
The treatment protocol was two scoops twice a day, supplemented with vitamins and supplemented with a branch chain amino acid rich product. Patients were treated for 12 weeks and assessed. In weeks 12 to 14 they were randomized, some where taken off and some left on. In weeks 14 to 20 the patients could choose - they could opt to maintain it, or opt to continue it, and we would follow their process. Nine people went on the study. Three people crashed and burned on this product within one week of taking it. Five people tended to improve over the 12 weeks and one did not. Those who were taken off in the 12 to 14 week period tended to worsen. It seems to help a subset of patients and another subset of patients seemed to deteriorate. It doesn't work in a small group of patients that tolerate it. The people who were intolerant of it were the ones with the low sulphate to creatinine ratio (ie a suggestion of glutathione deficiency).
Hydrotherapy
The concept is that the immune system is an issue of balance between suppression and activation. Immune activation typically produces a reactive suppression which is unique and precise. The idea is to use their own lymphatic fluid. We put them in a vertical floatation unit with tepid water one hour three times weekly. This procedure increases lymphatic return through the thoracic duct into the left internal jugular vein. It's like they're getting infused with their own lymphatic fluid. We have seen some absolutely dramatic improvement in the MSQ score in some patients - on average about 23% improvement of the MSQ; with the greatest improvement of 42%. Some people did get worse with this therapy and there seemed to be a grouping with low interleukin receptors that tended to get better with therapy and a group with high IL2) receptors that tended to get worse with therapy. Hydrotherapy is bidirectional, it can down regulate the patient, but it can also upregulate him/her and make them feel worse (which may not be bad in the long term if they need to be upregulated against a threat - viral perhaps)
Dr Mark Donohoe
email: mark@geko.net.au
revised 4/3/98