By Charles W. Lapp, M.D.
January 30 – February 2, 2003
Westfields Marriott Resort
The biannual scientific conference of the American Association of Chronic Fatigue Syndrome (AACFS) was attended by over 190 physicians and professionals from more than 14 countries. This year’s format was new. The first day was an introductory course on the diagnosis and basic management of CFS taught by Drs. Charles Lapp and Leonard Jason. This was attended by over 170 professionals, and was highly acclaimed by the attendees. (This entire program is available to professionals in text, video, or web-based formats at www.cfids.org or on the CDC website.
Professionals may earn 2-3 hours of CME credit, and earn a certificate of competency on successful completion of the course.) The next two days were devoted to summaries by the faculty and to new research reports.
At the Saturday night award ceremony, Dr. Ben Natelson was applauded as the outgoing president; Dr. Dan Peterson (Incline Village , NV) was given the prestigious Perpich Award for his outstanding devotion and contributions; and Dane Cook, PhD (Research Physiologist at the University of Medicine and Dentistry of NJ) was given the Junior Investigator Award. On Sunday, February 2, Dr. Dharam Ablashi assumed the presidency of the organization. For more information on the AACFS, log on to www.aacfs.org.
The following is my overview of the papers presented at this meeting. Summaries are short, and only the most relevant papers are reviewed. They represent my personal understanding of the material, of course:
Leonard Jason, PhD (Chicago, clinical psychologist and renowned CFS researcher) headed the epidemiology section. His introductory remarks compared the 1988, 1994, and Canadian case definition criteria for CFS.
Jason’s studies reveal that the 1988 research criteria select higher rates of sore throat and lymph node tenderness, and patients with poorer health (based on the MOS SF-36 survey). On the other hand, the new Canadian clinical criteria are less likely to select for psychiatric co-morbidity and more likely to select for functional impairment, fatigue, weakness, neuropsychiatric problems and neurological symptoms. Jason also points out that when CFS patients have psychiatric disorders, their primary physicians correctly identify the condition only 64% of the time. Lastly, Jason reviewed the results of his well-known community prevalence study.
CFS was most prevalent at ages 40-49 years, mostly in women. Surprisingly, Latinos and Afro-Americans were much more likely to have CFS than Caucasians (at least in the Chicago metro area), and skilled workers were much more likely than professionals to fall ill. This is contrary to previous common opinion, of course. Jason found the prevalence of CFS to be 522 / 100,000 persons for women, and 291 / 100,000 for men.
These prevalences are much higher than HIV (125/100K), lung cancer (43/100K), and even breast cancer (26/100K), in women. Lastly, his study of over 3000 nurses showed the greatest prevalence – over 1000 per 100,000. This may be attributed to on-job stress, rotating shifts, occupational exposures, or other factors, he surmised.
Dr. William Reeves of the CDC then reported on the 1994 case definition for CFS. A committee has met annually since 1992 to revise and improve the definition, and minutes of these meetings are available on the CFS section of the CDC home page. They specifically address ambiguities in the exclusionary and co-morbid conditions; and evaluate instruments to measure intensity, disability, and case-defining symptoms.
Sleep assessment in CFS was the topic addressed by Dr. Elizabeth Unger of the CDC. Her studies, performed at Moldofsky’s sleep lab in Toronto, confirmed that PWCs are indeed fatigued, not just sleepy, and that non-restorative sleep and nighttime restlessness were closely associated with CFS.
Trudie Chalder, PhD, a nurse and behavioral psychologist from England, addressed the epidemiology of CFS/ ME in 5 -15 year olds. 1354 children were identified by their parents as being fatigued. 24 (0.6%) were determined to have “chronic fatigue” while 8 were shown to have true Chronic Fatigue Syndrome (0.2%). The parents were only able to identify CFS correctly in 4 of these patients. Chalder concluded that the prevalence of CFS in children is lower than expected; anxiety and depression are highly correlated to fatigue (but not CFS, necessarily); and parents have difficulty identifying CFS in their own children.
Kim Buschio, MA (NJ Medical School) studied physical impairments in CFS and FM. She concluded that pain is a better predictor of impairment than fatigue in both CFS and CFS with FM.
Dr. Bob Suhadolnik of Temple University (Philadelphia) headed up the session on biochemistry and genes. He began with an excellent overview of biochemistry — nitric oxide formation, peroxynitrate, oxidative stress, elevated levels of RNaseL and PKR, decreased acyl carnitine, and increased glutamate in persons with CFS.
Drs. Suzanne Vernon ( research microbiologist at the CDC ) and Wilhemina Behan (Glasgow University, Scotland ) introduced us to the exciting new concept of gene expression profiling. It is now possible to take blood (or other tissue) and apply it to a small glass slide containing over 20,000 gene identifiers. When processed and scanned, scientists can determine which of those 20,000 genes is turned on, off, or somewhere in between. This vast array of information is specific for various states of health and disease in each individual.
Thus, gene profiling can now distinguish between several types of lymphoma in a patient, thereby allowing more specific treatment for the patient. Using 25 cases of CFS supplied by the CDC, Vernon could accurately distinguish CFS from healthy controls, and seven specific genes were identified as “turned on” in the disorder. Behan studied muscle biopsies of three patients with CFS and found 3 genes upregulated and 33 genes downregulated. 24 genes were positive in controls but absent in CFS.
Patrick Gaffney, MD (Minneapolis) also studied gene profiling and found 166 genes “different” in CFS when compared to normal controls. Thus, gene profiling might some day provide us a diagnostic test, as well as a means to distinguish infectious, immunological, or other causes.
Toxicology was broached by Gwen Kennedy (Ninewells Medical School, Scotland), whose studies indicated that oxidized LDL cholesterol and isoprotanes (oxidation radicals) were increased in PWCs, and blood glutathione levels were decreased. She compared CFS patients to those with organophosphate toxicity and Gulf War Syndrome, both of which have symptoms similar to CFS.
Infection and Immunology was headed by Dr. Jon Hay, SUNY/Buffalo. Dr.
Kevin Maher (University of Miami Medical School) described the molecular basis of immunological defects found in CFS, including activated T cells, elevated cytokines and immunoglobulins, reduced NK cell activity, and poor delayed skin hypersensitivity. His studies concluded that perforin and granzymes (used by T-cells for killing other sick or infected cells), was depressed in the T cells of persons with CFS. Also, activation of T cells is correlated with increased IL4 and decreased IL6, as typically seen in CFS.
Dr. Suhadolnik (see above) described the 2’-5’ OAS / RNaseL antiviral system and how the enzyme RNaseL is markedly and persistently increased and in CFS but not in control or depressed persons.
Dr. Ben Natelson (director of the CFS Research Center at UMDNJ-New Jersey Medical School) headed up the treatment section. He reviewed the recent multi-center randomized placebo controlled study of the stimulant drug modafinil (Provigil™), concluding that the drug did not seem effective in CFS although it has been shown quite effective in treating fatigue in FM and multiple sclerosis. Dr. Natelson, however, felt that the study was flawed.
He suggested that a different study plan using different instruments and end points would probably show that modafinil was useful in CFS. (At Hunter-Hopkins Center we have found modafinil extremely helpful in improving alertness and mental clarity particularly in CFS patients who report daytime drowsiness.)
Olof Zachrisson, MD, PhD, of Sweden hypothesized that immunity in CFS may be disturbed by repeated or persistent bacterial infection. He treated 51 PWCs with a staphylococcal (bacterial) vaccine for 12 weeks, and obtained a positive response in 16. There were modest decreases in pain and fatigue that correlated with antibody production in the individuals. However, the response was not maintained unless the vaccine was continued monthly. The vaccine is produced privately in Switzerland, but is neither publicly nor commercially available.
Dr. Dan Clauw (director of the fatigue research center at the University of Michigan) studied 1092 veterans with Gulf War Syndrome who were randomized to Cognitive Behavioral Therapy (CBT) alone, CBT plus an exercise program, exercise alone, or “usual medical care.” After 3 months, there were very modest improvements in those vets treated with CBT or CBT + exercise, especially for cognitive symptoms and mental health. When followed up 6 and 12 months later, these modest gains were lost.
Low intensity aerobic interval training was discussed by Dr. Claudia Lennartson (Huddinge Hospital, Stockholm, Sweden). She exercised 20 PWCs by walking them 15-30 minutes at their own pace, then taking a 15 minute break. This was done once weekly at the hospital, and twice weekly at home.
Participants completed an average of 25 sessions, but 5 dropped out of the study. Fatigue was no worsened in any subject, and there were modest gains in physical function and exercise duration. (NB: At Hunter-Hopkins Center, we recommend that PWCs start with 3-5 minutes of activity alternating with 5 minutes of rest. This level of aerobic interval activity is low enough to be tolerated well by virtually all patients, and rarely triggers significant flares of fatigue or symptoms).
Dr. Dan Peterson, Incline Village, NV, introduced the first morning session on February 2nd by describing his experience with Human Herpesvirus 6 (HHV6). Peterson reminded us that HHV6 subtype “b” is common in infants (roseola) and has been associated with MS, while subtype “a” is highly associated with CFS.
He studied 135 patients who had encephalopathic features (such as vertigo, headache, and significant neurocognitive symptoms) and abnormalities on both MRI and SPECT scanning. 29 of these subjects had viruses identified in their cerebrospinal fluid: EBV (1), CMV (1) and HHV6b (27), but none had HHV 6a, 7, or 8. Treatment with the antivirals valcyclovir and gangcyclovir were unsuccessful. However, on intravenous foscarnet 8 subjects improved and 4 were able to return to gainful employment.
Dr. Ben Natelson (UMDNJ-New Jersey Medical School) enumerated the encephalopathic features seen in CFS, namely cognitive dysfunction (tested by the PASAT and tests of complex attention), subcortical high intensity areas in the frontal cortex on MRI, and modestly increased ventricular (brain) volumes. Lumbar punctures in 39 CFS subjects revealed elevated protein or > 5 white cells per hpf in 15 cases. Interestingly, none of the subjects with abnormal CSF were depressed or carried an Axis I psychiatric diagnosis, while all CFS patients with normal CSF had concurrent depression.
Dr. Rich Gracely (University of Michigan) then present two papers on functional MRI (fMRI), which rapidly measures cranial blood flow in response to physical challenges such as pain. His group applied thumb pain either intermittently or constantly, and obtained fMRI scans of the Fibromyalgia subjects every 5 seconds. This demonstrated that with intermittent pain the FM patients had decreased blood flow in the cingulated, secondary somatosensory cortex, cerebellum, and insula; only patients with FM showed activation (increased flow) in the thalamus and putamen.
With constant thumb pain, FM subjects showed increased cranial blood flow in the mid frontal gyrus and inferior frontal gyrus (Broca’s speech area); only FM subjects showed activation in the caudate and lentiform areas. Only control subjects, on the other hand, had activation when the pain stimulus was released. These studies confirm once again that persons with FM (PFMs) respond differently to painful stimuli than do normal controls.
We were shocked to learn from Dr. Akemi Tomoda (Kumamoto University School of Medicine, Japan), that 2% of Junior High School students and 5% of High School students in Japan are disabled by CFS symptoms, especially fatigue and cognitive dysfunction. In a study of 319 students with CFS, Tomoda demonstrated that many (116) had abnormal responses to the Visual Evoked Potentials test, most had shortened R-R intervals on the electrocardiogram (a sign of autonomic dysfunction) and all had low scores on the KANA Pick Up Test, which measures attention and comprehension.
The Technology Session was ably headed by Yoshi Yamamoto, PhD, from the Educational Physiology Lab at the University of Tokyo. He first demonstrated that autonomic symptoms can be improved modestly by distraction with extraneous noise or electrical stimulation. That is, abnormal autonomic responses were blunted when the subject was distracted. This fits clinically because many patients report that their symptoms are not as noticeable when they are distracted by noise, bright lights, activity, commotion, or discomfort; however, it was not previously clear if such stimuli simply distracted the subject or actually improved the dysautonomia.
Next, Dr. Yamamoto introduced the ECOLOG Monitor Watch. This device looks like a watch and normally displays the time and date; but periodically it beeps to remind the wearer to record symptoms and to take a brief cognitive function test. Also, the device is an Actimeter that constantly monitors the activity of the wearer. After several days this data can be downloaded to a personal computer and the data utilized in standard Microsoft based programs such as Excel.
Dr. Yamamoto’s associate, K. Yoshiuichi, MD PhD, demonstrated the utility of this ED (electronic diary). In a preliminary study of PWCs versus controls, Yoshiuchi has demonstrated that PWCs are more active than controls, more fatigued, sleep less well, and have more performance difficulties on the neurocognitive test. Remarkably, PWCs performed more work over the course of the day than normal counterparts, but it was accomplished in short bursts of intense activity during the day and separated by periods of rest. This may have represented PWCs who tend to “push and crash,” and may not be a healthy trend at all.
Angela Lyden, MS, of the University of Michigan introduced another actimeter, the Actiwatch™, which measured general levels of activity over a 2 day period. Her 25 subjects also demonstrated considerable variability (i.e., “push and crash”) over the course of the day.
The Chief of Clinical Neuroendocrinology at the National Institutes of Health, Dr. Phillip Gold, gave a wonderful talk on the neuroendocrine differences between CFS and depressed patients. Profoundly depressed subjects were described as hopeless, anhedonistic, and anxious. Biologically they demonstrate increased plasma cortisol, decreased growth and reproductive function, immunosuppression, elevated blood pressure and heart rate. In CFS, on the other hand, plasma cortisol and ACTH are reduced and BP is frequently decreased.
Dr. Gold then described “atypical depression,” whereby patients are severely depressed but manifest increased sleepiness, overeating, lethargy, and profound fatigue. Unlike typical depression, these subjects have increased immunity and their stress hormones (cortisol, epinephrine, norepinephrine) are turned off. These patients clinically tend to be very anhedonistic, withdrawn, and socially isolated; they respond best to Wellbutrin but not at all to tricyclic antidepressants.
Dr. Gold also described the biochemical response to maximal exercise in PWCs: decreased levels of plasma cortisol, ACTH, and catecholamines in response to this physical stress. This highly suggests that such individuals would respond poorly to any stress.
A New York cardiologist, Dr. Julian Stewart declared that Postural Orthostatic Tachycardia Syndrome, a common autonomic abnormality in CFS / FM, was related to decreased arterial vasoconstriction in the lower extremities. He performed Whitney strain gauge plethysmography in adolescents with CFS to demonstrate that most have “low flow POTS.” This means that blood flow to the lower extremities is slow, peripheral venous resistance is high, and such patients frequently have acrocyanosis (skin turns bluish in color) on prolonged standing. He studied 14 subjects aged 13-19 years.
In the UK a number of farmers and shepherds have been reported with CFS-like symptoms, presumably due to chemicals they use in “dipping sheep.” These chemicals are typically organophosphates, which are well-known to cause CFS-like symptoms. Similar chemicals have been available in the US as diazinon and malathion, for example. In an effort to test the effect of such cholinergic drugs, V. Spence, PhD applied acetyl choline to the skin of PWCs and controls. Remarkably, only patients demonstrated an increase in skin blood flow and prolonged vasodilation after application.
Dr. Yoshiuchi returned to the dais to present a study of the R-R interval (on electrocardiogaphy) in 18 PWCs who did not have POTS, and an equivalent number of controls. Invariably the R-R interval was slightly decreased in patients compared to controls or – in other words – patients tended to have faster heart rate than controls.
Lastly, Dr. Dan Clauw (see above) described his extensive evaluation of autonomic function in “Chronic Multisystem Illness,” or CMI. CMI includes person with CFS, FM, and Gulf War Syndrome, all of whom typically demonstrate increased sympathetic tone and reduced catecholamine excretion. His subjects had either CFS, FM, or CFS + FM, and were admitted to a clinical research center where they submitted to 4 stresses: pain, a cognitive challenge, isometric handgrip exercise, and a submaximal exercise test.
To make a long story short, only the exercise test was able to demonstrate a slight increase in epinephrine and norepinephrine in response to “stress,” and the effect was most noticeable in those with FM alone. Dr. Clauw has concluded that PWCs and PFMs likely have slightly different responses of the Hypothalamic Pituitary Adrenal Axis.
Charles W. Lapp, MD
HUNTER-HOPKINS CENTER, P.A.
Charlotte, North Carolina
February 3, 2003