Cambridge, Mass., Oct. 10-12
AACFS Conference 1998
Research presentations offer new areas for exploration

Dr. Anthony Komaroff, conference chair, gave what he described as a cook's tour of the research conference to begin the patient conference. The more than 90 research presentations representing work from 27 different countries were exciting, he said, compared to a decade ago when there was very little research of any kind going on to study this disorder.

"The message from this meeting for me was that now the disease is being studied by people all over the world, and that can only be grounds for hope that as a result of those studies and future studies, we will soon have better answers to this very important problem," Dr. Komaroff said.

He cited as particularly interesting studies of circadian rhythms and the activation of the immune system. The evidence that calcium ion levels within cells may be a factor in cellular energy production supports a previously observed potassium deficiency in heart muscle tissue and below-normal pumping action. Studies such as one that found differences in the gait of CFS patients may give other researchers clues to develop new hypotheses. Some studies confirmed and expanded knowledge of the autonomic nervous system function in CFS, and others demonstrated a potential role for a reactivated herpes virus and other more exotic viruses.

The group of papers on the RNase L 2'-5'A anti-viral pathway still need to be confirmed with studies of more patients and in other diseases before that can be put forward as a diagnostic test, he said.

Several studies examined new approaches to treatment, notably NADH and growth hormone. The studies are plausible, but they are all small studies, with none of them "even close to reaching the level of maturity or size that would make them serious candidates for treatment of this illness, but they are nevertheless interesting because they represent new approaches."

Dr. Komaroff said the various presentations were all provocative, and some of them, particularly the epidemiological studies from the CDC of Wichita and DePaul University of Chicago (described in the Nov./Dec. 1998 Chronicle), were "pretty solid and conclusive." However, those studies that relate to what's going wrong in the body and to treatments are all very preliminary studies, "most of which I think are quite exciting but which I think are a long way from providing solid answers to what causes the illness or solid approaches to treatment."

Other than the 24% of CFS patients who said they avoided activity to prevent fatigue, day-to-day activity and rest patterns in CFS patients are similar to those of healthy people, found Gijs Bleijenberg, of the same research group in the Netherlands. The CFS patients do rest more following high levels of activity, but cognitive behavioral therapy might help them moderate their activity levels to stop the activity-relapse cycle.

The CFS fatigue may result from cell membranes that are leaking ions, similar to that seen in the neurological disorder Syndrome X, reported Peter O. Behan of Glasgow, Scotland. CFS patients require more energy than usual to maintain essential body function, he found. Thirty percent of normal resting energy expenditure is used for ion transport, so leaky cell membranes would increase a person's energy requirements, even at rest.

During exercise, CFS patients walk slower and take smaller steps than sedentary controls, but otherwise their gaits are similar, said Lorna Paul, who works with Dr. Behan in Glasgow.

CFS in adolescents is related to delayed-onset hypotension, asserted Julian Stewart of New York Medical College. In many patients, this autonomic defect is related to blood pooling in the extremities and postural orthostatic tachycardia syndrome (POTS).

Severely and moderately ill CFS patients may have different cardiovascular causes for their symptoms, announced Benjamin Natelson of the New Jersey CFS Center. The most severely ill patients seem to have extremely low blood volume, but the moderately ill patients appear to have a neurological defect that interferes with the body's ability to regulate blood pressure.

CFS patients don't have the expected rise in blood pressure in response to either cognitive stress or exercise, said Sue Ann Sisto also of the New Jersey CFS Center. The low systolic blood pressure common in CFS may be related to an inability to exhibit a normal range of blood pressure responses.

Treatment with growth hormone produced significant changes in body composition and metabolism of amino acids but no measurable improvement in quality of life, according to Greta Moorkens of Belgium, who noted the similarity of symptoms in CFS and patients with a growth hormone deficiency.

Nancy Klimas of the University of Miami is investigating a procedure in which activated and functional T-cells are injected into lymph nodes. The procedure has been tried in only a handful of patients, but there have been no adverse reactions and patients have experienced a sharp increase in the number of CD4 and CD8 cells.

In a study of patients with acute infections (specifically EBV, Ross River virus and Q-fever), Andrew Lloyd of Australia found that symptoms suggestive of CFS persist after the classic symptoms of infection are resolved. Resolution of the prolonged fatigue is associated with improvement in immune function. The 75 subjects have been followed for more than a year and the study is continuing.

Immunology
Abnormal daily patterns in the immune and endocrine system seem to be related to abnormal sleep-wake patterns and associated with the severity of CFS symptoms, said Harvey Modolfsky of the University of Toronto. Compared to people with no symptoms and people with a low level of fatigue or pain, CFS patients had altered cycles of the hormones cortisol and prolactin and the natural killer cells of the immune system.

CFS patients seem to have a unique form of autoimmune disease, concluded Eng Tan of Scripps Research Institute. CFS patients seem to react to a different part of the lamin-B1 protein than patients with lupus and other autoimmune diseases.

CFS patients immune status is related to the severity of their symptoms, reported Stacy Wagner of the University of Miami. In addition to the data in Table 1, sleep disorders were associated with a high number of activated cytotoxic (suppressor) T cells and overall sickness was associated with a low percentage of cytotoxic T cells and a high CD4/CD8 ratio (see chart below).

Gulf War veterans with CFS seem to have more immune dysfunction than civilians with CFS, but the civilians with CFS are sicker, said Benjamin Natelson of the New Jersey CFS and Gulf War research centers. The multiple vaccinations given to the vets prior to the war may have made their immune systems similar, although stress, sleep and activity differences between the ill vets and other groups may also have produced the unique immune profile.

Biological aspects
Despite claims to the contrary, researchers are learning a lot about the biology of CFIDS.

Ted Dinan studies the hypothalamic-pituitary-adrenal (HPA) axis in Peter Behan's CFS lab in Scotland. CFS patients have significantly lower adrenal gland volume compared to depressed patients, who typically have elevated adrenal gland volume, he said. Even the depressed CFS patients he studied had low adrenal gland volume, indicating that depression in CFS has a different biological basis than regular depression.

John DeLuca, a neurocognitive specialist at Benjamin Natelson's CFS center in New Jersey, reported that CFS patients have very similar problems to multiple sclerosis patients on neuropsychological tests. Although the CFS patients have cognitive impairments that are also found in depression patients, the people with the worst cognitive problems were the CFS patients without depression. Additionally, the patients with the most abnormalities on MRI tests were non-depressed CFS patients. Dr. DeLuca therefore concluded that the cognitive problems in CFS are not related to depression.

Nancy Klimas, an immunologist from the University of Miami, hypothesized about the factors that may cause CFS to persist. The most important thing in this type of research, she said, is to carefully define the study population. Dr. Klimas believes that lack of definitional rigor may be the reason study results have conflicted so widely. As an example, she stated that 60-80% of CFS patients and 18% of fibromyalgia patients report that their illness started acutely. If an investigator mixes these two populations (s)he risks getting different results, especially with immune-related research.

Dr. Klimas also talked about four possible causes of persistent immune activation: a persistent virus, bacteria or toxin (i.e., HHV-6, Lyme, etc.), autoimmune disease, a "super antigen" which turns on the entire immune system (i.e., silicone), or allergy. She also advised researchers to avoid drawing conclusions from a one-time immune test (called cross-sectional research) because the degree of immune upregulation in CFS seems to cycle with the degree of illness. What is unknown, however, is whether the immune upregulation causes latent infections to emerge, or whether the infections cause the immune system to become upregulated. Finally, because the immune, endocrine and neurological systems are interdependent, she recommended that scientists integrate their research findings with possible effects on the other body systems.

Psychiatric aspects
Psychiatric patients who develop CFS have a different pre-CFS pattern of brain organization than psychiatric patients who do not develop CFS, said Noble Endicott of the N.Y. State Psychiatric Institute. This study focused on such indicators of brain organization as speech and learning disorders, migraine headaches and handedness, and Dr. Endicott said it indicated that the same brain patterns associated with susceptibility to CFS also indicate a propensity to depression.

Stressful life events appear to play a role in the onset of CFS, but those who develop CFS following such an event may have been predisposed to illness by a period of infection or pain or elevated fatigue for the preceeding four to 10 months, according to a study by Brigitta Evengard of Sweden.

CFS patients demonstrate slowed information processing in a number of specific ways that indicated the inner workings of the brain are weak, according to Denise Fairhurst of England.

Richard Marlin of Canada compared patients with CFS and fibromyalgia with those who have chronic pain and found similarities in psychological and behavioral characteristics. He concluded that treatments that focused on patients' coping styles and behavioral and cognitive responses to their difficulties would be most helpful.