The Greater Philadelphia CFIDS Alliance (GPCA) is pleased to offer this summary of the keynote lectures by Dr. Robert Suhadolnik & Dr. Paul Cheney from our fall patient medical symposium.

Dr. Suhadolnikís working research hypothesis is that "the characteristic signs and symptoms of Chronic Fatigue Syndrome are associated with the dysregulation of the 2-5A synthetase/RNase L pathway." In laymanís terms, CFIDS patients have an abnormal enzyme that makes their anti-viral pathway malfunction. The effect is that, when they have a viral illness, their bodies cannot respond like normally healthy individuals, due to this underlying enzyme defect.

The 2-5A sythetase/RNase L pathway is really a complex biochemical reaction. When the 2-5A sythetase/RNase L pathway is activated by viral infection, 2-5A sythetase converts ATP (a source of cellular energy) to 2'-5'A oligoadenylate (or 2-5A). The 2-5A activates RNase L, and the RNase L attacks viral RNA. This is an oversimplification, but the effect is that the pathway provides a defense against viral infection, and regulates cell growth and differentiation. Studies up to this point have shown this pathway to be upregulated in CFIDS.

RNase L, the most significant enzyme in the pathway, degrades viral RNA. Dr. Suhadolnikís research group at Temple provided the first evidence of a new form of RNase L in some people with CFIDS. It has been called low molecular weight (LMW) Rnase L, as it is smaller (37 kDa) than the normal form (80 kDa).

Dr. Suhadolnik reviewed the series of Temple University investigations of RNase L, begun in 1990 with a study involving clinical sites in Incline Village, Nevada and Charlotte, NC, in collaboration with Drs. Dan Peterson and Paul Cheney. The latest study involved three separate laboratories, using two different research protocols. The 53 subjects in this study complied with the 1988 and 1994 case definitions, had a Karnofsky score of 60 or less, and experienced fatigue, neurocognitive dysfunction and pain.

This latest research done at Temple used the azido photoaffinity probe, while the studies done concurrently at Montpelier University in France, and R.E.D.D. Laboratories in Brussels used the periodate dialdehyde probe. Dr. Suhadolnik achieved an 83% success rate identifying the presence of low molecular weight R-Nase L in CFIDS patients, while the two other labs achieved an 86% success rate. The low molecular weight (LMW), 2-5A binding proteins found in individuals with Chronic Fatigue Syndrome are not seen in normally healthy individuals. The replication of Dr. Suhadolnikís findings in this study by two other labs, using two different techniques is indeed encouraging.

The studies also helped to distinguish the low molecular weight R-Nase from normal R-Nase. Dr. Suhadolnik found that the LMW RNase L is smaller, more active, and harder to control, compared to normal 80 kDa RNase L. Consistent with earlier studies, the CFIDS group in this investigation also had higher concentrations of bioactive 2-5A than the 37 healthy controls, higher activity of RNase L, and more of the LMW (low molecular weight) RNase-L. Also, as the amount of normal RNase L increased, the amount of the LMW RNase L decreased. Based on these findings, Dr. Suhadolnik conjectured that the LMW RNase L might form from the larger, normal 80 kDa RNase L. Also, all measurements of antiviral pathway activity for the CFIDS group increased as their Karnofsky scores decreased. In other words, the patients who felt the sickest, had the highest level of dysfunction in the 2-5A synthetase pathway.

Dr. Suhadolnik concluded his highly technical, but fascinating presentation, by observing that, "In essence, weíve defined a subset within the realm of this complex disease (CFIDS) and things will change as we learn more." Also, he stated that there is no question that this is a research marker, but it will be no small hurdle to develop a clinical marker. Further investigations will try to resolve whether the LMW RNase L is unique to CFIDS, and determine if the LMW RNase L originates from the normal 80 kDa RNase L.

• Special thanks to Nancy Reichenbach for her assistance with Dr. Suhadolnikís presentation.

He proposed a pathophysiology of CFIDS, involving the down regulation of cortisol, ostensibly affecting the hypothalamus in a way that upregulates the immune system. He sited elevated Interluken 2 and up-regulation of the 2/5 A pathway, observed in the Temple studies as evidence of this up-regulation. Dr. Cheney commented about the role that Ampligen appears to play in regulating and resolving the aberrant 2/5 A pathway. He also speculated about the role of HHV6 Strain B, alluding to evidence that it occurs in about 70% of CFIDS patients and nearly 100% of AIDS patients (as opposed to 1/3 of the healthy population.)

Dr. Cheney also discussed functional scans, including SPEC scans, which found CFIDS and AIDS dementia complex to be essentially identical in terms of the ratio of average blood flow in a view of the center of the thalamus, vs. the center of the cerebellum (Komaroff/Schwartz, Harvard.) The study used this ratio to account for naturally occurring variations in blood flow in individuals in any single area of the brain. Using this method, it was also determined that normal and depressed individuals have identical findings discrete from CFIDS and AIDS.

Dr. Cheney also sited that MRI scan studies demonstrate varying types of lesions in the brains of CFIDS patients. They range from small ones, similar to those found in aging individuals, to larger ones, similar to those found in M.S. Dr.Cheney speculated that if the similarities between HHV6 infection in CFIDS, and M.S., holds up, it may be that invasion of the central nervous system by HHV6 produces M.S. in some people, and CFIDS in others. On the other hand, despite the range of lesions in CFIDS from small to substantial, no significant clinical correlation with CFIDS has been established. There are people with completely clean scans who may be grossly demented, in contrast to people with fairly significant lesioning who may function relatively well. In fact, from 40 to 50% of CFIDS patients have completely normal brain scans.

Next Dr. Cheney alluded to findings, regarding sending the cerebral spinal fluid of several CFIDS patients to a company in Boston, that uses dual chromatography to analyze over 500 molecular species in the brain. A sophisticated analysis technique was used to determine if CFIDS patients are biochemically different from the normal population by measuring ten discrete compounds. The researchers in Boston had recently completed a study of Parkinsonís and Alzheimerís. They were intrigued to discover that CFIDS was the first disease, where patients could be completely separated out from normal individuals using this technique. This appeared to indicate that, at least on a biochemical level, there is more derangement in the brains of CFIDS patients, than there is in the brains of Parkinsonís and Alzheimerís patients.

The Demitrack/Strauss N.I.H. cortisol study of hypothalamic pituitary adrenal function in CFIDS was also discussed. The investigators originally tried to prove that CFIDS patients had depression, or were, at least, related to a subset of depressed patients. Contrary to the hypothesis of the study, the HPA axis was determined to be down-regulated in CFIDS, while the HPA axis was up-regulated in depression. Therefore, their hypothesis was disproved. The study results also lent support to the theory of hypothalamic injury (deep brain) in CFIDS, as opposed to pituitary or adrenal injury.

Dr. Cheney has done studies on the dynamic response of cortisol in CFIDS, as opposed to the static level, which is not that different from normal. The dynamic response, as measured using a stationary bike is a lot different from normal. Normal individuals, put on an exercise protocol, will usually double their cortisol 20 minutes post-exercise. CFIDS patients produce less cortisol, with the more disabled patients producing the least cortisol. Dr. Cheney included CFIDS patients with varying levels of disability in the cortisol test. He observed a linear relationship between cortisol response to a bicycle test, and level of functionality in CFIDS patients.

Dr. Cheney hypothesized from the cortisol findings, that it isnít the fatigue or the symptoms that disable the patients, although it impairs their quality of life. "What really disables them is that when they push themselves, physically, cognitively, or emotionally, they do not have the appropriate dynamic response at the hypothalamic level to have a significant enough cortisol and other hormone response to the dynamic exigencies of life." The result is a kind of push/crash phenomena. He explained that if cortisol goes down in response to a defined stressor, you crash. Dr. Cheney believes that this is perhaps the major reason why CFIDS patients cannot work.

Dr. Cheney also sited a Japanese study that showed an acetylcarnitene deficiency, which is a transport molecule imbedded in the mitochondrial membrane. The Cheney Clinic conducted a study with UNC, Chapel Hill, that examined CFIDS in terms of mitochondrial membrane potential, using laser scanning confocal microscopy. The technique facilitates the examination of a single mitrochodria within a living cell. Researchers measured membrane potential with a photoflorescent probe. They found that, as the membrane potential goes down, ATP generation or energy production goes down. Conversely, as the membrane potential goes up, ATP generation goes up.

Dr. Cheney has also observed in clinical experience, that CFIDS patients appear to be anaerobically conditioned, despite de-conditioning. That is, CFIDS patients use significantly less oxygen as compared to normally healthy individuals. He rhetorically observed that CFIDS patients donít need much oxygen, and may really be the first ëmartians.í Dr. Cheney bases these observations on the results of clinic testing to determine levels of oxygen consumption. He frequently uses a stationary bike in conjunction with computer monitoring equipment to determine oxygen consumption in CFIDS patients, as evidence in disability determinations.

Regarding treatments, Dr. Cheney reported that some CFIDS patients respond favorably to gentle bouncing using a ërebounding chairí. The chair is based on a NASA protocol for astronauts recovering from the negative effects of weightlessness, and may help to restore more normal autonomic nervous system functioning in some patients.

Another building block of his treatment protocol includes dietary supplementation. He has had some success with an enterohepatic resuscitation program, utilizing dietary supplementation. Also glutathione deficiency supplementation, GABA receptor up-regulation medications and supplements, and antioxidants, including a more soluable type of vitamin B-12 used in Great Britain as a detox agent, are helpful to some patients. He cautioned about using antioxidants with care, as they can also be pro-oxidants, and potentially hurt some patients. Behavioral modification to minimize the push/crash scenario was also recommended. He emphasized that treatment is as individual as the patient.

An "Ask the Doctor" panel of local CFIDS specialists answered questions from the audience during the time frame between the keynote addresses. Drs. Suhadolnik and Cheney joined Dr. Joseph Bellesorte, Dr. James Day and Dr. Stephen Halbert as participants. Issues discussed included elaboration on Dr. Suhadolnikís work, as well as, some discussion of Ampligen, differences between CFIDS and FM, the symptoms of cognitive dysfunction and itís possible treatments and theoretical mechanisms, nutritional supplementation, and NMH and low blood volume findings.

The symposium concluded with presentations by other area specialists, and a Q & A session regarding the issues of disability insurance, neurocognitive dysfunction, psychosocial issues, and physical therapy options. Although, these presentations were excellent as well, they are not included in this summary.

Special thanks to our speakers, sponsors, volunteers, and participants for making our first event a success.

The mission statement of the Greater Philadelphia CFIDS Alliance is the help conquer Chronic Fatigue and Immune Dysfunction Syndrome and related disorders, and to inform and empower those affected by these disorders until a cure is found.

CFIDS can be severely debilitating and can last many years. CFIDS is misdiagnosed often because it is frequently unrecognized and can resemble other disorders including mononucleosis, multiple sclerosis (M.S.), fibromyalgia (FM), Lyme disease, post-polio syndrome and autoimmune diseases such as lupus. CFIDS is also known as myalgic encephalomyelitis (M.E.) and chronic fatigue syndrome (CFS).

Persons with CFIDS (PWC's) have symptoms, which vary from person to person and fluctuate in severity. Specific symptoms may come and go, complicating treatment and the PWCís ability to cope with the illness. Most symptoms are invisible, making it difficult for others to understand the vast array of debilitating symptoms that PWC's have.