In the World – President George Bush made news by suddenly falling violently ill and doing a face-plant into the lap of the Japanese prime minister. The European Union is formed (perhaps to break up 20 years later?) and a 12-year civil war ends in El Salvador. Yugoslavia breaks up and the Bosnian war begins… Pope John Paul finally lifts the edict of inquisition against Galileo and Princess Charles and Diana separate…
Meanwhile in CFS, a retrovirus finding by Dr. Elaine Defreitas of Wistar the year before had generated enormous interest and efforts were underway to validate it.
The Year 1992
In this article we look at what happened to those 1992 findings and what they tell us about ME/CFS research? We took each finding and then went 20 years in the future. Was it followed up on? If so did it stand the test of time? Did a consensus emerge?
We termed a study a ‘hit’ if later studies proved it correct, a ‘miss’ if it was later proved wrong and (????) if it was somewhere in between.
The First Big, Big Disappointment
Gow finds no evidence of DeFreitas HTLV retrovirus in CFS, setting the stage for the repudiation of the first retroviral finding in this disorder.
- 20 Years Later – Two decades later Gow will reprise a similar finding for XMRV. After Gow several researchers are unable to find evidence of HTLV or other retroviruses and after DeFreitas is unable to replicate her own findings in a double-blinded study, the search, for now, is over. Later efforts using sophisticated arrays are unable to find evidence of HTLV as well. Rather eerily considering Dr. Mikovits troubles 20 years later, DeFreitas career tanks after HTLV’s demise, when she comes down with complex regional pain syndrome (CRPS) and is forced to retire. It’s a Hit (unfortunately)
Cerebral Spinal Fluid
In what Stephen Straus calls a preliminary finding requiring more study reduced levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and significantly increased basal plasma levels of 5-HIAA (serotonin) in cerebrospinal fluid. Straus reports that the findings are “evidence of persistent immune stimulation, and lend support to the idea that chronic fatigue syndrome represents a clinical entity with potential biological specificity.
- 20 years later – Straus never returns to the subject. Ten more cerebrospinal fluid studies using a variety of techniques are done over the next 20 years but no study appears to attempt to specifically validate the MHPG and 5-HIAA findings. A 2005 Natelson study finds evidence for immune activation, no evidence of pathogens are found in another, increased lactate levels are found in another but as to those MHPG and 5-HIAA findings…either for lack of trying or because they’re just not there, they never show up again. Conclusion – It’s a ?????
Cancer
Levy and Peterson are unable to find increased prevalence of non-Hodgkins Lymphoma in CFS but report that finer tuned studies are underway.
- 20 years later – A 1998 study finds evidence that higher rates of non-Hodgkins lymphoma are present in the Nevada county the Incline Village outbreak occurred in. Eleven years later a presentation at the 2009 Reno Conference showing greatly increased levels of some lymphomas in Incline Village area . That study is never published, however. Conclusion: Dr. Levine is reportedly still interested in 2012 but twenty years later the question whether increased rates of lymphoma are present in ME/CFS patients remains unanswered… It’s a ????
Muscle Metabolism
Wong finds skeletal muscle metabolism is normal but that ATP levels drop quickly suggesting oxidative metabolism is disrupted.
- A 1993 study suggests metabolic problems are present in a subset of patients. Another 1993 study finds normal muscle metabolism but an inability to activate skeletal muscles. A 1998 study finds reduced pH and ATP levels. 1999 and 2004 studies find impaired blood flows to the muscles but no problems with muscle metabolism. A 2003 study finds no problems with muscle metabolism. In 2012 Newton confirms problem with pH after exercise. Conclusion: 20 years later no consensus exists and few studies have tried to replicate the original findings. It’s a ????
SPECT
Spect scan study finds reduced cerebral blood flows in CFS patients
- 20 years later – a 1994 study finds reduced blood flows after exercise, a 1995 study finds reduced blood flows in brainstem, a 1996 study finds no differences between CFS and healthy controls, a 2000 study finds low blood flows in both CFS and depression, a 2001 twin study does not find reduced blood flows but in 2012 Dr. Lange reports that the findings overall are consistent and that newer, more accurate technology are validating out the original findings and that the low blood flows appear to cluster to some fairly well defined areas. More sophisticated and accurate studies are underway and the CFIDS Association is funding a study that attempts to explain why blood flows are reduced. Conclusion – Twenty years later researchers are now finally taking the next step; after determining the low blood flows are there – they are trying to determine why. It’s a Hit!
Cognition
Straus study finds slow response to cognition tests in CFS
- Twenty years later – the slower response to information processing holds up plus ME/CFS patients are found to have poor ‘working memory and poor ‘executive functioning’; overall the cognitive deficits are found to be ‘relatively mild’ but can work together to cause substantial problems. Conclusion – Straus was right on – Its A Hit!
Prevalence and Cost
A very large, multicenter, stratified, and random sample of a general population health finds that chronic fatigue was common only one in 13,500 people had CFS. Meanwhile a Lloyd study suggests CFS costs Australia $59 million/year.
- Twenty years later – A 1999 Lenny Jason study finds 800,000 people in the US have CFS and later CDC studies confirm that finding, indicate CFS a ‘a major health problem’ and that the disorder causes 9 billion dollars a year in lost productivity. A later study indicates total losses to the economy may top 20 billion dollars. Conclusion – this is one area consensus appears to have been achieved…at least for now…A Big Miss!
Mouse Model
US researchers claim that applying a bacterium to a mouse produces an’ CFS mouse’, setting the stage for a major breakthrough that could lead to extensive pathophysiological studies on possible causes of CFS.
A mouse model for CFS is ignored by NIH researchers for 20 years impeding progress Twenty years later – 15 years after US researchers proposed a mouse model for ME/CFS, Japanese researchers publish four studies using a similar mouse model using a brucellus antigen and an Indian researcher publishes several papers using a similar model. All findings suggest that immune processes in the central nervous system could cause CFS. Despite the NIH publically calling for the development of an animal model for CFS for at least 10 years on their website, they never devote any money to that and no US researchers participate in these projects. Conclusion – original findings appear to be correct making it a ‘Hit’ but despite NIH ‘interest’, US researchers drag their feet…keeping the mouse model focus decidedly secondary…
Report on the Outbreaks
Levine, Peterson, Cheney, Pocinki, Ablashi publish a large study on several CFS outbreaks in the 1980’s. They conclude that HTLV I and II, EBV and HHV-6 infections were not associated with the outbreaks and that Giardiasis precipitated one of them. They believe different outbreaks are probably caused by different agents and note that the prognosis of the disorder is ‘usually favorable’.
Twenty years later the role pathogens play is still unclear but studies underway should provide answers Twenty years later – early Moldovsky and Linde studies also find that EBV is not associated with CFS but a 1992 Japanese study, however, finds a correlation. EBV and HHV6 receive substantial study over time with mixed findings. Lerner champions EBV and it remains the focus of some research in the ME/CFS research community but has little traction outside of it. Twenty years later another report confirms that a Giardia outbreak can trigger ME/CFS. Conclusion – Little consensus exists but help is on the way as the CFI, CAA, WPI and CDC pathogen studies employing advanced technology in 2012 should finally help resolve the pathogen question in CFS. It’s a ?????
5-HT-2A Receptors
The results suggest upregulation of hypothalamic 5-hydroxytryptamine (serotonin) receptors are present in patients with postviral fatigue syndrome but not in those with primary depression.
- Twenty Years Later – Followup is very spotty. A 1995 paper reports high levels of antibodies to serotonin are present in CFS and FM. Several CDC studies suggest HT-2RA upregulation in CFS could have a major impact by altering the methylation process and impacting the transcription of important genes. In 2004 and 2006 Japanese studies find reduced serotonergic function in the anterior cingulate in CFS patients and 5-HT and immune upregulation in the central nervous system of fatigued mice. In 2003 Dutch researchers report that a small trial of the 5-HT3 receptor antagonist, granisetron has positive results (no followup). No studies examine whether serotonin receptor findings are different in CFS and depressed patients as the 1992 study suggests..Conclusion – The research is scattered but in general findings regarding serotonin are positive. Too few studies, however, keep serotonin from becoming a significant focus. Its a “Minor Hit”
Buproprion
In a very small study Dr. Klimas finds that buproprion may be helpful in treating ME/CFS.
- 20 years later – it takes 13 years before Buproprion is mentioned again. In 2006 Freudenmann suggests Buproprion “shows theoretical potential to improve fatigue symptoms” in a review article but no further studies are done. Conclusion – no follow up work 20 years later means…. Its a ???
Conclusions
Studies in 1992 did open up fertile ground in this underfunded field progress has been miserably slow. A couple of things stood out. 1) A positive finding is no guarantee of future research; twenty years later several positive findings were never followed up on and 2) if followup does occur it tends to be scanty and disorganized with few studies attempting to specifically replicate earlier findings. If 1992 is a representative year this overview suggests that many positive studies over the years may have not been followed up on and that given the scattered approach of the field to past efforts, the current effort to standardize ME/CFS research protocols should pay off.
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