Straus – A Research Review
The mention of Dr. Stephen Straus, an early leader of the NIH effort on CFS, prompted me to take a look at his research. A greatly disliked figure in the ME/CFS community, Strauss was a key player in shaping the government’s early response to ME/CFS. A measure of his influence can be seen in the outsize response to his negative enteroviral study which, despite never being published, still managed to effectively end research in that area, until Dr. Chia. That, however, was only the beginning.
Dr. Straus’s failed acyclovir trial, using standard treatment protocols for that time (which we now know do not work in ME/CFS), put the kabosh on antivirals in general. An intravenous immunoglobulin (IVIG) trial (unabstracted/1991) apparently did the same for IVIG. (Dr. Chia will point out at the Workshop that a certain of his patients do very well on IVIG. )
Hepatitis C was knocked out in 1991 (never to return).
A 1991 HPA axis paper that revealed mild adrenal insufficiency helped to kick off what would become dozens of papers examining what turned out to be, yes, mild HPA axis problems in many patients.
A 1992 conference review sported the rather gut-wrenching statement below, which emphasized that progress on the research level will very likely depend on finding subsets in this heterogeneous population – words that are no less true today than almost 30 years ago.
“ Because CFS is not a homogeneous abnormality and because there is no single pathogenic mechanism, research progress may depend upon delineation of these and other patient subgroups for separate data analysis. “
Straus then moved on to the brain in 1992 and 1993, finding little evidence on one small study for attentional or short-term memory problems but then uncovering altered metabolite levels in a cerebrospinal fluid study
http://www.ncbi.nlm.nih.gov/pubmed/1282370 that he felt could account for some of the fatigue and which suggested ‘persistent immune stimulation’ was present.
A 1993 lymphocyte study that found evidence of reduced T-cells and responses to antigens suggested to him it was” a consequence of an underlying neuropsychiatric and/or neuroendocrine disorder or because of exposure to antigens or superantigens of an infectious agent.”
http://www.ncbi.nlm.nih.gov/pubmed/8095270. (Note that Dr. Huber is currently studying the possibility of superantigen activation in ME/CFS. Straus’s review of herpesvirus research
http://www.ncbi.nlm.nih.gov/pubmed/8387907 later that year concluded that herpesviruses probably do not play a role in CFS.
Straus’s biggest role in CFS may have been his co-authorship (along with Fukuda, Hickie, Dobbins, Sharpe and Komaroff) of the 1994 Fukuda or International definition of CFS that 17 years later, still, somehow dominates the field.
It was back to the brain in 1996 in a fascinating study that which suggested that the brains of ME/CFS patients, were, for want of a better term, ‘sluggish’ post-exercise compared to those of healthy controls and people with depression
http://www.ncbi.nlm.nih.gov/pubmed/8960719. The paper stated “We conclude that postexercise cortical excitability is significantly reduced in patients with chronic fatigue syndrome and in depressed patients compared with that of normal subjects.”
A hydrocortisone trial
http://www.ncbi.nlm.nih.gov/pubmed/9757853 that showed mild improvement but adrenal suppression in some patients had important implications for many doctors seeking to turn around the mild HPA axis abnormalities seen in their patients. An HPA axis stress test documented more HPA axis abnormalities in 2001 and then Strauss tried another treatment angle with a failed fludrocortisone trial that ended up in the prestigious JAMA journal
http://www.ncbi.nlm.nih.gov/pubmed/11150109. This would be another unfortunate trendsetter whose effects Dr. Rowe, the lead author, would bemoan at the SOK Workshop. The problem again was the paradoxical approach of a research community that readily acknowledged subsets were present but then treated all the patients like they were the same once they got them into a study. And so there it was – in black and white in a top medical journal – the finding that fludrocortizone does not work in CFS. Dr Rowe says he uses fludrocortisone in CFS every day. . .
A very large 2001 study (n=744)
http://www.ncbi.nlm.nih.gov/pubmed/11531735 looking at symptoms failed to produce concretely identifiable subsets, but emphasized the toll the lack of proper subsets was likely taking on CFS research, stating that “substratification of patients is essential for further aetiological and treatment research”.
In 2002, Straus performed another stress test of sorts, injecting CFS patients with IL-6 to see if cytokines might be at the heart of the cognitive and symptom problems in ME/CFS. Evidence of increased symptom activation suggested that while immune activation might very well be part of the problem, it was not all of it, as cognitive problems remained unchanged.
http://www.ncbi.nlm.nih.gov/pubmed/12214788
After 2002, Straus mostly stopped participating in ME/CFS research. His final (small) study before his death suggested people with CFS (as well as those with rheumatoid arthritis and polymyosistis) have reduced aerobic capacity.
http://www.ncbi.nlm.nih.gov/pubmed/19627955
The CDC did look at symptom patterns and made a stab at subsets during the ‘Pharmacogenomics era’ but they also employed a random sampling methodology that made it difficult to build up the large sample sizes needed.
Conclusion – The Straus studies, some of which were surprisingly small, had an outsize influence on the field. Straus’s studies opened up ground or validated findings of altered brain metabolite levels, reduced cortical excitability, altered exercise metabolism and immune system dysfunction in CFS.
Strauss’s studies also negated several treatments that are commonly used today by some doctors to positive effect including antivirals, fludrocortisone, hydrocortisone and IVIG. Strauss was also a key figure in asserting the herpesviruses were probably not a major factor in ME/CFS.
Some of Strauss’s mistakes in the treatment arena can be attributed to his unwillingness or inability (low sample sizes?) to look for subsets – a problem that is hardly less common now. If blame must be placed for the research community’s unwillingness to follow their own advice and make a serious effort at finding subsets, where should the blame be placed? Obviously at the federal level – at both the CDC and the NIH – and at Stephen Strauss, who was entirely aware of the dangers that failure to identify subsets posed to making progress on ME/CFS research level, and yet did nothing about it.
