[Ed. Note: Since the artificial construct of CFS was created in 1988, it has been essentially impossible to get a diagnosis of ME in the US, although ME is still diagnosed in other countries. These three articles represent the quest to return to the historic name, or at least, some less derogatory name, so that patients can receive the respect and treatment they deserve. When CDC made the CFS name mandatory, my original diagnosis was changed, even though the virologist didn't agree with the new name; if he had stubbornly refused to change the diagnosis, there was no code for the old one on the insurance forms, which would've made getting treatment paid for difficult.]
ORIGINAL SIN:
CFS, ME and Incline Village
By Cort Johnson
Incline Village is ground zero for the modern era of CFS/ME. It is where
CFS/ME first (re)emerged in a big way and made it onto the national
scene. What a scene it was; we had a bucolic (upper class) community in
a resort town in the Sierra’s beset by a bizarre epidemic. We have the
embattled good guys (our doctors) struggling against their supposed
allies (big, bad government bureaucracy – the CDC) and the rest of the
medical establishment all the while defending their scorned and disabled
patients. What a stirring story it was.
Incline Village is a place where, paradoxically, things went right in a
big way (CFS/ME finally gets attention) and wrong in a big way (CFS/ME
called ‘yuppie disease’.) Not so long after the Incline Outbreak the
name ‘chronic fatigue syndrome’ was coined and down the slippery slope
of ‘fatigue’ this disease slid.
Both ME and CFS advocates claim Incline Village as their own. Some
believe it was our first big chance – perhaps our only chance - to fix
this disease in the research community’s mind before it got tainted by
the fatigue label. The facts were all there they say! All the powers
that be had to do was open their eyes. Instead they turned them away and
we have suffered the consequences ever since.
The CDC, of course, was on the scene early but they weren’t the only
ones. A group of committed CFS researchers/physicians were there also.
This group came to this disease with open eyes and for several of them
it was a career changing event. The pedigree of this group is amazing;
many (Cheney, Peterson, Ablashi, Komaroff, Bastien, Buchwald) will go on
to take central roles in CFS research or treatment. Early on they were
able to garner a series of large NIH grants and over the next six or
seven years they would come to publish at least five studies examining
the Incline Village (and other cohorts).
We know the CDC found nothing interesting but did ‘our side’ say? These
researchers - so passionately struck by their patients suffering - knew
they were facing a real disease. What did they report? What kinds of
patients did they find? Were they CFS patients or ME patients? Were
their conclusions listened to or were they dismissed? What kind of start
did CFS research get off to? Twenty-two years later we take a look at
Incline Village and what it meant and didn’t mean for CFS/ME patients.
The Studies: These were not small efforts. Much of the information in
this paper will be taken from a major paper published in 1992 (Buchwald,
Cheney, Peterson, Ablashi, Komaroff et. al. 1992). It was one of the
first major studies ever done on CFS/ME and it is still one of the
largest. It involved cerebrospinal fluid draws, MRI’s, HHV-6, HTLV and
lymphocyte testing in at least a portion of over 200 patients.
Defining CFS: One of the first problems the investigators of the 1992
study faced was one researchers are still struggling with; how to define
an often debilitating disease that is marked, for the most part, by
rather common symptoms. As most definitions have done, these researchers
focused on the predominating symptom, fatigue. They required each
patient in the study to have at least three months of chronic,
debilitating fatigue with at least two of eight other symptoms (fever,
headache, sore throat, earache, rhinnorhea, cough, diarrhea or muscle pain.
Aside from fatigue the symptom set was somewhat unusual; fever, earache,
post-nasal drip, cough and diarrhea will not appear in the 1994
definition or be prominent in others. Headache, sore throat and muscle
aches will. A perhaps special kind of fatigue – post-exertional fatigue
– that some researchers believe characterizes CFS was not mentioned and
had not yet been delineated. Neither cognitive problems nor joint pains
were part of the definition but both were common (79-88/67-82%) in this
group.
They noted that a ‘few patients’ (8%) developed ‘transient periods’ of
an encephalitis-like symptoms including confusion, gait problems,
paralysis and seizures. These early symptoms are similar to some
described in early ME epidemics. Was this an ‘ME’ subset? Like ME
patients earlier studies described the most severe nervous system
problems (paralysis, seizure) were described as ‘transient’. As the
disease progressed these patients looked more and more like the other
patients and they were not segregated out again.
Acute (infectious) vs. Gradual Onset or Acute and Gradual Onset? Debate
persists in the CFS/ME community whether infectious onset patients are
fundamentally different from non-infectious onset patients. While ME
researchers do not require an infectious onset for ME the presence or
absence of an infectious onset is used by some to differentiate ME from
CFS patients; ME patients tend to have an infectious onset while CFS
patients do not. This has at times morphed into the belief that ME
patients have a real illness while CFS patients have psychological problems.
These two groups of patients were also found in the Incline Village
studies. The acute onset epidemic type patients could not be
distinguished symptomatically or with regard to laboratory tests from
the gradual onset endemic type patients and they were lumped together.
Neither an acute onset nor the presence of flu-like symptoms led to a
more severe illness. In the end the investigators believed it didn’t
matter whether the trigger was an infection or some other event or
nothing visible at all; the patients were essentially, so far as they
could tell, the same. They believed a ‘common pathogenetic pathway’ was
present in all of these patients.
THE PATIENT. As expected about 65% were women. Most were middle-aged
(average age of about 39). About 25% were either bed ridden or shut in.
Even in this severe outbreak, though, almost half the patients (49%)
were able, despite their fatigue, to fulfill ‘all work or home
responsibilities’ (but with nothing left over).
(This explodes the myth that all or even most CFS/ME patients are
‘disabled’. While a significant number of CFS/ME are disabled
substantial numbers of CFS/ME patients are able to work. Rates of
employment in CFS studies have varied dramatically from study to study
(32% to 73%) with an average employment rate probably around 50%).
A large 1993 follow up study found that most patients got better over
time; the researchers, in fact, stated that ‘the overall prognosis of
chronic fatigue syndrome is usually favorable.’(!) and that ‘After 3
years of follow-up, almost all study subjects were able to return to
pre-illness activity’ (!). While most apparently got well a subset of
these patients had “More-serious and longer-lasting neurologic
impairments, including seizures, psychosis, and dementia”.
LABORATORY FINDINGS – Were these CFS researchers findings taken
seriously? Were they on the right track? Let’s find out.
MRI BRAIN SCANS. The MRI findings have been described as objective
evidence of central nervous system damage, something that only an agency
determined to subvert CFS patients could ignore. Indeed the researchers
‘frequently saw areas of abnormal signal intensity in the white matter
of the central nervous system” of CFS patients. The meaning of those
abnormal signal intensities were, however, unclear. In a few patients
they were able to correlate problems in, say, vision with abnormalities
in the visual cortex but in most they were not. The fact that ‘similar
white matter changes were found in many disease and conditions (multiple
sclerosis, Alzheimer’s, metastatic disease, post- chemotherapy, trauma,
viral infection, etc.)’ suggested some pathology was at work but left
the cause of it unclear.
Problematically while significantly more CFS patients demonstrated these
abnormalities than the healthy controls a significant percentage (20%)
of the healthy controls had them as well. The researchers noted that
this was not unexpected stating “such..areas..can also be seen in
apparently health people of all ages”.
A further problem involved linking these areas to the actual disease
since they occurred in different areas in different patients. While they
suggested that at least some patients were ‘experiencing a genuine but
as yet undefined pathologic process” they concluded that the
significance of these ‘incidental’ areas ‘is not known’.
The significance of the MRI findings was muddied by a lower rate of MRI
abnormalities in the New England cohort of patients and by the fact that
they were not found in all the patients. Suggestions that these
abnormalities increased with age did not help clarify matters. Finally,
since the clinical significance of the tests was unclear they did not
recommend the routine use of MRI in CFS patients. It was clear the
authors thought they might be onto something but were unsure what it was.
The Medical Community’s Response. At least nine studies will examine MRI
findings in CFS between 1990 and 2000. All will display variable
findings; a 1993 study found abnormalities in 27% of CFS patients; a1994
study in 50%; another found them in 32% of CFS patients (and a
statistically equal numbers of controls). The inability to find
abnormalities in all or at times in a majority of CFS patients or to
find them in specific areas of the brain will continue to leave the
scientific community unclear as to their significance.
The Present. Things will change for the better around 2000 as
researchers refine their techniques and imaging technology improves. Dr.
Natelson’s finding of increased central nervous system abnormalities in
CFS patients without mood disorders as opposed to those with mood
disorders will help to increase interest in this area. Functional MRI’s
and other brain imaging techniques now consistently show abnormalities
in certain parts of the brains of CFS patients. CFS patients have had to
wait for brain imagining technology to catch up to them before it could
reveal consistent results.
IMMUNE FINDINGS. These researchers concentrated on two herpesviruses,
EBV and HHV-6. Both were relative newcomers to the medical world at that
point. EBV was discovered in 1964 and HHV-6 in 1986. Several of the
Incline Village studies did find evidence of increased EBV and HHV-6
activation in their patients but all were unclear as to their
significance. The 1993 Levine, Cheney, Pocinki, Ablashi, Peterson study
noted that HHV-6 reactivation might either be an epiphenomenon,
secondary to immune dysfunction….or could have no relation to patients
symptoms” or it could be destroying nerve and immune cells. This study
concluded that “None of the viruses evaluated--human T-lymphotropic
viruses I and II, Epstein-Barr virus, or human herpesvirus-6--could be
etiologically linked to these outbreaks”. They postulated that one
outbreak was caused not by HHV-6 or EBV but by giardiasis.
Medical Communities Response. EBV and HHV-6will both be studied
intensively in CFS in the aftermath of Incline Village. Between 1987 and
1996 over twenty studies will examine the relationship between EBV
infection and CFS and between 1990 and 2000 at least 14 studies will
examine the relationship between HHV-6 infection and CFS. At one point,
Dr. Komaroff, now an advocate for HHV-6’s effects in CFS, will co-author
a paper concluding the opposite (Buchwald 1996). This very large study
(548 CF and CFS patients and controls) found no differences in the
levels of 13 viruses in CFS patients relative to the other groups or to
CFS patients with acute onset. (This size study is almost unimaginable
today!) Researchers will end up concluding that increased EBV activation
does not play a role in CFS. A similar but less strong consensus will
emerge concerning HHV-6.
The Present. Again, improved testing and knowledge will re-ignite some
interest in both these pathogens. Dr. Komaroff recently detailed a
series of factors suggesting that HHV-6 reactivation does play a role in
some CFS patients. Dr. Glaser has continued to explore the possibility
that some types of EBV activation are damaging in CFS. While
underfunding is a problem resolving the role these pathogens play in CFS
may await further technological advances. In particular inadequate
testing for HHV-6A virus still limits our understanding of its effects.
CFS and ME and Post-viral Syndrome and. Icelandic Disease and Royal Free
disease, etc. or Not? Debate rages in the CFS/ME communities whether CFS
and ME are similar diseases. The authors of the 1992 paper (Buchwald,
Cheney, Peterson, Ablashi, Gallo, Komaroff, etc.) were faced with a
similar question. Notice that the title of the paper ‘A Chronic
Illness..” doesn’t mention CFS or ME or any other names. Because CFS and
its definition – which differed from the one used – came after the study
began they couldn’t refer to their patients as CFS patients. The most
they could say was that ‘most patients probably would have met the case
definition forchronic fatigue syndrome”
They didn’t refer to their patients as myalgic encephalomyelitis (ME) or
Icelandic disease or Royal Free disease, etc. patients either. Instead
they noted that ‘the illness we have observed shares many features with
entities variably called…“postviral fatigue syndrome, myalgic
encephalomyelitis, Icelandic disease, etc.”
It was clear that seven years after they first encountered these
patients that they felt that their group (still one of the most
intensively studied group of CFS patients ever) was very closely allied
with if not identical with these other groups.
After all this study these researchers felt competent to address some
basic questions regarding not just their group of patients but all this
entire group of patients (CFS/ME/Royal Free, etc.). In the beginning of
the discussion section of the paper they asked whether all these
diseases were each caused by one pathogen, were caused by different
factors, or did they all represent one general illness that could be
triggered in numerous ways?
They came down on the last possibility –the one that prevails in the US
today. In the last paragraph of the paper they stated that ‘we think
that this is probably a heterogeneous illness that can be triggered by
multiple different genetic and environmental factors (including stress,
toxins and exogenous infectious agents)”
Thus while some ME advocates may single out the Incline Village outbreak
as an ME as opposed to a CFS outbreak the researchers and physicians
involved in treating and examining these patients did not. Nor did they
believe that acute infectious onset patients differed from gradual onset
patients. While many point their fingers at the CDC for turning an
infectious illness into a grab bag of undifferentiated and fatiguing
illnesses, they should note that this group, which featured many who
will go on to be outspoken advocates for CFS/ME – will come to much the
same conclusion; CFS/ME is an illness that can be triggered in many
different ways but which reveals itself by a core group of symptoms.
Overall Conclusion. The ‘CFS friendly’ researchers at the Incline
Village outbreak (and elsewhere) raised questions that the scientific
community did look more closely at. EBV and HHV-6, in particular, were
exhaustively researched butsubstantial numbers of MRI studies were done
as well.
The progess in unraveling CFS has been slower than one would have hoped.
Much of the blame for this has been laid at the hands of an inattentive
if not biased research community. CFS has certainly never enjoyed the
amount of research funding it deserves but this short survey suggests
that the research community did respond to many of the issues raised.
The blame for the slow progress in understanding CFS can be laid at many
different feet; the bias evoked by the name, the poor performance by the
CDC, the poor leadership at the NIH, an inherent conservatism at
research institutions around the world, an inadequate technology, a lack
of creativity, etc. but a good share of it must be laid at the
complexity of the disease itself. Many of the issues that plague
researchers today such as how to define CFS, the difficulties
replicating study results and the obvious presence of subsets showed up
in these early studies as well. CFS/ME was a puzzle from the beginning –
not only to the research community at large but to those intimately
involved in studying it. Even when they have had adequate resources to
study it CFS/ME has often yielded its insights slowly and grudgingly.
Addendum. Ironically the research community may have been more amenable
to embracing CFS before much was known about it. The search for
pathogens that much early research was focused on is, after all,
something the research community knows well. The large size of several
early studies suggests a commitment to understanding CFS/ME that is not
be present today. Ironically while much more is known about CFS today
and more intriguing research avenues exist than ever before the CFS/ME
research program has been cut back severely at both the NIH and the CDC.
There are many easier diseases to study, many diseases that provide much
better expectations of success for researchers. The difficulty CFS/ME
presents researchers requires that we a) be appreciative of those that
have joined us for this hard slog and b) be vigilant in demanding that
the scientific community commits the resources needed to adequately
study it.
____________________________________
Buchwald, D., Cheney, P., Peterson, D., Henry, B., Wormsley, S., Geiger,
A., Ablashi, D., Komaroff, D.etc. 1992. A chronic illness characterized
by fatigue, neurologic and immunologic disorders, and active Human
Herpesvirus Type 6 Infection. Annals of Internal Medicine 1116: 103-13.
Daugherty SA, Henry BE, Peterson DL, Swarts RL, Bastien S, Thomas RS.
Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S39-44. Chronic fatigue syndrome
in northern Nevada.
Buchwald D, Ashley RL, Pearlman T, Kith P, Komaroff AL., J Med Virol.
1996 Sep;50(1):25-30.Viral serologies in patients with chronic fatigue
and chronic fatigue syndrome.
Levine PH, Jacobson S, Pocinki AG, Cheney P, Peterson D, Connelly RR,
Weil R, Robinson SM, Ablashi DV, Salahuddin SZ, et al. Arch Intern Med.
1993 Mar 8;153(5):661. Clinical, epidemiologic, and virologic studies in
four clusters of the chronic fatigue syndrome.
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