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ORIGINAL SIN: Incline Village, Chronic Fatigue Syndrome and Myalgic Encephalomyelitis 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.

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-6 will 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 for chronic 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 but substantial 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 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.