by Lucy Dechene, Ph.D.

 

[Note: For help understanding some of the statistics in this paper, see Research Notes about statistics used in medical studies]

Does the character of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) change over time? Published results from the 10+ Long-term Chronic Fatigue Syndrome Study indicate that the illness becomes more neurological after fifteen years or more.

Fred Friedberg, Ph.D of the SUNY Stony Brook Medical School, Maggie McKenzie of the Connecticut CFIDS Association, Robert Fontanetta of Floral Park, NY and myself (of the Fitchburg State College Mathematics Department and MassCFIDS) reported this fact in another of our series of papers on the 10+ study of patients ill with ME/CFS for more than 10 years.¹

Since we were forced by reviewers to eliminate some important information from our paper, I will include more information in this article than occurred in print. For instance, another major result was that long-term ME/CFS patients who are gradually improving, were significantly more severely ill during their first year of illness than the others in the sample.

There are some other significant results concerning the unusual fatigue characteristics section on the questionnaire which I will omit here, since they will be published in a paper still under revision and peer review. ²

Origin of the 10+ study

The 10+ study was the brainchild of Maggie McKenzie and Rob Fontanetta. They walked out of the ME/CFS international research meeting in Albany, NY in 1992 and decided that they had heard one time too many the then-prevalent myth that most ME/CFS patients recovered before five years were up. Both long-term patients themselves, they conceived the notion of the study, and without funding, set out trying to contact people with ME/CFS who had been ill for more than ten years. Eventually long-term patients Fred Friedberg and I joined the team.

The final study had useable responses from 258 patients who had had ME/CFS for more than 10 years (with a range of 10-59 years and median duration 16 years), patients with ME/CFS less than seven years (with a range of 1-7 years and median duration of 3 years), and 179 "healthy" spouses, significant others and friends (27 of whom [15.1 %] met the 1994 Centers of Disease and Control Prevention (CDC) definition of CFS on paper, at least, but in other portions of the study did not indicate the level of impairment shown by the ME/CFS patients. So we kept them in the "healthy" group). 

Diagnosing ME/CFS in the participants

Since this was a self-report study, ME/CFS was diagnosed by responses to the questionnaire. The study contained detailed questions pertaining to both the CDC's 1988 and 1994 case definitions.

In the long-term group 188 subjects met the 1988 case definition of CFS and another 70 met only the broader 1994 definition. 19 short-term subjects met the 1988 case definition and the other 9 met only the 1994 definition.

We also asked about concurrent conditions. So none of the respondents we used in the analyses also had AIDS, multiple sclerosis or systemic lupus erythematosis, for instance. In addition, we asked how they had been diagnosed with ME/CFS. Of the original 287 long-term respondents (a 72% response rate to the questionnaire), 75 patients had been diagnosed with ME/CFS by one of 19 prominent ME/CFS research physicians, 198 by another physician and 12 were self-diagnosed. 29 of these original subjects had to be eliminated from the analysis because missing data or the presence of a contra-indicated condition prevented the applications of both the 1988 and 1994 case definitions.

Demographics

Our respondents came from 42 states and 9 foreign countries, with perhaps only Dr. Les Simpson having conducted a more geographically diverse study of ME/CFS patients. The mean age of the long-term group was 48.4 (SD = 10.4, range 19-80 years). That for the short-term group was 45.5 (SD = 12.4) and the significant-other group was significantly older at mean age 51.8 (SD = 12.4, P = .003). 96.8% of the long-term participants were Caucasian, and 3.2% were either Hispanic, Asian or Native American. Other demographic data is summarized in Table 1 below.

 

 

 

 

 

 

 

 

 

 

Table 1. Demographic data for the 465 participants 

                        Long-duration    Short-duration     Significant-other

                           ME/CFS              ME/CFS                   group_______

  N                             258                 28                         179  

Age (years)              48.4                45.5                       51.8*

% women                 85.1                89.3                      32.2*

Education (years)     15.5                16.1                      15.1

% married                 51.6               37.0*                     76.5*

% working (full or    28.2*             63.6                       61.8*

part-time)

% on disability due     40

to ME/CFS

Median Income   U.S. $20,000-30,000                U.S. $20,000-30,000

Illness duration           16 yrs          3 yrs

    (median)  

_______________________________________________________

* p < .01

Symptom patterns in the long-term group

All groups were asked to respond to a list of 48 symptoms with "never", "rarely", "sometimes", "often", or "constantly" for each symptom. The two ME/CFS groups were asked to respond to each symptom twice. The first response was to indicate the level of severity of the symptom during the first year of illness.

The second response concerned the level of severity of the symptom at the time the questionnaire was filled out (1994).

I am sorry to say that the peer reviewers of the paper made us take out the information about the first year of symptoms because they felt the long-term group couldn't remember accurately that long ago.

We strenuously disagree with that position. We feel that the first year of illness was sufficiently traumatic that the general impression of what happened then would be correct even 59 years later.

Our position was bolstered by the fact that there was no significant difference in the symptoms and their severity reported by the two groups for the first year of illness.

There was a very significant difference in the two groups concerning their current symptoms, which I'll discuss later. Just looking at the differences in the percentages in the long-term ME/CFS group responding "Often" or "Constantly" to certain symptoms in their first year versus currently is very instructive.

The problems with neurological symptoms have significantly increased over the ensuing decades, while the level of more flu-like symptoms has declined.

The pattern is striking in Table 2 below.

 

Table 2. Symptoms Most Frequently Reported "Often" or "Constantly" in

Long-term ME/CFS

Symptom________________________First year   _________     _Currently

Prolonged fatigue after                       63.4%                               83.3%

exercise

Severe persistent fatigue                     73.2%                              84.3%    

Muscle aches and pains                        54.7%                              79.8%  

Forgetfulness                                       38.3%                              73.2%     

Distractibility by noise                         44.9%                              69.0%

Concentration difficulty                        48.8%                              66.2%

Word-blocking                                      32.4%                              65.9%

Distracted when reading                       41.1%                              63.1%

Sensitivity to light                                41.1%                              62.7%

Difficulty thinking                                 43.6%                              61.3%

Gait less fluid                                        37.3%                              58.5%

Pain in the extremities                          38.7%                              54.7%

Joint pain                                              38.3%                              54.4% 

Confusion                                             38.0%                               53.7%

Trouble matching                                  30.7%                               52.6%

     names/faces

Insomnia                                               43.6%                              52.3%

Trouble with written                              59.6%                              47.4% 

    instructions

Trouble with attention                           58.2%                              46.0%  

    in conversation

Mild fever                                               56.8%                              41.5%    

Sore throat              ___________  _  _ 55.1%________ ______ 33.4%

Co-morbid conditions of all groups 

We were interested in the occurrence of co-morbid conditions in ME/CFS patients.

We asked not only if a person had had a certain condition, but whether

• the condition had started and ended before the start of ME/CFS
• started before ME/CFS but was still going on
• started after ME/CFS but was resolved, or
• started after ME/CFS and was still going on.

Unfortunately, I have still not had time to analyze the data to see if there were any significant occurrences of certain conditions after ME/CFS. So the following table will only give lifetime occurrences of the various conditions.

We did not include HHV-6 because the test for it had just been invented. We decided that very few patients would have been tested at that point.

I also regret that we did not distinguish between hypothyroid and hyperthyroid conditions. We also failed to ask about cancer.

It is important that the reader note the very high incidence of allergy in the significant-other group as well as the other two groups. 83. 7% of those reporting allergies in the long-term group had been formally tested and had at least one allergy documented. Similar high percentages of the atopics in the other two groups had had formal allergy testing with positive results.

Thus these were not just "self-diagnosed" or "imaginary" allergies, as some researchers insist must be the case. It is also clear from the table that the incidence of each condition was significantly less in the significant-other group compared to the two ME/CFS groups, and the incidence of fibromyalgia, major depression and cardiac arrhythmia were significantly higher in the long-term group compared to the short-term group. Lyme disease occurred significantly more often in the short-term group compared to the long-term group. (Note that the study took place before the existence of Chronic Lyme Disease was acknowledged. Thus the handful of participants who had had Lyme disease at one point in their lives may have been suffering from Chronic Lyme Disease instead of ME/CFS. There were so few subjects like this, that our results would not have been affected.)

 

Table 3.  Co-morbid Medical Conditions in All Groups

 

 

*** p < .0001    ** p < .01         * p < .05

Allergy, Chemical Sensitivity and ME/CFS

As noted above, allergies were the most frequent co-morbid condition in both ME/CFS groups. We had a very extensive section on the questionnaire concerning allergies and chemical sensitivities.

Long-term ME/CFS patients had a very high level of reported chemical sensitivities ranging from 24.1% sensitive to chlorine to 61.6% sensitive to tobacco smoke.

Similar results hold for the short-term group.

In the significant-other group, the highest sensitivity was 14.0% to tobacco smoke.

Since we had extensive questions concerning the types of allergens and the severity of the allergy to each, we formulated different indices for allergy severity, chemical sensitivity (pre and post ME/CFS), current or 1st year neurocognitive symptoms, and current or 1st year flu-like symptoms. We checked the correlations among each of them.

We also checked if they were related to the onset of certain types of allergic reactions (i.e., skin reactions, anaphlaxis, etc.) occurring before or after ME/CFS. A high score on this index meant the person had more types of reactions and these tended to have occurred both before and after ME/CFS started.

A correlation coefficient Pearson's r lies between zero and one (since these were positive correlations). A coefficient close to 1 is an excellent result.

For a sample of 258 subjects, an r around .22 is a modest correlation. It means that both indices being compared were generally high or low at the same time. A result is statistically significant if there is a p-value less than .05. That means there is less than a 5% chance the result could have happened randomly.

p < .0001 is extraordinarily significant. It means the result really couldn't have happened by chance. Correlations aren't causations, but they suggest the two phenomena are somehow related to each other, either directly, or via a hidden factor.

In Table 4 we show some of the more interesting significant correlations for the long-term group. The results for the short-term group were similar.

 

Table 4. Correlation of Illness Severity Scores in Long-term ME/CFS

 

 

Treatments for ME/CFS

We asked about 29 common (in 1994) treatments for ME/CFS. Efficacy ratings for the treatments for the combined long and short-term groups revealed that the highest percentage of "moderate to major improvements" were reported for Ampligen (100%, n=3), anti-allergy diet (32%, n=186), antidepressant medication (28%, n=249), anti-yeast diet (27%, n=183), and stress reduction/biofeedback (26%, n =133).

Treatments most likely to be rated "felt worse" were IV antibiotics (39%, n = 38), oral antibiotics (36%, n= 195) and antidepressant medication (31 %, n=249). So, more people got worse on antidepressant medication than got better.

Sudden onset vs. gradual onset in long-term ME/CFS

55.6% of the long-term group reported "sudden" onset of ME/CFS, which we defined as occurring over a few hours to a few weeks.

Those reporting a gradual onset had a significantly higher allergy severity score (t = 2.07; df = 248; p< .04).

We found no significant differences between sudden vs. gradual onset on any of the other illness severity measures, nor any difference in age at onset between the two groups.

Pregnancy, female hormones and long-term ME/CFS

Maggie and I made sure we included a very detailed section concerning pregnancy, hysterectomy, Hormone Replacement Therapy (HRT), birth control pills and ME/CFS. We found that women's experience ranged over the whole gamut of possibilities pretty evenly between categories.

So about an even number of women reported improving during pregnancy, getting worse or staying the same. (We did ask each person to answer the same questions for each different pregnancy. Not too many women had had multiple pregnancies and those who did, had the same experience each time with ME/CFS.)

Those that had a change in ME/CFS severity were pretty evenly divided among which trimester the change occurred.

No significant results were found in the effect on symptoms of the menstrual cycle, birth control pills, hormone replacement therapy or hysterectomy. 

Illness progression in long-term ME/CFS

We asked detailed questions concerning how ME/CFS had progressed over time. Of the 67.1% of long-term subjects reporting significant relapses and remissions, 17.7% stated that overall illness severity was roughly constant, 27.4%  reported more severe illness over time, and 22% reported less severe illness over time.

The remaining 32.9% of the long-­term group classified their illness as not having significant relapses and remissions. Of this group, 19.1 % reported progressive worsening illness, 4.0% were progressively improving, and 9.8% reported roughly constant severity.

On the whole, long-term patients found ME/CFS to be severe. Another multiple choice question asked subjects to quantify their severity of illness over each 5-year period of their illness (years 0-5, years 5-10, etc.).

For each time segment up to 30, 52% of those responding claimed they had felt severely ill with ability to function at only 0-50% of ­normal during the period. After 30 years of illness duration, this rose to 61.5%.

As a mathematician, I had gotten very annoyed when attending American Association of Chronic Fatigue Syndrome (AACFS) conferences and seeing some speakers slapping a graph on the screen and claiming, "This is the typical course of illness." When I had spoken to them later, each admitted he had based the graph on "gut feeling", not data.

So in this study, I asked as the very last question (question #589) that the participant draw a rough graph of the progression of their illness. I had ended the graph at 40 years, but some participants extended that.

I had my Russian student from Rybinsk assign numerical y-values to various points and use linear interpolation, so I could recapture relative ups and downs in a database. I then used cluster analysis to look for patterns.

While I derived many patterns, it is pretty clear they are the results of this particular sample.

The most accurate statement that I can make is that "anything goes", including remissions of ten years or more followed by terrible crashes. So there is no "typical" course of illness. 

Worsening vs.improving groups in long-term ME/CFS

The worsening (n = 128) and improving (n = 70) group of long-term patients were well differentiated on measures of ME/CFS symptom severity, stress, depression and functional status. The age at onset was significantly lower (27.5 vs. 32.5) and the duration of illness significantly longer (20.5 years vs. 17.4 years) in the worsening group.

The worsening subgroup was also significantly more likely to report the co-morbid conditions of fibromyalgia, chronic sinus infections, thyroid problems, asthma and previous suicide attempt. The worsening group was significantly less likely to endorse "persistent stress" as a perceived initial cause of ME/CFS, although this group showed elevated levels of stress and depression.

Unexpectedly, the worsening group of CFIDS patients showed significantly lower symptom severity scores than the improving group during the first year of CFIDS. This is a result other researchers should look into.

No significant differences between the groups were found in age, sex, education, social support scores, or on the type of illness onset reported (sudden or gradual). The symptom measures of allergy severity and chemical sensitivity were not significantly different between the two groups. 83.3% of the worsening group could not work, while 51.5% of the improving group could not do so.

Long-term vs. short-term ME/CFS

Although our short-term group was small, it was large enough to do statistically meaningful comparisons between the groups.

The mean age at onset was significantly lower in the long-duration group (28.8) as compared with the short-duration group (41.4) years, F = 3.10; df 1,315; p< .000005).

While there was no significant difference in severity of the illness for both groups during the first year, the long-term group was currently more severely ill than the short-term group.

Neurocognitive symptoms accounted for most of the increase in severity in the long-term group.

Table 5 shows which of the 48 symptoms were significantly different between the groups. The frequency denotes the percentage reporting experiencing the symptom at least "rarely", not just "often" or "constantly" as reported in Table 2.

Table 5.  ME/CFS Symptom Frequency in Long-term and Short-term Groups

(Significant Differences Only)

_________________________________________________________

Symptom                               Long-term ME/CFS (%)   Short-term ME/CFS (%)

Word block                                 92.8                                          78.6**   

Bumping into things                  77.1                                          50.0***   

Putting the wrong word in         76.7                                          43.1***

Trouble with directions              71.0                                          44.0***

Burning sensations_        _____33.6_____________________14.3*____

***p < .0001

 

Most of the long-term cases were not working due to their illness, while most of the short-­term group were still working. No significant differences were found between the long-term and short-term groups on measures of fatigue severity, stress, depression, coping profiles social support or functional status.

A very interesting result occurred when comparing the long-term group's perceived causes of illness and the short-term group's perceptions. The short-term group members were significantly more likely to endorse causes over which they had control. Both groups strongly endorsed immune/viral factors and persistent stress, however. The perceived cause results are in Table 6.

 Table 6.  Perceived Causes of ME/CFS

Perceived Cause                        Long-term ME/CFS (%)     Short-term ME/CFS (%)

Immune/viral factors..                         90.6                                      82.1

Persistent Stress                                  63.9                                      75.0

Genetic/Hereditary                               45.7                                      23.1 *

Toxic exposure                                     43.8                                      53.9

Allergies                                               37.6                                      32.1

Emotional trauma                                 34.1                                      57.1

Physical trauma                                    28.4                                      18.5

Diet                                                      22.5                                       50.0**

Vaccination/Immunizatio                    18.1                                       10.7

Pregnancy                                               9.3                                        3.7

Birth control pills/estrogen                    8.5                                        7.4

          supplements

**p<.OOl  *p<.O5

 

The coping style did not significantly differ between long-term and short-term groups.

However, when we did an analysis based on a median split of duration ( < three years vs. > three years) in the short-term group, an analysis of symptom and coping scores showed a trend toward higher scores on the maintaining activity scale of the Illness Management Questionnaire in the less-than-three year duration subgroup.

This subgroup also showed a trend toward higher fatigue severity, higher depression and higher stress symptom scores, compared to the over-three year duration group. The combination of higher activity and higher symptom levels suggest a denial of illness may be a coping strategy used by the more recently ill. The other coping extreme, high levels of symptom preoccupation, was not seen in this group. Thus, some cognitive behaviorial therapy might help the more recently ill who use a denial strategy rather than the long-term ME/CFS patient.

Conclusion

The above is only the very outline of our results. It should be borne in mind that since we asked 589 complex questions, only the least cognitively affected and the most determined were able to complete the survey. So, our results apply to the least ill long-term patients. We hope that our study will interest a fully-funded researcher to do a more complete study of long-term ME/CFS patients—the lost and forgotten in the jungle of research.

 

Acknowledgements

We thank:

• all the hundreds of people who participated in the study

• all the impoverished ME/CFS patients who sent their nickels, dimes and more as support to the CAA who gave us a grant which was actually funded by the Massachusetts CFIDS Association and who advertised for us

• Fitchburg State College

• the librarians of Fitchburg State College

• Chancey Currie, a short-term patient in her 80 's who sent a generous contribution

• the physicians who advertised our study to patients

• Dmitri Sarvhin, who helped me with the illness progression graph analysis

• Tamera Schneider, who did much of the statistical analysis

• Laura Plourde, who input all the mountains of data

This study was truly an endeavor of the whole ME/CFS community.

All of us owe a sincere vote of thanks to Maggie McKenzie and Robert Fontanetta who not only had the vision to conceive of the study, but the unflagging optimism that it could be carried out by four long­-term patients without any initial funding.

 

Reference

1. Friedberg, Dechene, McKenzie and Fontana, "Symptom patterns in long-duration chronic fatigue syndrome," J Psychosomatic Res 48 (2000): 59-68.