GOOD HEALTH MAGAZINE : Medicine : THE MYSTERIOUS MALAISE : All tests are normal, yet you’re totally exhausted. The doctor says it’s all in your head. Then you find that you have Chronic Fatigue Syndrome--and that no one knows quite how to treat it.

Nan Cooper’s first symptoms were bizarre. She was sitting in a restaurant, having dinner with friends, when she began to shiver. The restaurant wasn’t cold and she wasn’t feeling chilled. But she couldn’t stop shaking.

Cooper, an artist from Santa Cruz who now lives in Bethesda, Md., was mystified but not especially worried. It was January on the East Coast and she assumed she was coming down with a bad cold, or the flu.

As the days wore on, she was sure she was right. She had fever and aching joints. She couldn’t concentrate. And the fatigue was overwhelming. “It felt like a double case of the flu,” she says.

But that was in 1985--and the condition still hasn’t gone away.

“I’d go to my night art classes and when everyone else was taking a break, I’d go out in the hall and lie down,” she says. “If there wasn’t a bench or a chair available, I’d just lie down on the floor.”

Cooper went to numerous physicians and complained: “I am dying of exhaustion.” And they wrote prescriptions for tranquilizers.

“I was a graduate student then and they probably thought I was a little nervous and overworked doing my thesis, but I knew this wasn’t physical exhaustion from overwork or stress,” she says. “This was something else.”

In the fall of 1987, Cooper started a job with an accounting firm but wasn’t able to stay with it very long. She would arrive 30 minutes early “just so I could sit in the coffee shop and pant to recover from a three-block walk.” And even that didn’t help. “I couldn’t concentrate,” she says. “I would make mistakes, especially with numbers. I couldn’t even do the mail.”

It was three years from that eerie beginning in the restaurant before Cooper found a physician who could tell her what seemed to be wrong. By then, she was convinced she was losing her mind.

“I remember sitting in his office and writing on the family history sheet ‘I think I’m going nuts, so let’s just eliminate every other possibility,’ ” she says. “But after he looked at the list of symptoms I’d written, he said: ‘I can tell you that you aren’t going nuts.’ ”

Cooper was fortunate. She finally found a doctor who had seen numerous other cases of Chronic Fatigue Syndrome, or CFS. He recognized immediately what she had--although he did run numerous tests for other ailments, just to be sure.

Many people with this affliction--the majority of whom are women between the ages of 20 and 40--often suffer for long periods without knowing what is wrong with them. It is all the more frustrating when all their tests come back normal and they are told it’s all in their heads. Indeed, there is a segment of the medical community that believes that emotional disorders do play a role in CFS, although little research has been conducted in that arena.

“It was wonderful to finally have a label for what I had and to know I wasn’t going crazy,” Cooper says. “But the bad news was they couldn’t do a whole lot for it.”

Chronic Fatigue Syndrome is a complex and mysterious disease that has stymied researchers and clinicians across the country in recent years because there is no solid scientific evidence as to what causes it, and no one really knows the best way to treat it.

Theories abound as to its cause, but none has been proved. For a long time, scientists focused on Epstein-Barr virus--a member of the herpes family of viruses and the one that causes mononucleosis. Indeed, the syndrome is frequently referred to as “EBV,” but most have since dismissed the Epstein-Barr virus as the primary villain. Researchers speculate that the cause is much more complicated--perhaps an initial infection that triggers an immune system irregularity; or independently, an imbalance in the secretion of brain chemicals.

This fatigue is not the kind of tiredness that most people experience when they are overworked, or when a new baby has kept them awake for weeks at a time.

“That tiredness goes away when you finally get some sleep. This exhaustion lingers and it’s out of proportion to what you feel based on what you’ve been doing,” says Dr. Robert T. Schooley, professor of medicine and head of the infectious-disease division of the University of Colorado Health Sciences Center. “Having this disease is like coming down with the flu and never getting over it.”

Dr. Edwin Jacobson, a Los Angeles internist affiliated with UCLA, who has seen hundreds of cases of CFS, agrees.

“There is a big difference between tired and this kind of fatigue. This fatigue is an oppressive sensation, like a weight.”

For Sondra Brown, a mother of two and a visiting nurse from the Boston suburb of Newton Highlands, it started with a headache six years ago. “I got a totally encompassing headache from the back of my head to the front that persisted for five days.” Brown felt well for a month--and then it started all over again, this time with additional symptoms: cold spots around the body, numbness and tingling and joint pain.

“Then I started to notice something really strange,” Brown says. “When I was driving, the car often seemed to be still moving when I stopped at a traffic light. It was scary, and I compensated like crazy when I was behind the wheel. I would go really slowly and brake a lot. If I was very tired, I would pull over and nap for 10 minutes.”

At first doctors thought Brown had an inner- or middle-ear infection. A neurologist ruled out multiple sclerosis and a brain tumor. He told her she was probably working too hard. But she knew better.

As a nurse, she had access to professional medical literature and one day she found a reference to chronic fatigue. All of her symptoms were right there.

For Toni McKinney, a Denver secretary with three young children, the onset of CFS began when she woke up one morning six years ago and couldn’t move. Her skin felt hot. She had trouble breathing.

And the fatigue. “I’ve never experienced anything like it before,” she says. “I felt so bad that putting on my socks was a major effort.”

Like Cooper, she went through an infuriating cycle of visits to doctors before one of them finally identified the problem.

Chronic Fatigue Syndrome is characterized by a group of related symptoms that include powerful fatigue, headache, sore throat, fever, weakness, pain in the joints, muscles and lymph nodes, memory loss and an inability to concentrate. It is not a progressive disease: Symptoms hit a plateau early in the illness and recur with varying degrees of severity for at least six months. CFS varies with the individual. In many people, it can persist for years; in others, it can vanish as spontaneously as it began.

It is not a new so-called “Yuppie Plague,” a description that became popular because many who complained of it in the early 1980s were well-educated, affluent women in their 30s and 40s. Although CFS does predominantly afflict white women, it has also been seen in small children, in the elderly, in men and in people of all races and classes.

No one knows how widespread CFS is in this country. Many physicians are not familiar enough with the disease to always recognize it. As a result, it is often misdiagnosed or under-diagnosed. One national CFS support group lists 7,000 members and describes itself as “the tip of the iceberg.” Earlier this year, the federal Centers for Disease Control in Atlanta initiated a surveillance system to gather data to determine how widespread the syndrome is in this country. CDC officials say that preliminary information may be available by year’s end.

Because the symptoms often resemble those of other ailments, and because routine tests cannot positively confirm the presence of physical disease, “these patients are likely to suffer rejection by physicians, emotional stress, problems with family and friends and conflict socially and at work,” says Dr. Gary Holmes, a CDC medical epidemiologist.

Indeed McKinney felt terribly embarrassed when she had to ask her mother to help take care of her children. “I was afraid people would start to think I was lazy,” she says. And she had to endure the continuing skepticism of other loved ones. “My dad used to say, ‘Honey, if you wanted to feel better, you would.’ ”

CFS “is a controversial subject,” Holmes says. “There is a sizeable percentage of physicians who believe it is nothing more than a psychiatric disease. And the problem is that there really isn’t sufficient evidence to totally refute that yet. There is plenty of room for argument.”

Dr. Thomas C. Merigan, professor of medicine and an infectious-diseases specialist at Stanford University, believes that too little research is being conducted into the psychological aspects of CFS.

Merigan himself is not involved in any CFS studies; thus “all I can do is speculate,” he says. Nevertheless, “there are two schools of thought. One is that there is some unknown virus or infectious-disease pathogen triggering the disease for prolonged periods. The alternative is that there is a psychosomatic component and that people are searching for a disease to explain what is primarily a psychological state.

“I don’t know which is the more important possibility. But we’ve got to pay attention to that second thing. We need to study both.”

But medical experts familiar with the disease insist it is real. “The fact that I can’t tell someone why she is tired doesn’t mean she isn’t,” Schooley says.

Researchers continue scrambling to unravel CFS’s cause.

As noted, the culprit first thought to be responsible was the Epstein-Barr virus. But studies have been inconclusive. Some research has demonstrated that CFS patients have elevated levels of antibodies to fight EBV in their blood. But it is unclear whether that is meaningful; in the United States, an estimated 80% to 90% of adults have been exposed to EBV by the time they are 40 and will have antibodies when tested.

Further, a study conducted by the federal government’s National Institute of Allergy and Infectious Diseases showed that CFS patients treated with the antiviral drug acyclovir, a treatment for herpes, did not improve, suggesting that EBV was not a primary cause of CFS.

“However, Epstein-Barr as well as other viruses may still act to trigger the illness,” says Dr. Stephen E. Straus, chief of NIAID’s medical-virology section. Indeed, a study reported last month linked CFS to a rectrovirus similar to those involved in some forms of leukemia and AIDS.

Most researchers have moved away from the EBV and have begun concentrating on certain body systems as playing a major role.

Jacobson, for example, has been studying the impact of antidepressant drugs in treating the disease and has seen some encouraging results from a pilot study of 45 patients who were given the antidepressant Sinequan (or the generic doxepin). The test produced “a striking improvement” in the condition of many of the patients, compared to their condition before taking the drug.

“Eighty-seven percent of them improved and no longer fell into the CDC definition of Chronic Fatigue Syndrome,” Jacobson says. “Of that 87%, about 70% rated themselves as being at normal function.”

In about 10 or 15 patients, Jacobson says, “we stopped the drug after six months, and so far, eight continue to be asymptomatic off the medication.”

Now Jacobson is conducting a larger study of about 140 CFS patients in Los Angeles to determine whether certain antidepressants--in doses smaller than those used to combat depression--in combination with antihistamines are effective in alleviating the symptoms of the disease. In the larger trial, half of the patients are receiving the drug while the rest are taking a medically worthless placebo.

Jacobson hopes that the larger study, scheduled to last a year, will confirm the results of the pilot study and perhaps offer new hope to those suffering from CFS. He also wants to be certain that the improvements seen in the earlier study were not the result of spontaneous remission.

Jacobson believes that there are probably several factors acting in combination that cause the disease. He is convinced that CFS involves an overstimulation of the immune system, since many of the symptoms are known to result from an immune system that is responding to an invading organism. Also, a large majority of CFS patients have allergies, which are known to be immune-system malfunctions. Jacobson also believes that the disease has a relationship to the secretion of neurotrans- mitters, or brain chemicals--specifically, noradrenalin and serotonin, neurotransmitters implicated in depression--and the only known targets of the drugs he is testing.

Jacobson suspects that there is a stimulation of the immune system in response to an initial event, probably an infection that occurs at a time of high stress. At the same time, he says, there is probably “some type of imbalance with one or more of these neurotransmitters,” which move information between the brain and the rest of the body, “probably including the immune system.”

Jacobson finds it fascinating--albeit ironic--that the majority of his patients do not otherwise experience colds or other kinds of illnesses caused by viruses or bacteria; he speculates that is related to the immune system’s ongoing overreaction.

Fatigue, malaise, muscle aches and other symptoms that accompany many illnesses--and that characterize CFS--are the result of the immune system’s attacking the invader with two chemicals, interferon and interleukin, Jacobson says. He believes that in CFS patients, however, the immune system simply doesn’t know when to stop.

“I believe they are so overstimulated that another virus can’t live in their systems, that the transmitters are getting a false message that there’s something to attack when there’s nothing to attack.”

Jacobson is not alone in thinking that the underlying cause of CFS is an abnormality in the immune system. Numerous researchers are focusing on that theory.

“It could be that in a vulnerable person, the immune system reacts in a funny way when set off by an infectious agent,” says Dr. Anthony Komaroff, chief of the division of general medicine and primary care at Brigham and Women’s Hospital in Boston. “I don’t believe that only one infectious agent causes this condition. I think many do. But there is one thing they all have in common: They are able to live within the body for long periods of time--even for a lifetime--without the body being able to completely wipe them out.

“That doesn’t mean you can’t control the symptoms, but it does suggest that whatever triggers them is always present.”

NIAID’s Straus and Dr. Mark A. Demitrack at the National Institute of Mental Health, and their colleagues, are trying to determine whether CFS is related to the neuroendocrine system. In an as yet unpublished study, they injected a group of CFS patients and a group of healthy controls with corticotropin-releasing hormone, a naturally occurring brain hormone involved in regulating the hypothalamic-pituitary-adrenal (HPA) axis, to observe hormonal responses. In preliminary results, patients with CFS appeared to show a mild but statistically significant decrease in the functional activity of the HPA axis, indicating CFS may be related to that body system. In healthy individuals, the hormone typically would accelerate HPA activity.

Some researchers have also investigated the role that mental disorders and emotional stress play in the onset of the condition. A University of Washington study released in July found a “strikingly higher rate of lifetime and current major depression” among CFS sufferers than among non-sufferers. And Straus and Dr. Markus Kruesi, of NIMH, conducted a study that indicated that psychiatric illness may predispose some patients to CFS.

Says Kruesi: “Looking at the data, you see that people were more likely to have had psychiatric difficulties before they developed CFS than to have had CFS and then later develop psychiatric problems.”

But Straus and Kruesi emphasize that the findings do not suggest that CFS is a purely psychiatric disorder, only that mental illness may make some people more vulnerable. Many are more likely to experience depression as a result of their disease.

There is no evidence that CFS is contagious; no one is known to have caught it from family members, co-workers or others in close proximity. But there is also no way to prevent it and no way to know how long it will last. Most medical experts recommend a balanced diet, adequate rest, and moderate exercise to maintain muscle tone that might otherwise be lost because of a decrease in activity brought on by the disease. And, most important, they urge pacing.

Nan Cooper knows about pacing.

Since Cooper’s symptoms began nearly six years ago, “it’s been up and down and up and down. Since I’ve been resting all the time, I feel much better. But there are days when I’m fuzzy and so confused and so tired that I don’t do anything. There’s still a part of me that keeps hoping it’s just going to go away.”

CHRONIC FATIGUE SYNDROME: A SYMPTOM CHECKLIST

The symptoms of Chronic Fatigue Syndrome vary widely among people who have been diagnosed as having the ailment. A typical CFS patient, however, will have at least 11 of the following 17 symptoms. The percentage of CFS sufferers with each symptom is set in parenthesis.

Check if symptom is present.

* 1. Fatigue--usually made worse by physical exercise (95%).

* 2. Cognitive function problems (80%).

(a) attention-deficit disorder

(b) calculation difficulties

(c) memory disturbance

(d) spatial disorientation

(e) frequently saying the wrong word

* 3. Psychological problems (80%).

(a) depression

(b) anxiety--which may include panic attacks

(c) personality changes--usually a worsening of a previous mild tendency

(d) emotional liability (mood swings)

(e) psychosis (1%)

* 4. Other nervous-system problems (75%).

(a) sleep disturbance

(b) headaches

(c) changes in visual acuity

(d) seizures

(e) numb or tingling feelings

(f) dysequilibrium

(g) lightheadedness--feeling “spaced out”

(h) frequent unusual nightmares

(i) difficulty moving your tongue to speak

(j) ringing in the ears

(k) paralysis

(l) severe muscular weakness

(m) blackouts

(n) intolerance of bright lights

(o) intolerance of alcohol

(p) alteration of taste, smell, hearing

* 5. Recurrent flu-like illnesses (75%)--often with chronic sore throat.

* 6. Painful lymph nodes--especially on sides of the neck and under the arms (60%).

* 7. Severe nasal and other allergies--often worsening of previous mild problem (40%).

* 8. Weight change--usually gain (70%).

* 9. Muscle and joint aches with tender “trigger points” or fibromyalgia (65%).

* 10. Abdominal pain, diarrhea, nausea--”irritable bowel syndrome” (50%).

* 11. Low-grade fevers or feeling hot often (70%).

* 12. Night sweats (40%).

* 13. Heart palpitations (40%).

* 14. Severe premenstrual syndrome--PMS (70% of women).

* 15. Rash of herpes simplex or shingles (20%).

* 16. Uncomfortable or recurrent urination--pain in prostate (20%).

* 17. Other symptoms (seen in less than 10% of patients).

(a) rashes

(b) hair loss

(c) impotence

(d) chest pain

(e) dry eyes and mouth

(f) cough

(g) TMJ syndrome

(h) mitral valve prolapse

(i) frequent canker sores

(j) cold hands and feet

(k) serious rhythm disturbances of the heart

(l) carpal-tunnel syndrome

(m) pyriform-muscle syndrome causing sciatica

(n) thyroid inflammation

(o) various cancers (rare)

From the Chronic Fatigue Syndrome Institute, Beverly Hills. Some of statistics were compiled with the assistance of data provided by several researchers in this field.