Digging for clues to fatigue.

Digging for Clues to Fatigue

Dr. Lauren Krupp is onto a provocative thesis shared by other scientists working in her field: that there is some immune or neuroendocrine abnormality in people with multiple sclerosis that explains the overwhelming fatigue that afflicts 80% to 90% of them.

The Society grantee, who is assistant professor of neurology at the State University of New York at Stony Brook, hopes ultimately to find biochemical changes in the blood or an alteration in the immune response that she can match up with a patient's degree of fatigue.

What is so special about MS fatigue? Dr. Krupp defines it as "a sense of tiredness, a lack of energy, really a total body give-out. It's not weakness; instead, it's a generalized low-energy feeling. The fatigue is not related to depression. Almost all patients find their fatigue gets much worse on a hot and humid day; and many people say the fatigue makes other MS symptoms worse. So it's a really special problem, and one I want to address."

Dr. Krupp became interested in fatigue during a neurology residency at Albert Einstein College of Medicine in the Bronx; later, doing immunology research at the National Institutes of Health, she continued to study fatigue. Now at Stony Brook, she is seeing a variety of patients with fatigue problems. She recently completed a study, with Dr. Nicholas LaRocca of Einstein and Dr. Alfred Steinberg and Joanne Muir-Nash of NIH, comparing the fatigue of MS with that of patients with systemic lupus erythematosis and with healthy people. She reports in the October Archives of Neurology that fatigue had a more harmful impact on daily living for MS and lupus patients than for the controls.

In looking for an immune abnormality, Dr. Krupp is working with Stony Brook's Patricia Coyle on cytokine levels and immune complexes in serum and spinal fluid samples to see if they correlate with MS fatigue. "These things can be easily quantified," she explains. "But we have to come up with a way of quantifying the symptom of fatigue. Until we have that part of the equation, we can't relate it to the laboratory studies."

The first thing she did was to interview patients at the MS clinic at Einstein, asking them many questions about their fatigue. She did the same for a group of healthy people of the same age and sex, since 50% of healthy people also complain of occasional fatigue. She found that 87% of the MS patients said they were bothered by fatigue. Among both groups fatigue seemed to result in loss of patience and lowering of motivation. Some things that help healthy people--resting, sleeping, positive experiences--work well for MS patients, too. Some things that worsen fatigue--stress, physical activity, late afternoon doldrums--have the same effect on both groups. The small proportion of MS patients who don't suffer from fatigue seemed to respond to Dr. Krupp's questions in the same way healthy people did.

The sharply distinguishing feature was the impact that fatigue had on activities of daily living. "With healthy people, fatigue does not interfere with social, family or professional responsibilities," the clinician commented. "In contrast, 67% of MS patients said that fatigue alone prevented them from meeting their responsibilities. Some 89% said that fatigue alone prevented sustained physical activities."

Some doctors unfamiliar with MS tend to ascribe patients' fatigue to depression, Dr. Krupp says. But she found otherwise. "We looked at the question in a statistical way, trying to see how well fatigue matched depression. That is, if somebody was very depressed, was that a good indicator of fatigue? Or if someone was not depressed at all, would that mean there was no fatigue?" It turns out neither one correlates strongly with the other: fatigue bears no relationship to depression.

Most recently, the Stony Brook neurologist has been developing questionnaires to elicit a more quantitative, reliable measure of fatigue. She has also devised a diary in which patients rate the intensity of their fatigue on an hourly basis.

The diary figured prominently in a small clinical trial recently reported by Dr. Krupp before the American Neurological Association in New Orleans. In the study she gave five MS patients a daily dose of a nervous system stimulant called pemoline (Cylert), while a control group of MS patients was given no drug. All patients kept a diary of fatigue intensity for three weeks.

The results of the pilot study were promising, says Dr. Krupp, though she emphasizes that it was very preliminary, very small, and not designed in "any rigorous way." Of the five treated people, three showed diary entries indicating their fatigue seemed to get much better. They also felt better. Two on pemoline didn't show much change. The five people who were not treated stayed the same, their fatigue was unchanged, and their diaries reflected that fact.

This fall Dr. Krupp is embarking on a major clinical trial with 180 MS patients whose severe fatigue is one of their three worst symptoms. All patients will be ambulatory and free from depression. The trial will be conducted by neurologists at various MS centers: Dr. Krupp at Stony Brook, Drs. Charles Smith and Labe Scheinberg at Einstein, Dr. Aaron Miller at Maimonides Hospital in Brooklyn, and Dr. Anne Cross at Holy Name Hospital in Teaneck, N.J. Patients will be given placebo, pemoline or amantadine, an antiviral drug previously found helpful in MS fatigue by Drs. T.J. Murray of Dalhousie University and Gary Rosenberg of the University of New Mexico.

Patients will be asked to complete questionnaires and diaries on their condition; they will also get thorough psychological, psychiatric and neurologic evaluations to determine whether fatigue is affecting their thinking processes. Dr. Krupp will have blood samples collected from the patients and sent to her for evaluation.

As the research doctor spells it out: "By using our latest analytical techniques and rigorous methodologies, we hope to get a handle on fatigue and ultimately to be able to develop a rational and effective approach to treating this major disabling MS symptom."