Kerry Szymanski, 36, remembers early 1993 as "a very exciting time."

Szymanski, who lives in Tucson, Ariz., and has Becker muscular dystrophy (related to Duchenne dystrophy, but less severe), says he can remember "almost every day waking up and feeling just a little bit better." He had been using a wheelchair or motorized scooter but, in late 1992, he started walking, at first just around the house and then at the mall.

"I finally bought a walker," he recalls, "and I started walking. I went from a sixth of a mile to in excess of three-quarters of a mile over the course of the next year. I just kept getting stronger and stronger, and the next thing I knew I wasn't using my walker or scooter at all."

But by late 1993, things had begun to level off. "From that time forward, the disease has become, I would say, pretty active again," Szymanski says, "and it is slowly nibbling away at my strength."

Szymanski has been taking prednisone (brand names Deltasone, Orasone), a corticosteroid, and has also tried its close cousin, deflazacort (Calcort), which is generally not available in the United States. Szymanski got his deflazacort from Mexico. He's back on prednisone now, which is much cheaper and easier to get, but he hasn't seen any dramatic effects in the last few years.

"I wouldn't say that it has worn off," he says. "I would say that the drug's still useful, but it does not cause the deterioration to stop. It does seem to me that for a period of at least the first two years, the disease ceased to progress and I got stronger. There's no doubt about that. The physical therapist's notes bear that out. But that appears to be of a limited duration and, at some point, the drug reaches its maximum benefit and the disease continues to progress."

Szymanski also developed an ulcer that he and his doctor attribute to the drug.

CHANGING NATURAL HISTORY

Dr. Richard Moxley, an MDA-funded researcher at the University of Rochester Medical Center in upstate New York, is a strong advocate of catabolic corticosteroids (very different from anabolic steroids, the kind athletes sometimes take) for children with the more severe Duchenne dystrophy.

His point of view is based on the results of more than a dozen clinical trials involving prednisone or deflazacort in this disease that have been conducted at major medical centers since 1974.

"We're not talking about a gigantic increase in strength," Moxley says, referring to a study of 103 boys with Duchenne dystrophy that was published in the New England Journal of Medicine in 1989. "We saw a small increase in strength averaged over 34 different muscles. But that's a radical departure from the natural history of the illness."

More recent studies, including one to be published later this year, found similar results and refined the dosage of prednisone and deflazacort.

"The way I explain it to parents is, you seem to be buying two to four years of function," says Dr. John Kissel, co-director of the MDA clinic at Ohio State University Hospital in Columbus. "After six months, boys on prednisone begin to lose function. Two to four years later, they're back where they were when they started the drug. Of course, they're stronger at this point than they would have been without it."

Many physicians now advocate the use of corticosteroids in Duchenne and Becker, and occasionally have tried them in other muscular dystrophies. A recent small trial of prednisone in facioscapulohumeral muscular dystrophy didn't show any benefit.

SIDE EFFECTS

Catabolic corticosteroids, available since the 1950s and used for a large number of conditions, have serious side effects when taken for long periods.

Some of these side effects, long known to physicians, include significant weight gain; fluid retention; high blood pressure; cataracts; ulcers; destruction of bone (osteoporosis), skin (with severe stretch marks, especially over the areas where weight is gained) and muscle; slowing or complete arrest of growth in children and adolescents; delaying of puberty in adolescents; and mental and emotional effects. They suppress the immune system and raise blood sugar.

Almost all patients who take corticosteroids for more than a few weeks develop rounded faces, and many develop fat deposits between the shoulder blades that doctors refer to as a "buffalo hump."

Not all muscular dystrophy patients see dramatic improvements with corticosteroids, and some are upset about side effects. Mark Sias, 21, also lives in Tucson, where MDA medical consultant and clinic director Lawrence Stern prefers to use steroids in adults because he finds the side effects less severe than in children. Stern has tried steroids in several patients with Becker, such as Sias.

Sias, who can still walk, started taking prednisone when he was 18, hoping to improve or stabilize his deteriorating heart function. But the hoped-for improvement was temporary, the side effects severe. Within three months of starting prednisone, Sias' weight went from 145 to 180 pounds. He also developed red stretch marks on his stomach, thighs, arms and the insides of his knees. He's now trying to get off steroids, which must be tapered gradually to compensate for the loss of adrenal gland function that accompanies their use.

"I think this is important for people to know," Sias says. "The anger is quite a bit to deal with."

DOCTOR-CAUSED DISEASE?

"I've had very limited luck with steroids," says Dr. John Sladky, who treats patients in the MDA clinic at Emory University in Atlanta and formerly headed the MDA clinic at Children's Hospital of Philadelphia for 10 years.

At first, Sladky offered them to all his Duchenne patients. "I found there were probably two or three families who liked what happened," he says. "What generally happened is that the kids gained 25 percent of their body weight, and the improvement they got in terms of strength was offset by the extra body mass that they had to move around. The problem with steroids and Duchenne is, how long do you treat them? I don't like using a medication where the only end point is you go until you give them an iatrogenic [doctor-caused] disease."

Sladky says, "I think you can do an experiment in an individual kid. Put him on steroids for a month or two. If at that point the kid and the parents feel the improvement justifies the potential risks, you can monitor the risks. But by and large I think there's a very limited role for steroids."

Dr. Irwin Siegel, an orthopedic surgeon and rehabilitation specialist, directs the MDA clinic at Rush-Presbyterian-St. Luke's Medical Center in Chicago. He's also cautious about corticosteroids in Duchenne and Becker. "I have seen cases where patients were on steroids where they showed a course which was certainly not as rapidly deteriorating as those who weren't on steroids," Siegel says.

"But you have to accept this with a grain of salt, because this is a disease in which there is variable expression. I've had cases who weren't on steroids who did quite as well as some of the cases who were. And then we have to consider all the complications.

"I have seen two or three compression fractures of the vertebrae, secondary to steroid use. Now this never happens in the ordinary patients, because bone metabolism is not affected in Duchenne dystrophy, and they don't seem to get too much osteoporosis, at least not enough to cause compression fractures," he adds.

"One of the big problems we've had is that when steroids don't work, and I've seen them not work, then you have to get the patient off them. It's hard getting these patients off the steroids. It's a little tricky."

Kissel says he's also very concerned about side effects and has seen patients gain weight and lose bone. But, he says, "Based on the best data that we have, steroids can add about four years of walking."

He offers corticosteroids to parents and patients when a child with Duchenne begins to fall frequently, usually between ages 8 and 10. "I don't do it as a matter of routine," he says. "I offer it when I think the cost-benefit ratio is going to be very beneficial."

Kissel quotes a study published earlier this year that followed up on 129 boys with Duchenne who started on prednisone between 1986 and 1989. In 1995, 74 of them were still on the drug, with unacceptable weight gain the most common reason for reducing or discontinuing it.

"If you do the math," Kissel says, "it's about 57 percent of the patients who remained on the drug. The reason I bring that up is because parents often say to me, 'What about the weight gain?' To which I say, 'Most of the parents of the boys think the benefits outweigh the side effects and so elect to keep the boys on prednisone.'"

SATISFIED FAMILIES

Despite warnings of side effects and predictions of time-limited benefits, many families have opted for corticosteroids. For some patients, prednisone or deflazacort seem to have staved off the usual, inexorable muscle deterioration that takes place in boys with Duchenne, while side effects have been minimal. In any case, right now these drugs are the only game in town. They offer hope and promise, along with possible maintenance of strength.

Daniel Masterson is 15 and lives in West Seneca, N.Y. He has Duchenne and has been on prednisone for nine years. "It has worked real well," says his mother, Kathy. "Many of the boys really experienced a lot of weakening, and he really hasn't had that." Daniel recently finished ninth grade, taking regular classes, including gym. He's having trouble with stairs but is otherwise getting around fairly well. He's 6 feet tall and weighs 155 pounds.

Prednisone, Kathy says, hasn't interfered with her son's growth or development at all. "We were just down for a clinic visit last month. Everything looks real good. The heart looks good."

To outsiders, the strengthening effects of prednisone can seem like small victories. But, for some families, even these can be significant.

"I don't know where the disease is going to," says Darlene Simon of DeWitt, Mich., whose 17-year-old son, Doug, is on deflazacort for Duchenne. "All I know is I'm happy where we are, because before it was so hard to think positive when it was going in the other direction."

Doug was in a recent study of prednisone and deflazacort at Ohio State University in Columbus. He's been able to continue taking deflazacort that was left over from the study.

"I feel it's halted," Darlene says of her son's disease. "I think right now I don't see it going the other way at all." But the actual gains seem small. "I can tell I'm a little bit stronger," Doug says, referring to his ability to lift his arms up onto the dinner table and to move a little more in bed.

On the down side, he says he's gained about 20 pounds in the little more than two years since he's been taking deflazacort. He doesn't know whether his growth rate is affected, but he's 5- foot-2 and shorter than his parents.

Parents' perceptions of how their children are doing on steroids may differ from those of the teen-agers taking the drugs.

"From what I've seen of other kids, I kind of like it," says the mother of a 16-year-old with Duchenne who's been on prednisone for 10 years. "He has never lost any lung capacity or strength in his upper body." She says he has had no joint contractures. "He has shown none whatsoever."

The teen-ager mentions two bones he's broken, but his mother says he doesn't have osteoporosis. "Many Duchenne boys break their knees in the type of fall he had," she says.

When the boy is asked about mood-related effects of steroids, he expresses some concern. But his mother hastily adds, "I don't think so. I work with middle school kids all the time. I never experience him to have anything any different."

RATIONAL PEOPLE ON BOTH SIDES

Dr. Moxley says he hasn't seen severe side effects in his patients, even those who've been on steroids for years. Weight gain, slowing of growth, delay of puberty and mood changes have been the main problems, and Moxley says those can be tolerated or managed.

"Despite our anxiety that we would see more fractures, we're not seeing it," he says. "We are not seeing the kinds of fractures that we saw before [prednisone use], and I have the impression that it may be the fact that prednisone allows the patient to be active for a longer period of time, and maybe that's the reason that we're not seeing the problems we were worried about with bone metabolism." (Activity helps ward off osteoporosis.)

Moxley manages the weight gain with a calorie-restricted diet and thinks the growth retardation is a reasonable trade-off for the benefits of steroids.

"If you ask me how I feel about combining the side effects of decreased growth versus prolonged and increased maintenance of strength, it's not an issue, because of the severity of what happens in the absence of prednisone," Moxley says. "So I've actually found it easier to reconcile giving prednisone over a long period of time in these children than not doing it, simply because I have felt that a lot of the pioneering efforts in gene therapy and other kinds of treatment options that all of us are hopeful about are still in the future. By that I don't mean next year.

"Because of that, I've felt like it's important that I do the most I can for patients to maintain their level of function and their quality of life as high as possible for as long as possible. I think that's what prednisone has offered."

Moxley, who puts nearly all his Duchenne patients on prednisone at age 5, says there's a lot of scientific evidence to support his opinions.

"After this initial paper in the New England Journal that I've alluded to, some other papers were published," he says. "These papers included a study in which we compared the effects of 0.3 milligrams per kilogram (2.2 pounds) per day of prednisone to 0.75 milligrams per kilogram per day. What was apparent is that if you give a patient 0.3 milligrams per kilogram per day, it still has a beneficial effect. It's just not as pronounced as that with 0.75 milligrams per kilogram per day. So, yes, you have somewhat lesser side effects at that lower dose, but you just don't maximize the benefit."

Dr. Gerald Fenichel, MDA clinic director at Vanderbilt University Medical Center in Nashville, Tenn., is a little less certain.

"Steroids are not for everybody," he says. "But if you tell somebody ahead of time to get onto a low-fat diet and tell them about what the problems are... I've got patients who've been on it for 10, 15 years. I tell them the pros and cons. If they say, 'What do you think I should do, Doctor?' I say, 'I think you should give it a try. If you don't like it, we can always stop it."

Fenichel says, "The future of corticosteroids is not just the use of corticosteroids; that's not going to get us any further than we are right now. But, if we could find other drugs to use with them, working at other sites, then we might get even more improvement and a more sustained improvement."

WEIGHING THE TRADE-OFFS

Moxley remains a steroid advocate. He often tells a story about a teen-ager with Duchenne who attended his eighth-grade dance and felt out of his element because the steroids had stopped his growth, leaving him much shorter than his friends.

"Let me remind you," Moxley says, "that that was not an issue before prednisone. He wouldn't have been going to the eighth- grade dance. He wouldn't have been able to. He would have been in a wheelchair. There would have been other complications."

But not all patients would agree with the doctor's statements or the negative connotations of the wheelchair.

"Sometimes, to be honest with you, I want to just go ahead and get in the wheelchair and accept it," says Kerry Szymanski. "You can enjoy a lot of things more than you do otherwise. That's hard to understand, but it's true. For what it's worth, after 36 years of living, that's the conclusion I've come to. Sometimes I think it would be nice if someone else just came out and said that, because it's a hard realization to come to by yourself. It's wonderful to have hope, which MDA provides, but investing so heavily emotionally in that comes at a price, too."

(People with Becker may have an easier time accepting their slowly progressive disease than those with Duchenne, in which progression is more rapid and usually ends life by age 30.)

Dr. Sladky worries that parents are being pressured to put children with Duchenne on prednisone.

"We've created a myth that kids have to be on prednisone," he says, "and the families believe that if they don't put their kids on prednisone, they're depriving them of an important treatment. I think if you look at the data, yes, kids are stronger on prednisone and their strength improves for a period of time. And then they begin to deteriorate."

He says families need to know that there are "rational people on both sides of the issue. Parents need to make a rational decision. They don't need to feel guilty about not offering the kids steroids. These families have enough problems with guilt already."

Dr. Siegel also likes to keep a balance on the steroid issue, and wants parents and patients to do the same.

"I'm not against steroids," he says. "We have patients in our clinics who are on steroids, but not all our patients are. We feel it's only fair, when we have nothing else to offer in the way of medication, to offer steroids to parents at the intake visit or shortly thereafter and at least to let them know that it's available. We talk to them about pros and cons. We try not to bias them. We put them in touch with people who have kids on steroids and some who don't. We introduce them to the literature. We let them make the decision."

Siegel fights the popular notion that doing something is always better than doing nothing.

"That's not true," he says emphatically. "Sometimes it's better to say, Don't just do something, sit there!"

BETTER DRUGS AHEAD?

Corticosteroids like prednisone and its many relatives are synthetic drugs based on the natural substance cortisol, made by the cortex (outer layer) of the adrenal glands, which sit on top of the kidneys. Another name for these agents is glucocorticoids, because one of their jobs is to help regulate glucose. (The adrenal cortex also makes some other steroids - mineralocorticoids, and a small amount of anabolic steroids, or androgens. The testes make most of the anabolic steroids in males.)

Emergency Response

Cortisol has many actions, finely tuned to the body's moment-to- moment, overall needs. It's released in tiny amounts each day and increased at times of stress. Under these conditions, cortisol moves sources of energy from "expendable" tissues, like muscle and bone, to "non-expendable" tissues, like the brain and heart, to meet an emergency. The expendable tissues are broken down, and glucose, or sugar, is released into the blood. Parts of the immune system are turned off, possibly to divert energy for more immediate needs or to protect the body from an overzealous immune response.

When cortisol-like drugs are given for long periods, growth stops, which may also be related to this overall energy-shifting response. People gain weight, especially in the trunk and face, which is probably caused by the combined effects of high blood sugar along with the actions of insulin and the cortisol-like substances. Bone and muscle deteriorate, and inflammation and other immunologic responses are slowed.

How Do Corticosteroids Help?

Last year, scientists figured out what may be the most important way that corticosteroids block inflammatory and immune responses. They do so by increasing production of a chemical called I kappa B alpha, which in turn locks up another chemical, NF kappa B, a major activator of inflammation and other immunologic responses. In autoimmune and inflammatory conditions, this action of steroids is highly desirable.

The discovery is of more than academic interest. If drugs could be developed that block NF kappa B without doing all the undesirable things that steroids do, millions of people would be saved from the perils of steroids and still reap their benefits.

But there's a lot of debate about whether these effects are of any benefit in muscular dystrophy. When a recent trial of azathioprine (Imuran), another potent immunosuppressant, failed to influence the course of Duchenne dystrophy, doctors concluded that immunosuppression may not be the way steroids work in this disease. Another possibility is that patients with Duchenne need the particular kind of anti-inflammatory or immunosuppressive action of corticosteroids.

There's some evidence that glucocorticoids may slow the breakdown of muscle in Duchenne, but, since these substances usually have opposite effects on muscle, these experiments are confusing. Other evidence suggests that corticosteroids help keep cell membranes from breaking down.

A present focus of MDA research is to determine how steroids help in muscular dystrophy, with the hope of finding other drugs that do more good and less harm.

Deflazacort

Deflazacort is a cortisol-like steroid that seems to do what prednisone does with fewer undesirable effects, particularly with regard to weight gain and bone loss. By the early 1990s, after intriguing findings with prednisone, doctors were interested in trying deflazacort in Duchenne.

Marion Merrell Dow of Kansas City, Mo., and Nordic Merrell Dow, its Canadian branch, were at that time interested in marketing deflazacort in North America and supplied the drug to several medical research centers in the United States and Canada (including the University of Rochester, Ohio State and Vanderbilt) for a study. Unfortunately, after the first year of the study, the company lost interest in marketing deflazacort in North America and withdrew its support of the study, except for continuing to supply the drug.

Rochester and the other centers banded together under the leadership of Dr. Fenichel in Nashville and Dr. Michael Brooke at the University of Alberta in Canada, and finished the study without the drug company. Final results of the 18-month study have yet to be analyzed, but, at the end of 12 months, deflazacort had equal benefit to prednisone in maintaining strength, and caused less weight gain.

Julie O'Dell, company spokesperson for what is now Hoechst Marion Roussel of Kansas City and Frankfurt, Germany, says the company had to abandon deflazacort because it couldn't afford to do what the Food and Drug Administration required of it to prove effectiveness and safety.

Deflazacort is available in Italy, Spain, Germany and Mexico. The drug isn't approved in Canada, but the Canadian Health Protection Branch, the equivalent of the FDA, allows doctors to prescribe it if they apply for permission. Hoechst Marion Roussel then supplies the drug to the doctor, in return for which the doctor submits reports to them about its effects. Canadian doctors can see U.S. patients and prescribe deflazacort.

Some U.S. physicians are willing to monitor patients who have obtained deflazacort from other countries, but they may be putting themselves in legal jeopardy. Lawyers at Ohio State University Medical Center recently warned Dr. Kissel that he had "no leg to stand on" if someone reported a problem with deflazacort. Doctors can monitor patients who've been on deflazacort following a clinical trial and are still taking drug left over from the trial, but time is running out for this group.

Dr. Fenichel has contacted the FDA to see whether deflazacort might be approved for use in muscular dystrophy under the agency's Orphan Drug program.