October 25, 2014

   A Publication of the James Buchanan Brady
   Urological Institute Johns Hopkins Medical Institutions

Volume VI, Winter 2003

The Next Frontier in Surgery:
Preserving and Protecting the Nerves


“What happens with the FK506 solution is nerve regeneration —these nerves start to come back over time. They just start to reawaken, regrow, resprout, reconnect.”

Say you’re planning a grueling trip, an iron-man endurance trek through the tropics. Your goals are fairly simple: To make it out alive, of course—but more than that, to avoid illness, injury, and dehydration. Because your best hope for staying healthy is prevention, you do everything you can think of to prepare: Load up on vitamins, water, and electrolyte-boosters, pump iron to get your muscles in shape, and get yourself injected with a battery of disease-preventing shots. Now, as much as possible, you’ve evened the odds.

To the tiny, frail nerves involved in erection, radical prostatectomy is just such an endurance test. The first trick is simply surviving the surgery—which, for about seventy years, didn’t happen, because the surgeons performing the radical prostatectomy routinely cut right through these microscopic nerves, never realizing they existed. Then came the “nerve-sparing” procedure developed by Patrick Walsh, and the knowledge that if even one of the two bundles of nerves—one on either side of the prostate—that are responsible for erection can be preserved during the surgery, is still possible for a man to recover potency. Now, thanks to prostate cancer screening, more men are being diagnosed with early-stage, curable cancer—which means it’s increasingly common that both nerve bundles are preserved in surgery.

Burnett’s pioneering work in rats with nerve injury and erectile dysfunction has had such promising results— stronger erections, recovered earlier—that he and colleagues are patenting the technology, and the drug industry is very interested in developing it.


And yet, for reasons that no one yet understands, even when the radical prostatectomy is flawless and the scalpel stays well away from the nerves, the recovery of potency—the ability to have and maintain an erection—is not always immediate. For some men, it can take up to two years for potency to return; for some men, potency doesn’t return at all. The kicker is that nobody can predict which men will recover potency fairly quickly, and which men will have trouble. Indeed, two men the same age, with the same degree of cancer, can have exactly the same operation, performed with the same skill by the same surgeon—and the time to the return of erections can vary greatly.

“We know that despite the very best surgical techniques, nerves still will be injured,” says urologist Arthur L. Burnett, M.D., “and this can occur apart from any direct nerve-cutting or trauma. It could happen by stretching the nerves, or by dissecting in the area where the blood supply to the nerves is diminished.” Whatever the reason, “nerve function is depressed.” The nerves take a beating. Which brings us to what Burnett and others are calling the next frontier of radical prostatectomy—a solution using special proteins called immunophilins, administered nerves take a beating.


Which brings us to what Burnett and others are calling the next frontier of radical prostatectomy—a solution using special proteins called immunophilins, administered during or shortly after surgery, that soothes, protects, and even invigorates these nerves. Burnett’s pioneering work in rats with nerve injury and erectile dysfunction (similar to that found in men after radical prostatectomy) has had such promising results—stronger erections, recovered earlier—that he and colleagues are patenting the technology, and the drug industry is very interested in developing it. The rats treated with immunophilins—the particular drug is known as FK506—had dramatically less nerve damage, and much greater recovery of function.

How does it work? The short answer is, nobody knows exactly. Immunophilins are proteins made by nerve tissue. When a nerve is injured, they respond like a local rescue squad, dispatched to the scene, that helps the injured nerve repair itself. “We’re really talking about the ligands for the immunophilins,” says Burnett. “Ligands like FK506 are very specific stimulants for immunophilins, and apparently enhance nerve recovery after injury by acting on specific receptors.” Future generations of these nerve-recovering agents may work even better, and be even more targeted. Immunophilins are abundant in brain as well as nerve tissue, and these proteins now are being studied for their potential to help many people—organ transplant recipients, for example, or sufferers of trauma, stroke, or neurological ailments. And, as scientists learn more about what immunophilins do, they’re also hoping to pinpoint exactly how these proteins work their magic. Do they somehow shield the nerves from inflammation and an immune reaction to injury? Is their action directly on the nerves, or on one of the processes that affect them? Going back to our iron-man image, are they the Gatorade, the vitamins, or the shots? And how do they protect, and also, as Burnett describes it, “vivify?”

“We use the word neurotrophic. They’re nerve-protective and regenerative, and that’s the key, really,” Burnett says.

“We think there’s more to it than just preventing immune cells from doing damage.

Usually, once nerves are injured, they undergo degeneration. If you crush or cut a nerve at one focal point, over time, the tissue shrivels up. But what happens with the FK506 solution is nerve regeneration —these nerves start to come back over time. They just start to reawaken, regrow, resprout, reconnect.”

What About Nerve Grafts to Restore Potency?

Surgeons at some hospitals are offering nerve grafts as a means of restoring a man’s potential for erection. Although it’s getting some publicity now, the idea of nerve grafts in radical prostatectomy patients is not that new. The first experimental work on nerve grafts to restore sexual function was reported from the Brady Urological Institute in 1989, by Patrick Walsh and colleagues. Walsh’s studies in rats were encouraging, and in the early 1990s, collaborating with a neurosurgeon, he carried out a study of nerve grafts in patients who underwent wide excision of the neurovascular bundle. He followed the patients for more than five years, and found no difference in the recovery of sexual function in men who received a nerve graft and those who did not. At the same time, another trend was emerging: With the widespread use of PSA testing, more men were being diagnosed with early-stage, localized cancer, and as a result, fewer men needed to have a nerve bundle removed.

Recently, some urologists elsewhere have reported that in men who had both neurovascular bundles removed and received nerve grafts (using small nerves taken from the side of the foot), 30 percent had recovery of sexual function. However, a review of these surgeons’ results found that 58 percent of the men who underwent nerve grafts had no evidence of capsular penetration on either side—which means they didn’t need to have either nerve bundle removed in the first place.

What about nerve grafts in men who have one bundle removed? This same group of surgeons stated that when they removed one neurovascular bundle, only 25 percent of their patients were potent. These results, frankly, are not as good as they are at other hospitals. At Johns Hopkins, for example, without a nerve graft, 64 percent of our patients who have one neurovascular bundle removed are potent. Would a nerve graft improve these results even further? The argument is not terribly convincing. In a study done here several years ago, Walsh and colleagues analyzed the factors that influenced a man’s recovery of potency after surgery. It turned out that men who had more extensive disease—capsular penetration, or cancer involving the seminal vesicles—were less likely to have recovery of sexual function, even if both neurovascular bundles were preserved.

Also, nerve grafts are not without their own risks. Potential side effects include the development of numbness or nerve damage on the side of the foot (at the site where the to-be-grafted nerve is removed), and the possibility of a delay in walking after surgery. Also, removing a nerve, closing that site, and then grafting the nerve in the pelvis prolongs the surgery, and may cause men to lose more blood. Before nerve grafts become an added component to many radical prostatectomies, they need to be studied in many men, in a randomized, controlled investigation. For now, a man’s best chance to recover sexual function, if one neurovascular bundle must be removed, is to find a surgeon who is an expert at preserving the other bundle (the one on the opposite side).

Before an immunophilin solution can be used routinely on men who undergo radical prostatectomy—and Burnett expects clinical trials to begin in the near future— many logistics, such as dosage and side effects, need to be worked out. But Burnett envisions it this way: “One of the nice things here is that we can plan ahead. We know a man’s going to have surgery, and that he’s probably going to sustain at least some nerve injury, and we can start treating him in an immediately preventive way. We’ve got the pelvis open, and we can see the nerves. We put in the drug—maybe in a time-released wafer—and maybe also give the man some oral agents for about a week, and maybe that’s all we need to do.” And maybe the man will recover erections in three to six months after surgery, instead of longer. It sounds like science fiction now, but that’s where we’re headed.”

 

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