Science Meets Challenge

By Audrey T. Hingley From FDA Consumer
Mechanicsville, Va.

After days of cramming for college mid-term exams while holding down a
full-time job as a security guard, Marc Miller needed a break. So Miller
and two friends made the rounds of three Richmond, Va., nightspots before
going their separate ways at evening's end.

"I was more tipsy than normal, but I felt fine. I drove out of the parking
lot where we had left our cars, and reached over to roll down the passenger
window. That's the last thing I remember," Miller recalls. "It was so
quick. Suddenly my whole life was changed."

In that instant, his '84 Toyota pickup truck had crossed to the other side
of the road, slamming into a telephone pole. On that April 1989 evening,
Miller went from carefree college student to paraplegic, joining the 10,000
Americans paralyzed by spinal cord injury each year. After a two- month
hospital stay, he returned to college, earning an associate degree in
architectural engineering. Now 26, he works full-time as an engineering
technician, and lives in Richmond with his wife, Kimberly, 24, whom he met
on the job.

"I'm lucky. I have a good job, I play wheelchair basketball, I can still
have sex, and I found someone I really love. I couldn't have made it
without my friends and family. I wasn't very close to my mother before the
accident; now we're really close. I also got very close to my faith in God.
Being in a wheelchair gives you a different perspective," he says. "But
life is harder. You battle bladder infections. If you get sick, it's
harder. I get irritated more easily, and occasionally I get depressed.
Life is more of a struggle. It's a struggle to get in and out of cars-just
driving to Hardees for an iced tea is exhausting."

Comebacks like Miller's would have been unheard of as recently as the World
War II era, when 90 percent of spinal cord-injured patients died. It wasn't
until the late 1960s and early 1970s that survival rates began approaching
90 percent, primarily due to advances in handling bladder problems. Today,
estimates of the number of people living with spinal cord injuries vary
from 200,000 to 500,000.

Spinal Cord Complex

Spinal cord injury is devastating because of the complexity, delicacy and
importance of the spinal cord itself. Containing more than 20 million nerve
fibers, it is the major conduit for transmitting motor and sensory
information between brain and body. It runs vertically within the spinal
column, composed of 33 vertebrae separated by rubbery disks.

The nerve signals that travel the spinal cord help regulate sensation,
movement, and bodily functions, such as bladder control. When the spinal
cord's axons (long fibers that nerve cells send out) are damaged, paralysis
can result. Axons transmit nerve signals from cell to cell, so when they're
destroyed the cells can't communicate, causing loss of functions controlled
by the affected cells.

Spinal cord injury affects a number of body functions. Bladder control is
usually impaired, and sometimes completely destroyed. Some people retain
involuntary reflexes that help empty the bladder, but others have completely
flaccid bladder muscles. Urine left in the bladder breeds infection, which
can become chronic and cause kidney damage. Bowel management is another
challenge, since messages from brain to bowel to empty don't get through,
and anal sphincter muscle control is lost. Then there are skin problems
like bed-sores, common to wheelchair patients.

The location of a spinal cord injury helps determine the level of
disability: The higher the injury on the spinal cord, the more extensive
the paralysis. Injury above the C7 vertebra results in quadriplegia--impaired
function in arms, trunk, legs, and pelvic organs. Paraplegia results from
damage done to the thoracic, lumbar or sacral regions of the spinal cord.
Although arm function is spared, the trunk, legs, and pelvic organs may be
involved, depending on the level of injury.

Advances Bring Hope

For many years, medical experts considered extensive recovery of body
function after spinal cord injury hopeless. This is because in most
mammals, nerve cells of the central nervous system (brain and spinal cord)
show little evidence of being able to regenerate when damaged. But today,
researchers and clinicians alike share optimism about improvements for
people with spinal cord injuries. Electrical stimulation of muscles, use of
restorative devices, drug therapy advances, and advances in nerve
regeneration research are bringing hope to an area long deemed hopeless.

"Since the Vietnam war, there have been significant clinical advances as
research centers across the country learned how to care for severely
debilitated quadriplegic patients," says Paul R. Beninger, M.D., M. S.,
acting director for the Food and Drug Administration's division for general
and restorative devices. "For example, use of automated wheelchairs became
commonplace after the Vietnam war, and the pulmonary care of patients
improved."

FDA regulates devices like motorized wheelchairs, but does not regulate
accessories like mechanized van lifts for wheelchairs. A stair-climbing
motorized wheelchair FDA approved three years ago is a recent advance in
devices for patients with spinal cord injuries. The sophisticated chair has
sensors that monitor the steepness of stairs, altering both position and
speed depending on incline. But the chair is expensive (about $20, 000) and
heavy; home stairways need inspection to verify their capability for
handling the weight.

Muscle Stimulators

Muscle stimulators using electrical currents that stimulate muscles to
contract, especially FES systems (functional electrical stimulation), have
been the focus of much media attention. Some FES systems under development
are enabling paralyzed people to walk again. Such systems operate as a kind
of complex prosthetic device, meaning that although the stimulation can
cause muscles to contract and legs to move, it is a kind of "artificial"
walking, since no actual movement has been regained by the patient and
there is no sensation of movement.

Other FES systems stimulate nerves to give hand movement so quadriplegic
individuals without hand function can feed themselves. But FES systems are
not without drawbacks: They aren't for everyone, they're costly and still
largely experimental, and surgery to implant electrodes is required, which
can pose possible complications.

Stimulators aren't just for walking or movement. For example, FDA- approved
phrenic nerve stimulators allow people with high-level spinal cord injuries
to breathe without respirators. (The phrenic nerve goes from the spinal
cord to the diaphragm, and activating it causes the diaphragm to contract). But
again, there are use limitations; the phrenic nerve has to be healthy.
Robert F. Munzner, Ph.D., chief of FDA's neurological devices branch,
estimates that only a few hundred people nationwide can use the device.

According to Marie A. Schroeder, a physical therapist and chief of FDA's
restorative devices branch, many muscle stimulators have been cleared for
marketing, but not specifically for functional purposes.

"For example, if some muscles are not totally paralyzed and doctors want to
see how much improvement in movement or feeling someone will get, they may
use a stimulator to maintain range of motion to help provide muscle
reeducation, until they see how much voluntary control the patient gains,"
she explains. "But using stimulators for functional purposes gets into the
investigational area. The only functional use of a muscle stimulator that
has been cleared are those stimulators that might be used for a patient
with a localized nerve injury-for example, a patient who can't lift his foot up.
However, we consider the stimulation of muscles needed for the purpose of
walking to be investigational."

Physicians surveyed say electrical stimulation is not being widely used on
a routine basis because the technology is not yet "user-friendly." William O.
McKinley, M.D., director of spinal cord injury and rehabilitative medical
services at The Medical College of Virginia, notes that devices that assist
paralyzed patients in coming to a standing position, for example, are "very
expensive, very time-consuming to learn, and usefulness has to be determined
on a patient-by-patient basis."

Many other uses of stimulators are not common or remain investigational.
For example, although stimulators that offer pain prevention and
electro-ejaculation to collect sperm to enable paralyzed men to become
fathers are used clinically, their use is not widespread.

F. Terry Hambrecht, M.D., head of the neural prosthesis program at the
National Institutes of Health's National Institute of Neurological
Disorders and Stroke, says such systems are still technologically limited,
but he is optimistic about the future.

"The problem now is that we're in the Model-T stage. We don't yet have the
sophistication and reliability we need," he admits. "But there's no doubt
in my mind that eventually functional stimulation devices will be developed
for spinal cord-injured patients. We're funding quite a few projects for
people who are paralyzed."

Hambrecht says one current project involves electrode implantation to
restore bladder and sexual function to paralyzed men and women. Experts
cite the study as the first evidence that a medication can improve the outcome
of spinal cord injury, and today the drug is widely used for acute spinal cord injury.

Surgeons use the potent drug, which was approved some years ago by FDA as
an anti-inflammatory agent and is also approved to treat swelling around the
brain, to manage acute attacks of multiple sclerosis and for a variety of
allergic conditions.

Wise Young, M.D., Ph.D., part of the methylprednisolone study team, is a
professor of neurosurgery, physiology and biophysics and director of the
neurosurgery research lab at New York University Medical Center. Young
points out that the drug does not enable patients to immediately " leap out
of bed." Beneficial effects are usually not apparent until at least six
weeks after the drug is administered. Yet he believes the use of the drug
is a landmark development.

"It has changed the attitude of doctors toward spinal cord injury. They no
longer see it as a hopeless condition, and patients are rushed to hospitals
earlier," he explains. "It also has tremendous implications for chronic
spinal cord injury, since the finding that you only need a few axons to get
function back means you don't have to regenerate as many axons."

"Currently there are over two dozen drugs reported to be neural-protective
in animals," Young says. "The leap that was made in 1990 was between
absolutely no hope to some hope. There is a real sense of optimism now;
it's not a matter of if, but when, a drug will be available to aid
regeneration of the spinal cord."

Treatments Under Study

Another drug under study is GM-1 ganglioside. Fred H. Geisler, M. D.,
Ph.D., a neurosurgeon at the Chicago Neurosurgical Center, headed a
team at the University of Maryland Shock Trauma Center in Baltimore
that studied 34 people with paralyzing spinal cord injuries in a placebo-
controlled, double-blind, randomized study.

The study results were reported in the June 27, 1991, New England Journal
of Medicine. Within three days of injury, 16 of Geisler's patients began daily
injections of GM-1 for 18 to 32 days, while the rest received placebo
injections. Patients given GM-1 had improved recovery of motor functions in
the arms, and later in the legs. About half of the improvement occurred at
the two-month mark. Most of the improvements happened within four months of
patients' receiving GM-1 injections, but some improvements continued for up
to one year after GM-1 treatment.

Researchers theorize that GM-1 ganglioside, naturally present in cell
membranes of the spinal cord and brain, helps protect against additional
nerve cell death after spinal cord injury and also stimulates nerve- fiber
growth and repair.

"We saw some major improvements. ...In many cases, people were walking
where they could not ambulate at all before," Geisler says. He is now heading
a new study of this investigational drug, following 166 patients given GM-1
at 22 medical centers in North America. Geisler says the goal is to enroll 720
patients.

Neural grafting, or transplantation of tissue into the brain and spinal
cord, is still highly experimental. Possible sources of grafting material
include genetically engineered cells, human fetal tissue, and other tissues
from a patient's own body. Neural grafts are being tested in animal models
of brain and spinal cord injury to find out if they can induce growth or
replace damaged areas.

Other Improvements

Other factors besides drug advances and technology are improving the
outlook
for people with spinal cord injuries. Car accidents by far remain the
number one cause of spinal cord injuries (47.7 percent), followed by falls,
gunshot wounds, and recreational sports, particularly diving accidents.
Spinal cord injury happens mostly to young people, and mostly to males (82
percent).

MCV's McKinley says improvements in on-site emergency medical management,
with better-trained technicians skilled in stabilizing the spine to prevent
further injury, means doctors are seeing more patients with "non-complete"
injuries, or injuries where some function and motor sensation is preserved.

"We are also doing a better job of educating people in how to protect
against spinal cord injury, such as wearing seat belts, buying cars with
air bags, and not diving into shallow water," he says.

In rehabilitation, the emphasis remains on regaining as much functional
ability as possible.

"Chronic patients and rehabilitation are the real challenge. Research is
exciting and potentially part of the future, but it still has a long way to
go," McKinley says, pointing out that helping patients through the
adjustment period after injury remains challenging. "They need to know how
to self-catheterize, how to detect bladder infections," he says. "Are the
doors at home wide enough for a wheelchair? Do they need a ramp?"

McKinley says the first thing newly injured patients ask about is their
ability to walk, but questions about sexuality are not far behind.

"Paralysis can affect the ability to have an erection.... But with
adaptations, sexual relations are very possible. So I tell patients yes,
it's possible, but different. Loving and caring and other means of sexual
gratification take on new priority for injured patients," he explains.

Hope and patience may be the most important factors regarding the future
treatment of spinal cord-injured people. Hope comes from optimism about
recent advances in treatment, but research complexity and funding issues
make patience necessary as well.

"For at least the last decade, research papers have shown that spinal cord
injuries can be improved, or that the amount of injury can be decreased, "
Geisler says. "My hope is that lab findings will be able to move to the
clinical area."

Marc Miller, like many people with spinal cord injuries, is both optimistic
and philosophical about the treatment advances.

"I think in the next 10 years they will find treatments that reduce the
impact of spinal cord injuries. But I think it's important for people to
remember that we're just normal folks who can't walk," he says. " I have a
better grasp of who I am now; being in a wheelchair gives you a different
perspective. I'm not disabled, I just can't walk. I play wheelchair
basketball, I want to learn to water ski and to snow ski.... I just want to
do all I can do now."
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