A current of electricity
directed deep in the brain
of a person
with Parkinson's disease
has the power
to restore fluidity of
motion and erase tremors.
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Parkinson's disease patient Jim Haight walks gingerly
into the Movement Disorders Lab at Stanford, holding his right arm
stiffly at his side as if it were in a sling. Nurse Kay McGuire
gently helps him sit down before a keyboard and holds a mouse-like
device against his upper chest. She presses a button and warns him
to expect an electrical jolt. When the voltage reaches 1.7, Haight
says he feels the right side of his mouth droop. As he counts to
10, his speech is garbled. At a lower voltage of 1.3, Haight is
at his best: His right side loosens up, he can easily draw a cup
of water to his mouth and he is able to stand up without help. He
walks freely down the hall, his arms swinging gently by his side,
and shakes hands with a visitor with his once-useless right arm.
* "My right side
is really pretty mobile," marvels the 48-year-old attorney and musician
from San Francisco. "There's no rigidity. It's very fluid, right
down to the fingers. As you can see, I can tie my shoes." He leaves
the Movement Disorders Clinic with plans to try his hand again on
his piano, something he's been unable to do for some time. *
Haight is the beneficiary of a relatively new
technology known as deep brain stimulation (DBS). More than a month
before his November 16, 1999, visit to the clinic, he underwent
a 10-hour procedure in which neurosurgeon Gary Heit, MD, PhD, and
his colleagues strategically placed an electrode deep inside Haight's
brain. When turned on, the electrode delivers a continuous electrical
impulse that can silence errant cells in the brain responsible for
the symptoms of Parkinson's disease -- the tremors, rigidity, slow
movements and balance problems. The electrode is powered by a pulse
generator, a cardiac-like pacemaker buried under the skin in Haight's
upper chest. When the device is activated and calibrated, the symptoms
of Parkinson's disease promptly vanish. When it's turned off, all
symptoms return. Some patients nevertheless choose to stop the stimulation
while they're sleeping to preserve the implant's batteries. Others
turn it off occasionally because they find a break from the stimulation
enhances its effect when they start it again. Patients can flip
the device's switch by placing a magnet on their chests.
Scientists don't know precisely how DBS works, though
they believe it jams -- or overrides -- the signals sent by misfiring
nerve cells that control movement. It may also work by stimulating
the release of neurotransmitters that inhibit the activity of these
miscreant cells. The technology, developed in France and approved
in November 1997 for use in the United States by the federal Food
and Drug Administration, is now being applied in Parkinson's patients
for whom drug treatment is no longer effective. It's also being
used in patients with other movement disorders, such as essential
tremor and genetic dystonia (see sidebar).
With deep brain stimulation, "It's quite amazing
the improvement that we see, particularly in patients with Parkinson's
disease and dystonia," says Helen Bronte-Stewart, MD, MSE, assistant
professor of neurology and director of the Stanford Comprehensive
Movement Disorders Center.
Ultimately, DBS could prove to be applicable to other
conditions as well, such as depression and epilepsy, says Heit,
an assistant professor of neurosurgery. A dramatic report in the
May 13, 1999, New England Journal of Medicine described the
case of a 65-year-woman with Parkinson's disease who experienced
a crushing depression -- and then complete relief -- following treatment
with deep brain stimulation. Within seconds after the stimulator
was activated, the woman began to cry and voice despair, saying
she felt useless and hopeless, with no desire to live. When the
stimulator was turned off, the depression lifted within 90 seconds,
and the woman joked and laughed with the researcher, tugging on
his tie. Through careful placement of the device, doctors can avoid
the side effect of depression, Bronte-Stewart says. But the report
does suggest that it may be possible to provide relief to
sufferers of chronic depression by applying stimulation to specific
neural pathways in the brain, she says.
Deep brain stimulation has its origins
in the 1950s, when scientists observed that they could make tremors
subside by delivering high-frequency electrical stimulation to parts
of the thalamus, an area of the brain responsible for movement and
sensation. A similar effect could be achieved,
they found, by using a super-cooled metal tip to destroy cells in
the area of the thalamus responsible for tremors, a process known
as lesioning. This technique, when applied to the thalamus, is known
as thalamotomy. It remained a mainstay of surgical treatment for
Parkinson's disease in the 1950s and 1960s. But surgical approaches
to the disease fell out of favor with the introduction in 1967 of
levodopa (L-dopa), the front-line drug today for Parkinson's disease.
L-dopa did prove to have drawbacks, however, as it was found to
lose its effectiveness over time and produce a side effect known
as dyskinesia, in which patients experience twitching, jerking,
nodding or other involuntary movements.
The limitations of medical therapy led to a resurgence
of interest in surgical approaches to movement disorders, with a
team at the University of Grenoble in France leading the way in
the late 1980s. Their challenge -- and one that continues today
-- was to figure out which regions of the brain to target for best
results and then find ways of accurately pinpointing those regions
without harming other, delicate structures nearby. The work was
aided by new technologies, including imaging advances and new methods
for localizing tissues in the brain, which gave scientists more
precise direction for reaching their intended targets in the dark
recesses of the skull.
The French team, led by Alim-Louis Benabid, MD, began
by zeroing in on the ventral intermediate nucleus, a roughly half-inch-long
finger-like structure within the motor thalamus, in patients with
Parkinson's disease and essential tremor. They found that while
electrical stimulation was able to calm tremors in these patients,
it didn't alleviate the other symptoms of Parkinson's, including
muscle rigidity and slowed movement. The researchers then turned
to other sites, using stimulation in the pea-sized regions known
as the subthalamic nucleus and the globus pallidum, both deep in
the central core of the brain. Stimulation of the subthalamic nucleus
was found to produce the best results, with Parkinson's patients
experiencing a 70 to 80 percent average improvement in symptoms
when electrode implants were placed on both the left and ride sides
of the brain, Bronte-Stewart says.
"Most important, patients were able to reduce their
medications by 50 to 100 percent, so they didn't have to suffer
the side effects of these medications," she says. Parkinson's patient
Haight says he turned to DBS after he began to develop spasms in
his right arm and leg, a side effect of having been on L-dopa for
more than five years. The spasms became so debilitating, he says,
that they began to interfere with his day-to-day activities and
his legal work, making it difficult for him to even sit and type
at his computer.
"I started to find myself at sea with the medications
and thinking I'd rather take a chance and do something really affirmative
-- roll the dice, rather than be passive about it," he says. "I
must say, I was a bit shocked when they said I'd be awake during
the operation. I thought of several Frankenstein movies that were
quite popular."
A few years ago, Haight says, he had considered having
a lesioning procedure known as pallidotomy, in which doctors destroy
those cells in the globus pallidum thought to be responsible for
some Parkinson's symptoms. But he found this option a little daunting.
"I took myself off the list and decided I would wait
for something nondestructive," he says." The implant seemed a good
idea and apparently a low risk and high return. So it was a no-brainer."
Bronte-Stewart says doctors can elicit similar results
either by destroying aberrant cells or delivering electrical stimulation
to the cells. Both procedures can dampen the activities of these
misbehaving neurons. A lesion, however, can produce some undesirable
results if doctors miss their target by just a millimeter or two.
For instance, patients who undergo pallidotomy on both sides of
the brain can be rendered mute or have difficulty swallowing if
some adjacent cells are accidentally destroyed in the lesioning
process, she says. The advantage with stimulation is that it is
reversible and can be adjusted, with doctors changing the frequency,
voltage or duration of the electrical pulse.
"With a lesion, it's there and it's done. With DBS,
you can reprogram it," she says.
On the other hand, DBS patients must adjust to having
electronic gadgetry permanently resting in their skull.
"You're placing a foreign object in someone's brain,
with the potential problems of breakage and infection," Bronte-Stewart
says.
About five percent of patients who undergo DBS experience
complications, including infection and hemorrhage, Heit says. From
time to time, the wire connecting the implant and the pacemaker
can break or become dislodged, requiring a return visit to the operating
room, he says.
That was the case for DBS patient Joseph Bacchetto,
who returned for a surgical repair of his implant on September 17
-- his 75th birthday. The lead wire on his right implant had become
fractured, allowing only intermittent signals to get through. Bacchetto,
who suffers from essential tremor, had been fitted with a stimulator
on the right side of his brain in February 1998 and another on the
left side the following December. The implants effectively stopped
the shaking in his hands that had bedeviled him for some 25 years.
In recent years, the shaking had become so violent that Bacchetto
could no longer hold a cup, write his name or drive a car, he says.
"It did wonders for me," he says of the device. "I
can go out and eat out now and do things I couldn't do before. If
I did go out, I would go with friends who would cut my meat for
me."
Bacchetto's repeat surgery was much like his earlier
procedures -- an exercise in stamina as he lay awake for some seven
hours with his head immobilized inside a metal halo frame. The halo,
a standard tool of stereotactic surgery, serves as a reference point
for regions in the brain and offers a secure platform for instruments
used to gain access to those tissues, Heit explains. During DBS
surgery, patients remain fixed in this surgical frame while fully
conscious so they can give feedback to doctors during electrode
placement.
Positioning the electrode is one of the trickiest
aspects of the surgery, Heit says. In Bacchetto's case, Heit was
aiming for the ventral intermediate nucleus, which is near the sensory
nucleus of the thalamus, an area of the brain that controls sensation.
"If I'm off target, instead of suppressing the tremor,
he will feel an uncomfortable buzzing of the skin," Heit says.
He and his colleagues use a combination of methods,
based on both anatomy and physiology, to confirm their location.
These include use of MRI and X-ray, as well as an electrophysiological
mapping technique in which doctors literally listen to nerve cells
-- and observe their signaling pattern on a screen -- as patients
move or speak.
"I don't know if there is any other place that combines
the technologies that we're using," says Bruce
Hill, PhD, a medical physicist who is part of the DBS team. "Some
have the anatomical and some just do the mapping, but we have it
all."
During Bacchetto's surgery, Heit's first step is
to wheel him into the MRI room in the hospital basement, where he
can get pictures of the various landmarks and other identifiable
features in the patient's brain. He makes measurements based on
Bacchetto's anatomy and the known structure of the brain.
That is a starting point. Back in the
operating room, Heit locks the patient's head into position inside
the halo, clamps the frame to the floor and then prepares for an
X-ray of the brain.
"The X-ray is the gold standard for verifying where
we are," Hill says. "You can't rely entirely on the MRI because
it can produce distortions, and the brain can shift. An intra-operative
X-ray can tell if a shift has occurred."
The team injects a dye through a tube in the cavity
of the brain called the third ventricle. The dye lights up during
the X-ray, highlighting specific anatomical features. When the X-ray
is complete, Hill and Heit overlay the results on the MRI and make
sure that the two images correlate. They do. They mark an X on the
spot where they aim to plant the electrode. Then they make computerized
calculations and set the equipment accordingly to help them get
to that site. Later, when the electrode is in place, they will repeat
the X-ray to be sure the implant has reached its intended resting
spot.
Then Bronte-Stewart's work begins. She stands next
to the patient, dons headphones and faces a 7-foot tall piece of
equipment with an oscilloscope that registers signals from the brain
in a pattern on a screen. Bronte-Stewart gently turns a knob on
a machine that uses hydraulics to direct the electrode down into
the brain toward the target area.
When the electrode is in place, she asks the patient
to close his hand and reports hearing high-pitched chirps -- the
response from a neuron known as a bursting cell, because its sound
resembles that of a bird bursting forth with an occasional trill.
These bursting cells, she explains, are the "bad actors" of movement
disorders -- poorly synchronized players that send out abnormal
signals to cause movement difficulties.
Bronte-Stewart runs a brush down the patient's arm
and asks him to count backwards, testing both sensation and speech
to be sure that these areas of the brain aren't being touched. After
an hour, she is satisfied that she has identified the appropriate
place to implant the device.
Once the mapping is complete, she asks the patient
to flip his forearm back. His tremor improves as his hand goes up.
With a stimulus of three volts, the patient's hand is absolutely
steady. Bronte-Stewart turns the machine off, and the hand begins
to tremble again.
In first-time patients, the mapping exercise may
continue for hours, but because Bacchetto has been implanted before,
the team already has a good idea of where the electrode belongs.
The patient, meanwhile, seems unperturbed.
Though he was awake the whole time, he felt nothing
-- except the discomfort of the rack around his head, Bacchetto
says a few days later. Nonetheless, being immobilized for that long
is "quite an ordeal," he says.
Haight describes it as "more of an athletic event
than anything else. You have people manipulating your appendages
and talking you through the procedure. You're absolutely imprisoned,
so it's really a matter of girding up and getting through it."
Once the implant is in place, the surgeon channels
the wiring under the skin on the side of the head, down the neck
and into a cavity in the collarbone, where the pacemaker sits. The
patient is anesthetized for this last portion of the procedure,
when the implant is installed under the skin. The only visible sign
of hardware is a slight bulge in the chest where the pulse generator
lies.
Haight left the hospital the day after the procedure
and spent two weeks recovering at home before returning to work.
He returned to Stanford on December 3 to complete the process with
placement of an implant on his other side. He is completely free
of his tremors, spasms and rigidity now and is taking very little
medication, he says.
"The operation apparently was quite a success because
both sides are operating quite naturally," he says. "In fact, I
served dinner to 10 people without breaking any dishes. It was really
a treat."
Haight says he has only one disappointment: "I thought
they'd do me and I'd play Liszt -- but I can only play Mozart and
Beethoven. Maybe I'll work up to Chopin." SM
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