MINNEAPOLIS--There's an anxious strain in the voice of the neurosurgeon calling long distance from Toronto. He's beginning surgery and finds he's missing a special bar needed to attach a cannula through which he'll insert an electrode wire targeted for the patient's thalamus. On the other end of the phone line, Medtronic design engineer Lynn Otten tries to reassure the surgeon, then quickly swings into action. First, she gets Northwest Airlines to delay its next flight to Toronto. Then she convinces the local police chief to authorize a high-speed delivery of the precious part to the Minneapolis airport. Two hours and 42 minutes from his first panicky phone call, the surgeon is holding the attachment bar in his hands.
"I'm the kind of person who acts first--then asks for permission later," chuckles Otten, as she recalls the Toronto incident, which was by no means a rarity. As the engineering team leader on a revolutionary technology to treat victims of Parkinson's Disease and other movement disorders, Otten remains in constant contact with the neurosurgeons and neurologists who are introducing this vital new treatment around the world. And that can mean lots of troubleshooting.
The neurostimulation system Otten and her team designed--the ActivaTM Tremor Control Therapy--must be constantly scrutinized, based on feedback both from patients and from doctors who perform the procedure at some 300 medical centers in North America, Europe, and Australia.
Many experts in the neurological field view Activa as the first completely new approach in 30 years for treating millions of people worldwide who suffer from the uncontrollable and sometimes violent shaking associated with Parkinson's Disease and Essential Tremor. By blocking the errant brain signals responsible for these symptoms, the technology lets patients do the simple everyday tasks that most of us take for granted, like drinking a glass of water or writing our name.
Beyond that, the technology--which delivers mild electrical pulses to targeted areas of the brain--is seen as the first in a series of breakthrough therapies now being developed for disorders ranging from Alzheimer's and epilepsy to obsessive compulsive behavior.
Options open. The Activa system, approved for marketing by the U.S. Food and Drug Administration (FDA) in August 1997, consists of these basic implanted components :
Deep brain stimulation (DBS) lead, a thin, insulated multiwire coil with four electrodes on the end. Using magnetic resonance imaging or other medical imaging techniques as a guide, the surgeon carefully inserts the lead into the targeted area of the brain associated with motor control.
Itrel(R) II neurostimulator, a pacemaker-like device consisting of a battery and microelectronic circuitry that delivers mild electrical pulses to the brain. It is implanted just below the collarbone.
Extension, an insulated multiwire device that is passed under the skin of the head, neck, and shoulder to connect the implanted electrode lead in the brain to the implanted neurostimulator.
Once the device is implanted, the patient uses a hand-held magnet to turn Activa on or off--or to choose between high or low stimulation settings.
"The Activa System is a huge step forward for the treatment of motion disorders," says Dr. Steve Wilkinson, a neurosurgeon who has performed about 150 Activa implants at the University of Kansas Medical Center. "Not only does it result in dramatic improvements in people's lives, but it is reversible, allowing for new advances in the future."
Wilkinson adds that, for many patients, neurostimulation is preferable to thalamotomy, a procedure in which a surgeon uses a probe to essentially burn away a section of tissue in the thalamus, the communications center in the brain associated with motor control. The surgery sometimes can result in permanent side effects, such as slurred speech or mild paralysis.
In a widely publicized December People article, actor Michael J. Fox, 37, revealed that he had undergone a thalamotomy to control the tremors he suffered as a result of Parkinson's Disease. "If he were my patient, I probably would have recommended the Activa implant, especially because of his young age," adds Dr. Wilkinson.
So far in the U.S., the FDA has given commercial approval for using the Activa system to stimulate one side of the brain. This allows for the control of shaking on one side of the body. In Europe, however, CE mark approval, received in April of 1998, permits patients to have two neurostimulator implants, which can reduce virtually all tremor. In addition, surgeons there are permitted to place the electrodes into deeper regions of the brain--the subthalamic nucleus or the globus pallidus. This reduces other problems associated with Parkinson's disease, such as stiffness in limbs and joints,slow movement, and poor balance and coordination.
Medtronic hopes to have FDA approvals for this broader range of treatments by the spring of the year 2000. Lynn Otten and her colleagues also are working on newer and more patient-friendly versions of the neurostimulator.
Progressive problems. The technology comes none too soon. It could benefit tens of thousands of patients worldwide who have watched the quality of their lives degenerate bit by bit from the onset of Parkinson's and related diseases. In Parkinson's, cells die in the substantia nigra, a corner of the brain that produces dopamine, a neurotransmitter chemical that allows communication among the brain cells involved in the control of movements. The reduced level of dopamine leads to the symptoms of Parkinson's disease. About 1.5 million people in the U.S. suffer from the condition, including Muhammad Ali, Attorney General Janet Reno, and the Rev. Billy Graham.
To obtain relief from the tremors and other symptoms, most patients first try levodopa drugs, a natural substance that converts to dopamine. However, over time the majority of these patients find that the drugs lose their effectiveness. Worse still, the drugs themselves will sometimes cause sudden and unpredictable movements, such as a wild flailing of the arms.
Up until Activa, the only real alternative for such patients when drugs failed was surgery, such as the thalamotomy procedure, or pallidotomy, which destroys the globus pallidus, a structure in the basal ganglia involved in motor control. However, not only do these procedures bring the risk of side effects, but they may need to be repeated as Parkinson's progresses and symptoms reoccur. This heightens the danger of destroying more brain cells that control speech, movement, and thinking.
Since clinical trials for the Activa device first began in Europe in 1992 and in the U.S. in 1993, thousands of patients have received the implant. And study after study has shown clear--if not astounding--benefits to patients, who pay about $20,000 for the operation, which includes $10,000 for the device. The procedure is covered by most insurance carriers.
"It is marvelous that we can return these patients to an almost normal state," reported French neurosurgeon Dr. Alim-Louis Benabid in an ABC 20/20 segment on Activa. "Patients say to me, 'Thank you for giving me the second birthday of my life.'''
One such patient--Michel Placeman of Belgium--noted that he was "in a terrible state, living my life in a wheelchair." After the implant, he could do things he hadn't done in years, like driving a car, typing a letter, or playing table tennis."
Another Parkinson's patient, Californian Nicole Stedman, traveled to France in August of 1997 to receive bilateral Activa implants from Dr. Benabid. "It was scary, but I really had no choice," she told Design News. "The quality of my life had become atrocious. Now, after the operation, I've gone from night to day. I can play the piano again, tie my shoes. My general health is improving, too. I'm sleeping better and gaining weight."
Research to reality. Dr. Benabid, who is based at Fourier University in Grenoble, has logged some of the longest studies on patients who have received the implant. In a group of 80 Parkinson's patients who had received the implant, 92% reported good to excellent suppression of tremor--including some who had been using the neurostimulator for as long as eight years. Minor side effects, such as a slight slurring of speech or a mild tingling or numbness in the fingers, were "well tolerated and immediately reversible," by adjusting the stimulation, according to Benabid's report in the Journal of Neurosurgery. And the majority no longer had to take medication.
From the very beginning, Dr. Benabid has played a major role--along with engineers like Lynn Otten--in the development of the Activa device. Like other neurosurgeons, he had been doing thalamotomies to control tremor. But one day in 1986 he noticed during surgery that patient tremor subsided when he turned up the frequency in an electrode used to locate the area where he would burn in the lesion. Soon he began his own neurostimulation experiments, using Medtronic pacemakers. He also called for research support from Medtronic.
Progress, however, was slow. Medtronic already had developed a deep brain stimulation device that FDA had allowed to be used under a special provision in the 1976 Good Medical Practices Act. But it had been used on a very limited basis--about 200 patients in all--as a last resort for patients suffering intense, unretractable pain from such conditions as degenerative bone diseases.
In fact, Lynn Otten's first assignment upon joining Medtronic in 1989--after an eight-year stint developing cochlear implants at 3M's medical division--was to travel to Saskatchewan to find out why the brain stimulation device had stopped functioning properly on one patient. "When the physician there saw I was a woman, I practically had to show him my resume before he'd talk to me," she jokes. But with nearly 18 years of experience designing implant leads and a master's in materials science, Otten soon spotted the problem--a wear fracture in the DBI lead as it exited the brain.
About the same time, FDA was rethinking its stance on these long-term implanted devices to stimulate the brain and called for more clinical trials. Medtronic officials were at best lukewarm. Only a handful of surgeons worldwide seemed interested in doing the procedure, and the costs to Medtronic of improving the device did not seem to be justified by the limited number of patients who would use it for relief of chronic pain. "It was a device looking for the right therapy," recalls Otten, who at the time was spending most of her time on devices to stimulate the spinal cord.
Even so, Otten and a small team of three engineers pushed on with the design and extensive testing of better electrode leads and extension wire systems. "As far as the company was concerned, in those years it was definitely a 'do it in your spare time,' back-burner project," notes Otten.
Adds manufacturing engineer Don Romfo: "Lynn was the real champion in keeping the Activa project going. She pulled the team together and got them to focus on the key work that had to be done."
Since the neurostimulator used in the Activa device borrowed from pacemaker technology that Medtronic has produced since 1960, the real challenge on Activa was the electrode lead. "We needed a lead that would survive long term in the body, yet have enough flexibility to move with the brain but not pull out of position," notes Michael Selzer, former vice president of Medtronic's STIM and Movement Disorders business. "Then there were other issues, like the precise spacing of the electrodes at the tip of the lead. Our goal was never to have to go into the brain again to replace these leads,so the challenges involved were a mechanical engineering nightmare."
Technology veteran. The mechanical engineer that Selzer depended on for insuring this robust design was Lynn Otten. She was by no means a rookie. In fact, developing the right components for implants had been Lynn's mission since leaving medical school at the University of California at San Francisco in 1972. She went to work for her stepfather, an electrical engineer whose contracts included work on some of the earliest cochlear implants. Though she completed three years of med school, Otten, with an undergraduate degree in biology and chemistry, recalls that "I never really wanted to just treat patients. I wanted to fix their problem."
Moving to Minneapolis in 1980 to join 3M's health care division, Lynn continued her cochlear implant work, with its goal of bringing sound to the profoundly deaf. With this technology, sound is captured by an external audio processor worn on a belt. The sounds are converted to electrical signals that are carried up a cable to a transmitter, which sends the signals across the skin via a wire antenna to a receiver inside the ear.
On this project, Otten designed all the internal parts, including the implanted electrical leads, made out of platinum covered with silicone rubber. She also worked on the receiver, which included the microchip for signal processing and gold-plated cobalt magnets inside a tiny ceramic can. "It was truly micro-miniaturization work," says Otten. "For example, the wires we used in cochlear implants are thinner than a human hair."
Otten worked on the cochlear implant project from 1980 to 1989, seeing it through FDA approval in 1986--and all the painstaking documentation that entailed. This experience caught the eye of Medtronic senior engineer Warren Starkebaum, who had done some of the earliest work on the company's neurostimulator leads. "You just don't find very many engineers with that kind of background," he says. "Not only do you need a good knowledge of materials when you design leads, but you must be a generalist with a sound understanding of the whole engineering process."
A market emerges. Fortunately, by about 1992, Otten's team began to see evidence of some potential payoffs from their labors. Dr. Benabid had done 10 implants on Parkinson's patients in Europe under an experimental program, and the results were significant enough to trigger formal clinical studies both in Europe and the U.S. Otten helped the process along by going to Europe to personally supervise new manufacturing facilities to insure that Benabid and other surgeons would have sufficient Activa leads for their clinical trials.
Meanwhile, support for the program began to grow at Medtronic. With the prospects of applying the neurostimulator technology to the large population of patients suffering from motion disorders worldwide, the company could now see a sufficient market to justify development.
Interest also spread quickly in the medical community. By 1993, surgeons in Europe had done some 300 implants of the Activa system in clinical trials. And by 1994, the results were so satisfactory that the technology received the European CE mark, allowing the first commercial use of the implant for thalamic stimulation in motion disorder patients.
The next big hurdle was FDA approval in the U.S., and Lynn Otten was in the thick of it. Even though materials such as polyurethane and platinum had been used for many years for medical implants, FDA wanted Medtronic to provide more evidence of their safety and efficacy for long-term implant in the human brain.
By the time Lynn and her colleagues appeared before the final FDA panel in March of 1997 on Medtronic's application for commercial approval of Activa, they had submitted 23 volumes of documents--each about 350 pages. Lynn had written and edited most of the technical sections herself, which, she says, "amounted to about 3 1/2 years of my life." Meanwhile, she was stealing time to earn several Medtronic patents on such technologies as epidural needles, catheters, and implantable drug infusion devices.
The good news came on August 4, 1997: FDA would grant commercial approval for surgeries involving a single implant in the thalamus. The regulators wanted to see more technical and clinical evidence before allowing bilateral implants, as well as implants below the thalamus.
Medtronic officials are unanimous in praising Lynn's role during the grueling FDA process. "The FDA documents wouldn't have been written without Lynn," says Don Harkness, the Activa venture team manager. Moreover, when the FDA auditors come to Medtronic for site visits, the buck invariably stops with Lynn.
More challenges. In many ways, FDA and CE approvals brought a new round of challenges for the Activa effort. For example, Otten spends much of her time working with neurologists, who typically are the ones who initially recommend the procedure for patients, and with the neurosurgeons, who must perform the operation. She has attended some 40 Activa implant operations and is in constant contact with surgeons, advising them on implant procedures. "Our bread and butter depends on how well we satisfy the patients and the doctors," says Lynn.
It is not unusual for her to get a call on her (800) number from a surgeon, asking "What do I do next?" In addition, she must always be prepared to design and modify ancillary equipment used in the implant procedure, such as the various types of attachment bars used on the stereotactic frames that stabilize the patient's head during the surgery.
"One of Lynn's greatest strengths is her relationship with the medical community," says Laurie McBane, senior clinical research associate at Medtronic. "Neurosurgeons are technical people, and Lynn speaks their language."
Nor is she shy about discouraging surgical "shortcuts" that might compromise her product. For example, when some surgeons reported fractures in a section of the lead outside the brain, Lynn found that they had inappropriately mounted the connector joining the lead and the extension wire in the neck--not on the skull above the ear, as called for by the design. Result: excessive flexing and twisting of the lead as patients moved their necks during daily activities.
"Lynn has taught me a lot about this device," notes Dr. Wilkinson of the University of Kansas Medical Center. "She perhaps knows more about this product than anyone in the world."
High stakes. Minding all the P's and Q's on Activa is crucial, say Medtronic officials, not just for the technology itself but for a whole succession of new treatments that could build on the Activa experience.
Medtronic, a 50-year-old medical giant with annual sales of more than $2.6 billion, views its neurological products as one of its shining stars. Sales for this business unit are increasing at a compound annual rate of more than 25%. Noreen Thompson, who heads the Activa business unit, estimates that sales of the system could easily reach $100 million in the U.S. within 5 years. What's more, there are virtually no direct competitors in this technology.
|In Europe, neurosurgeons are now pioneering Medtronic's Kinetra neurostimulator, a dual-channel system that provides pulses to stimulate both sides of the brain to treat advanced Parkinson's disease.|
Clinical programs are beginning to test the Activa system as a treatment for epilepsy, obsessive compulsive disorders, and dystonia--a disorder that causes involuntary muscle contractions in children. Besides neurostimulation of the brain, Medtronic is also pursuing other related technologies, such as drug infusion and the delivery of growth factors to regenerate cells in diseased areas of the brain. "There are so many opportunities that we almost don't know where to go first," says Marcus Flipovich, the senior worldwide marketing manager for STIM and Movement Disorders.
Lynn and her engineering colleagues at Medtronic view their work as just beginning. They see the need for smaller, more patient-friendly systems. For example, the new Kinetra neurostimulator, now in use in Europe, is designed to accommodate two extensions and two leads. This eliminates the need to implant two separate electrical pulse generators. Also, in 1999, Medtronic will begin clinical trials of Restore, a rechargeable battery system for the implanted pulse generator that would eliminate the need for battery replacement surgery. The nine-volt battery now used in Activa lasts about five years. Engineers also would like to introduce sensors into the system, much like those used in cardiac pacemakers.
All of this, of course, will mean many more hours of development work, tests, clinical experience, not to mention the mountains of documentation. Yet the deep satisfaction that Medtronic engineers derive from the results of their handiwork is rare in engineering. They see it, for example, at the annual company Christmas party, where patients whose lives have been restored by Medtronic technology come back to tell their stories. "There's not a dry eye in the house," notes Jim Budnicki, the general manager of the STIM unit.
For her part, Lynn Otten couldn't imagine doing anything else. Thinking of the Parkinson's patients, who often become virtual recluses because of the embarrassment they feel about their illness, Lynn says: "We can give these people back their confidence, their self-esteem. And that's worth all the 12-hour days. It's an unbelievable ego trip."
Activa Tremor Control Therapy
As approved by the FDA in August 1997, the ActivaTM system stimulates the ventral intermediate nucleus of the thalamus to interrupt wayward signals that cause tremor.
The totally implanted components of the system include: quadripolar deep brain stimulation (DBS) leads, the Itrel(R) II implantable pulse generator (IPG), and an extension that connects the lead to the IPG.
The lead, measuring 1.27 mm in diameter with a standard length of 40 cm, consists of platinum/iridium wire insulated with polytetrafluroethylene (PFTE) and polyurethane. On the tip of the lead is an array of four 1.5-mm platinum/iridium electrode contacts spaced 0.5 to 1.5 mm apart. While only one electrode is activated during use, the multi-electrode design helps insure that electrical stimulation can still be delivered, even if the lead shifts slightly in the brain over time. Completing the DBS lead kit is a tungsten stylet, which the surgeon uses during the operation for precise lead placement. A 14-mm burr hole ring and cap anchors the lead to the top of the skull.
Pacemaker legacy. While engineers consider the lead design to be the toughest challenge in the Activa, the implantable pulse generator borrows from Medtronic's long history of heart-pacing technology. Weighing 49 grams and measuring 52 X 60 X 10 mm, the titanium Itrel II features microelectronic circuitry powered by a lithium vinyl chloride battery, with a typical life of five years. Pulse amplitude can be set for 0 to 10.5V, with settings of 2 to 185 Hz (pulses per second).
Linking the IPG with the DBS lead is an extension wire, measuring 1.47 mm in diameter and 51 cm in length. It is made of nickel alloy and stainless steel and covered with PFTE and silicone rubber insulation.
After surgery, the patient uses a hand-held magnet to turn the IPG on or off--orto toggle between the programmed normal amplitude or a lower amplitude. From time to time, the patient visits his neurologist or other clinician, who uses a console programmer to adjust the parameters of the IPG noninvasively through telemetry.
The making of a miracle
No one claims that the Activa surgery is anything but long and tedious--from four to eight hours or more--but the results of this neurostimulator implant may well be the most dramatic in medicine today.
"In 25 years, I've never seen anything like this," observed ABC's Dr. Tim Johnson in a 20/20 segment on the technology.
Among the basic steps of this medical breakthrough:
The neurosurgeon attaches a stereotactic frame--a halo-type device--to the patient's head. This stabilizes the head not only for surgery but for the initial mapping of the brain using magnetic resonance imaging or computer-assisted tomography. These techniques determine the precise coordinates for the target site in the thalamus to receive the implanted electrodes.
Beginning the operation, the surgeon makes a small hole about the size of a dime in the skull and inserts a cannula through which he'll pass a test electrode. This is done while the patient is under mild sedation and a local anesthetic. The patient literally feels no discomfort as the electrode passes deeper into the brain, since brain tissue does not sense pain.
Moment of truth. When the test electrode is within 10 to 20 mm of the target, the neurosurgeon connects it to an external pulse stimulator. This is the stage that ushers in a medical miracle. As the neurologist activates the stimulator to determine the optimal position, patients are asked to hold a cup, stretch out their arms, draw a tight circle, or write their name. Often through tears of joy, they readily perform these tasks, which formerly would have been impossible for them because of uncontrollable tremors.
Once tremor suppression has been successfully demonstrated, the neurosurgeon implants all the components of the Activa system--the permanent deep brain stimulator, the extension wire, and the pulse generator. For this part of the operation, general anesthesia is used. Often, the patient can return home the very next day--typically after a clinician has activated and programmed the neurostimulator.
"We are used to treating such horrific problems, like brain tumors or severe head trauma," says neurosurgeon Steve Wilkinson of the University of Kansas Medical Center. "So it is fantastic to see, with this procedure, such a fast, positive impact."
For patients-a rebirth
On the golf course, Morrie Long can't resist a little hustle--especially when it's all in fun. Suffering from Parkinson's disease since 1982, the former mutual funds salesman looks like an easy mark. That is until he turns on his Activa neurostimulator, which instantly puts an end to the almost constant tremors that once made it impossible for him to even put a ball on a tee, or swing a club.
Long, of Hutchinson, KS, is one of hundreds of people whose lives have been transformed by what medical authorities say is the most impressive new therapy in decades for Parkinson's Disease and other movement disorders.
"On a scale of 1 to 10, I'd rate my tremor at about a 9," says Long, 72. "I've seen some people with worse, but to me it was as bad as it could get."
Since surgery to receive the ActivaTM Tremor Control therapy in 1996, Long's tremor is now almost undetectable. And he no longer needs medication. The only side effect has been a mild tingling on the right corner of his mouth when he first turns on the neurostimulator.
Rapid decline. Among others who have shared their stories with Medtronic is George Shafer of North Fort Myers, FL. In 1990, at age 59, he was forced to quit his job. The tremors he battled as a result of Parkinson's Disease made it impossible to operate a computer. Nor could he button his clothes, comb his hair, brush his teeth, or feed himself without getting help.
"George didn't want to go out to eat with friends, because he couldn't keep food on his fork or drink without spilling," notes his wife, Bee.
After years of living with such physical decline, imagine Shafer's reaction when doctors asked him to write his name during October 1993 surgery to implant the Activa tremor control system. "For eight years I couldn't write my own name, and all of a sudden I could!" he recalls. Soon he was able to resume activities he used to love--tennis, biking, and fishing. And he took up a new hobby that would have been impossible before the implant: building intricate model airplanes.
Studies have shown that the vast majority of patients--upwards of 90%--experience similar marked improvement as a result of the implant. As with any surgery, however, there can be risks, such as bleeding and infection. And, in about 10% of the implant cases, patients get little or no benefit from the therapy, either because doctors cannot locate the precise target area for the electrode or because these individuals may not be able to tolerate a high enough stimulation to correct their tremors, notes Dr. Jean Hubble, a neurologist who heads the Parkinson's Disease Center at Ohio State University.
Even so, Hubble echoes the views of many in the medical community in stating: "This neurostimulation technique has been a major advance not just in our ability to treat tremor but the other symptoms of Parkinson's as well."