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Advances in Neurology Stimulate FDA Device Approvals

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An MD&DI  December 1997 Column

R&D HORIZONS

The market response to nerve stimulators might eclipse the success enjoyed by cardiac pacemakers.

After decades of research, neurologic devices are becoming increasingly available to patients for use against a range of maladies, including epilepsy, paralysis, incontinence, and muscle tremor. During the past six months, FDA has approved four neurostimulators, and more advanced versions are on the way.

The pulse generator transmits an electrical charge to the wire in the brain, thus reducing involuntary tremors. Illustration courtesy of Medtronic (Minneapolis)


These new technologies might transform the treatment of neurological disorders the same way pacemakers and defibrillators changed the outlook in cardiology. Given that biomedical engineers already know how to miniaturize electronics, neurotransmitter development could proceed even faster. The road ahead is not without its challenges, however. A critical component of the revolution is missing. According to William Opel, executive director of the Huntington Medical Research Institutes (Pasadena, CA), "We lack a basic knowledge about neurological mechanisms."

ENGINEERING CHALLENGES

Nowhere is that clearer than in the treatment of epilepsy. Several companies are developing products designed to alleviate epileptic seizures by regularly sending impulses to the vagus nerve. This longest of the 12 cranial nerves sends messages from the brain to many organs and relays information back to the portion of the brain stem responsible for certain epileptic seizures. For some patients, chronic, random stimulation of the vagus nerve helps relieve the frequency and severity of seizures.

"We can tell you that the treatment works, but the smartest people on the topic can’t tell you exactly why," says Shawn Lunney, vice president of marketing at Cyberonics (Webster, TX), the company that developed the first and only commercially available vagal nerve stimulator.

The brain, spine, and peripheral nervous system each present unique challenges to the development of neurostimulators. Decades of research at the Huntington Medical Research Institutes have focused on the subtle differences in the tissues that make up the human nervous system. William F. Agnew, MD, director of the institute’s neurological research laboratory, says the brain is protected by dura mater, pia mater, and arachnoid tissue. The spinal cord, although similar in composition, is further encased in a heavy sheath of crisscrossing collagen.

Understanding these subtleties is essential to the development of optimal electrodes for interfacing between human tissue and manmade technology. Researchers must consider the size, shape, and composition of the electrodes when deciding how they should connect. Depending on the nerve involved, the electrode could either wrap around or penetrate it.

Choosing the right metal for the connection is another engineering challenge. Platinum fell from favor at Huntington after Agnew and his colleagues discovered that it becomes soluble during stimulation and is deposited in tissue, causing a potentially toxic reaction in a confined area. Iridium is the current metal of choice because at a diameter of 12 µm—about a third the size of a human hair—it is strong enough to penetrate nerve tissue without buckling.

The electrode’s shape is also critical. A conical tip leading to a blunt end, says Agnew, with the electrodes configured in a ring of six surrounding one in the center, appears to be the best for penetration. Even the surgical technique has been refined to reduce collateral damage. Minimizing movement, he says, has reduced the slashing effect on the tissue, which produces the microscarring otherwise common in these procedures and which is linked to suboptimal performance of the electrode.

PUTTING KNOWLEDGE TO USE

Leveraging the research conducted by Agnew and his colleagues allowed Cyberonics to develop the electrode in the NeuroCybernetic Prosthesis, which has effectively controlled partial-onset epilepsy in a significant number of patients. Wrapped around the vagus nerve in the left side of the neck and held in place by a tether, this electrode unleashes electrical bursts every few minutes from a silver dollar­sized generator implanted near the collarbone. This technology can help many patients whose seizures cannot be controlled adequately by drugs, according to Bruce Burlington, director of the FDA Center for Devices and Radiological Health.

NeuroControl (Cleveland) pairs external and internal electronics to provide quadriplegics with a functional hand grasp.


FDA passed swift judgment on the epilepsy device. The agency received the premarket approval (PMA) application in January 1997, convened an advisory panel in midsummer, and acted on the panel’s unanimous recommendation for approval just 19 days later. Approval was based on a study of 454 patients at 45 medical centers. About half showed at least a 20% reduction in the number of seizures per day.

The device, which costs about $6000 and another $2000 to implant, stimulates the vagus nerve every few minutes to decrease the brain’s sensitivity to the stimuli that trigger seizures. Whereas neurological patients commonly require increasingly stronger dosages of a medication to maintain an effect, the opposite appears to be true for vagal stimulation. "In patients who have used the device for two, three, or four years, the efficacy seems to keep getting better," says Lunney, who believes the repeated shocks may rehabilitate the brain. "It is like a relearning phenomenon."

The success of the electrode signals has not dampened interest in a closed-loop system that would detect the early signs of a seizure and fire a preventive electrical charge. Lunney envisions the day when an implantable device will provide chronic stimulation to "strengthen" the brain and also stop seizures in their earliest stages. "Cardiac pacemakers started out as chronic pacers, then went to rate-responsive pacing, and now have on-demand defibrillators with rate-responsive pacing," Lunney notes. "So, technologically, I see parallels."

HELPING PATIENTS WITH PARKINSON’S DISEASE

Medtronic, Inc. (Minneapolis), best known for its cardiac pacemakers and implantable defibrillators, is working on a closed-loop system to detect, monitor,

and prevent seizures. Meanwhile, the company’s recent success is the Activa Tremor Control Therapy device, which blocks the brain signals that cause essential tremor, a disabling, involuntary shaking in patients with Parkinson’s disease.

"Before the implant, patients could not raise a glass of water or a spoonful of food to their mouths without spilling something or striking themselves in the face," says William Koller, MD, PhD, chairman of the neurology department and professor of pharmacology at the University of Kansas Medical Center (Kansas City), where the device underwent clinical study prior to FDA approval. "Within hours, these same patients are sipping tea from a cup and eating peas with a fork."

Activa fires an electrical charge along an insulated wire surgically implanted in the thalamus, the brain’s communication center. A lead transmits the charge from an extension wire passed under the skin to a pulse generator implanted near the collarbone. Prior to implantation, physicians evaluate each patient to determine the optimal stimulation level at which to program the generator. Patients can turn the device on and off or increase and decrease stimulation by waving a handheld magnet over the implanted generator.

Activa’s disadvantage is its limited clinical utility. Tremor is only one of several debilitating symptoms of Parkinson’s disease, and the device doesn’t alleviate those other problems. "Drug therapy helps a lot more symptoms than tremor," says Angelo Patil, MD, a neurosurgeon at the University of Nebraska Medical Center (Omaha), who evaluated the device in clinical trials. "You don’t want to subject patients to the risk of a surgical procedure if they can be managed with medication." Activa is thus restricted to patients who do not respond to medication, but Patil says many Parkinson’s patients eventually become drug refractory. Work is under way to extend the clinical reach of this neurostimulator. By stimulation of other parts of the brain, symptoms such as rigidity and dyskinesia—impairment of voluntary movement—might be relieved.

DEEP BRAIN STIMULATION

A neurostimulator designed to relieve rigidity was among the research projects featured at a mid-October closed briefing at the National Institutes of Health. A video depicted a patient with uncontrollable movement of his right leg. With great difficulty, he took small steps, shuffling laboriously behind his wife. "Then, after the implant, they showed him walking briskly across the room, swinging his arms," recalls Agnew. "Very impressive."

Agnew did not identify the research group whose work was shown in the video, but Medtronic has already achieved positive results using a stimulator. "Most of these patients are already drug refractory and their only other option is surgical destruction of the brain, which cannot be undone," says Jessica Stoltenberg, Medtronic spokeswoman. "Our probes can be adjusted or removed."

Medtronic is studying the effects of probe implantation in two sites, the sub-thalamic nucleus and an internal portion of the globus pallidus. Only one probe is implanted in a patient. The location, says Laurie McBane, Medtronic clinical evaluation manager, depends on a physician’s evaluation of the patient’s symptoms and their severity.

Brain stimulation is just one facet of the company’s research. Medtronic previously developed and began marketing two pain management stimulators in the United States—the Itrel 3 and Mattrix. Both are fully implantable in the spine, and the dual-lead Mattrix allows independent control of the two leads to block difficult-to-treat bilateral pain patterns.

OTHER APPLICATIONS OF NERVE STIMULATION

In late September, FDA approved Medtronic’s Interstim Continence Control Therapy, which stimulates the sacral nerves to manage urinary urge incontinence. Interstim fires electrical pulses into the sacral nerves, located at the base of the spine, to help avoid or reduce accidental urination. Physicians can tailor treatment to the patient, adjusting stimulation frequency and strengths to maximize therapy benefits.

Three of four subjects in the clinical trials experienced at least a 50% reduction in leakage episodes and severity of leaks, according to Steven Siegel, MD, of Metropolitan Urologic Specialists in Minneapolis. "These individuals could see some real improvement in their quality of life, not only regaining control of their bodily functions but also regaining self-esteem and confidence," he says.

NeuroControl Corp. (Cleveland) also has a sacral nerve stimulator, the Vocare, which it is evaluating at 10 clinical sites across the United States. The company already has another neurologic device on the market—its Freehand System, which restores partial movement to some quadriplegics. "Patients are now able to feed themselves, write, operate a computer, and answer the telephone," says Ronald Podraza, NeuroControl president and CEO. "These are people who once needed assistance with everything and who now have substantial independence."

FDA approved the use of the Freehand System in August for adult quadriplegics with C5 or C6 (fifth or sixth cervical vertebrae) spinal cord injuries. These patients have retained some upper body mobility because the portion of the spinal cord that controls the upper body is above the injured area and can thus still communicate with the brain. Freehand uses both external and surgically implanted electronics. A position sensor, mounted on the chest and shoulder, translates small movements into a control signal. An external controller, usually mounted on the wheelchair, processes this signal into radio commands that are beamed to a microprocessor implanted in the chest. When the eight electrodes wired into the paralyzed hand and forearm muscles receive stimuli from the microprocessor, the muscles contract—for example, making a finger and thumb pinch together—providing the person with a functional hand grasp.

ENHANCING QUALITY OF LIFE

One of the challenges facing NeuroControl was demonstrating device efficacy to meet FDA requirements for approval. "We had patients perform activities of daily living," says Julie Grill, manager of clinical studies and regulatory affairs. Their ability to manipulate objects was documented with the device turned on and then turned off. "One of the advantages of the device is that you can turn it off," Grill says. "We were able to have the patients act as their own control subjects."

Engineers are now expanding the device’s capability. At present, Freehand enhances motor control for only one side of the patient, and its eight channels stimulate a limited number of arm muscles. "Our next step is to extend the stimulating channels so we can recruit more muscles," says Zi-ping Fang, PhD, director of R&D at NeuroControl. "We want to get into the muscle of the hand itself."

Fang hopes to expand the patient population that might benefit from the Freehand System to those with C4-related paralysis. Their spinal cords are injured farther up than those with C5 and C6 injuries, so they have even less mobility. Eventually, Fang would like to develop a closed-loop system to provide the sensory feedback needed for precise finger and wrist control.

As engineers exercise more finesse in their approaches and designs, this evolving technology will become even more appealing. Opel believes that electronics and biochemistry will eventually merge into a technology that is neither tissue nor device. Electrical activity in the nervous system is chemically modulated, as in the transmission of a signal across the synapse or the depolarization and repolarization of the neuron. "Ultimately, we will be able to establish a bias state chemically and use electronics to do discrete switching of signals," Opel says. Such a merger of microchemistry and microelectronics into a manmade technology, he predicts, "will lead us to better therapy of the nervous system."


Copyright ©1997 Medical Device & Diagnostic Industry

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