Beauty of Botox is more than skin deep

Yale scientists employ botulinum toxin, known for its cosmetic uses, to treat neurological disorders.

For centuries, botulinum toxin has been known as the cause of the paralytic and sometimes fatal illness known as botulism. Best known by the brand name Botox, the toxin’s type A variant has a reputation as a cosmetic and is famous for smoothing furrowed brows.

Bahman Jabbari, M.D., professor of neurology, is among a small number of clinicians with expertise in the toxin’s many therapeutic uses. He and his Yale neurology colleagues are using it to treat a constellation of neurological disorders, migraine headaches and other complaints in a growing practice that saw 300 patients last year.

“It is a remarkable drug,” said Jabbari, the former chief of neurology at Walter Reed Army Medical Center in Washington, who was among the first researchers to establish the drug’s effectiveness in treating pain. “It is something that gives very few side effects, yet the patient sees results that are so dramatic, so sustained.”

Botulinum A is used to treat muscular symptoms in head trauma, stroke, cerebral palsy and multiple sclerosis. In these conditions, the relief comes from the toxin’s muscle-relaxing properties—the same properties that make it useful to combat wrinkles, said Jabbari. But, he added, the drug has a range of biochemical actions effective in many conditions, including excessive sweating and salivation. Botulinum A offers a palliative option in many cases where other medicines had been unable to offer much comfort.

“It is very satisfying to be able to give relief to patients with a chronic neurological disorder who previously had no hope,” said Jonathan M. Goldstein, M.D., associate professor of neurology and director of clinical services in the department.

Jabbari’s current investigations focus on pain relief, which he believes is the greatest area of potential for botulinum A. Patient H. Stuart Engar volunteered for one of Jabbari’s studies, hoping for a reprieve from excruciating neck pain. An undiagnosed neurological disorder had left Engar unable to work or perform such simple tasks as bending to unload the dishwasher. Though the study is completed, Engar continues to get botulinum A injections every three to four months for pain and mobility. He called the treatments “life-changing.”

On a recent visit, Jabbari administered a series of injections in carefully pinpointed muscles along Engar’s neck. In some cases, physicians use electromyographic guidance to make the injections. Jabbari asked Engar if he experienced side effects from the treatment. Like most patients, he did not. The most common side effects are flu-like symptoms and muscle weakness, the latter of which is often prevented by proper dosage, Jabbari said. There is no danger to patients who take botulinum A long-term, he added, because the toxin gets deactivated in the body after three months.

Patients do, nevertheless, express misgivings about Botox. When Huned S. Patwa, M.D., associate professor of neurology, picked up a syringe, the patient—a migraine sufferer—asked, “Do you know where it came from?”

She was referring to a Florida physician who injected patients with a counterfeit version of the drug. The unlicensed product contained much higher concentrations of the toxin, causing patients to contract botulism.

Ironically, botulinum’s promise as a weapon helped to unlock its healing potential. Army officer Edward J. Schantz, Ph.D., first purified botulinum toxin type A in a crystalline form in 1946 when the U.S. military was studying it as a weapon. Schantz later collaborated with Alan B. Scott, M.D., who used the toxin to relieve strabismus (crossed eyes) in monkeys. Over the course of 20 years they developed a version of the toxin that won FDA approval for testing on humans. They sold it to the pharmaceutical company Allergan, which branded the drug Botox. In 1989, the FDA approved it for the treatment of strabismus, blepharospasm and hemifacial spasm in patients over 12 years old.

Researchers like Jabbari see the drug’s future applications as broad and promising. For patients like Engar, clinical botulinum has already made a dramatic difference. “I can hold my grandchild,” he said. “That may seem like a small thing, but … no, that’s a big thing.”

—Colleen Shaddox

Anesthesiologist finds a new way to manage blood loss in the operating room

The most common method for tracking blood volume during surgery—a catheter inserted into the heart that transmits information to a monitor—is not only invasive, but not very accurate.

This leads, according to Kirk H. Shelley, M.D., Ph.D., associate professor of anesthesiology, to a delicate clinical balancing act with very high stakes. “Too little fluid can put a tremendous amount of stress on the kidneys, the cardiovascular system and the central nervous system,” Shelley said. “But if you give too much fluid for the heart to pump, it backs up, causing bloating and pulmonary edema.”

Now Shelley, who as chief of ambulatory surgery oversees about 8,000 surgeries a year at Yale-New Haven Hospital, has found a possible solution to this surgical dilemma. By combining a clinical insight from the 1870s with data provided by the modern pulse oximeter, a clothespin-like clip placed on a fingertip, ear or toe to measure the oxygen level in the blood, Shelley has discovered a noninvasive, precisely quantified method to monitor blood loss and guide difficult decisions in the operating room.

The pulse oximeter has become a common sight in hospital hallways since it was first introduced in the 1980s. The clips contain light-emitting diodes that shine both visible red and infrared light through the skin. Because deoxygenated hemoglobin allows infrared light to pass but absorbs red light, while oxygenated hemoglobin allows red light to pass and absorbs infrared, the oximeter can detect changes in the blood’s oxygen saturation by calculating the relative absorption of red and infrared light.

In those early days of the pulse oximeter, Shelley discovered that oximetry clips generated exceedingly complex waveforms that were “cleaned up” by oximeter manufacturers in favor of clear, simple signals. But Shelley’s curiosity about the wealth of information produced by early oximeters prompted him to devise software to sift through the raw oximetry signal for potentially valuable clinical information.

Shelley found that pulsus paradoxus—a drop in blood flow after a deep breath caused by the mechanical ventilation used in anesthesia—could be detected in the raw oximetry waveform.

“There’s all sorts of wild, raw data that comes off the pulse oximeter that companies have worked hard to eliminate, because it has been seen as just noise,” said L. Alan Carr, Ph.D., then a senior licensing associate in Yale’s Office of Cooperative Research who shepherded the discovery through a patent application. “What’s ironic is that the background data actually had useful information in it.”

Shelley plans to mine the pulse oximeter for even more clinical treasure, and he is adapting his method for use in nonventilated patients suffering from blood loss, such as trauma patients arriving at emergency departments.

—Peter Farley

et cetera

Work, habits and health

Researchers in Epidemiology and Public Health have received $1.7 million from the National Institute on Aging to study the interplay of work-life, health habits and health over a lifetime. For the study, “Work-life, Health Habits and Health: Longitudinal Analysis of Aging,” researchers will build a life cycle model, covering adolescence to late life, that evaluates occupation, smoking and drinking and obesity.

The study began in March and will continue through February 2010. Jody L. Sindelar, Ph.D., professor of public health, is the principal investigator. “Since much of life is spent working, characteristics of work are potentially important risk factors and can be viewed in the same vein as health habits,” she said.

—John Curtis

Yale to study leishmaniasis

Yale researchers have received a $5.4 million grant from the National Institutes of Health for the study of cutaneous leishmaniasis (CL), a parasitic disease spread by the female sand fly.

The grant will support three projects in Colombia. The first will develop the infrastructure for clinical trials. The second will identify factors responsible for transmission as well as vector control measures. The third will study immunological responses to the parasite.

“With over 400 species of sand flies in the Americas alone and at least a dozen species of CL occurring all over the world, the epidemiology of leishmaniasis is complex,” said co-principal investigator Leonard E. Munstermann, Ph.D., senior research scientist in epidemiology (microbial diseases). “However, we believe that the current study in Colombia can become a sound epidemiological model for other endemic regions.”

The program is a collaboration with the Centro Internacional de Entrenamiento e Investigaciones Medicas in Cali, Colombia. Diane M. McMahon-Pratt, Ph.D., professor of epidemiology, is the co-principal investigator and the Yale program director on the grant.

—J.C.


			Originally published in Yale Medicine, Autumn 2006. Copyright © 2006 Yale University School of Medicine. All rights reserved.