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From OncoLog, April-May 2010, Vol. 55, No. 4-5

Imaging Nerves
Tetanus Toxin Offers Promise for Neurography

By John LeBas

Graphic: Artist rendering of nerves
The goal of neurography is in vivo imaging of nerves, as suggested by this artist’s rendering.

Unintentional damage to nerves remains a significant problem in cancer treatment. Many cancer treatments can potentially harm nerves, resulting in neuropathies with such symptoms as impotence, weakness, abnormal sensations, and difficulties with bowel control and bladder function. Many of these problems might be prevented if peripheral nerves could be made visible, but currently there are very few options for visualizing peripheral nerves in vivo.

Recent research at The University of Texas MD Anderson Cancer Center points to a potential solution. Using laboratory animals, MD Anderson investigators have demonstrated a way to make peripheral nerves literally light up with fluorescent imaging. The work is believed to be the first demonstration of nerves preferentially taking up a contrast agent to enhance visualization, which has researchers excited about its potential not only in cancer treatment but in other health care applications as well.

The novel imaging approach taps into a natural nerve transport pathway usually used for the growth and maintenance of nerves. “This retrograde transport pathway is what the neuron itself uses to get growth factors back from peripheral tissue to the brain or spinal cord,” said Dawid Schellingerhout, M.D., an assistant professor in Diagnostic Radiology and Experimental Diagnostic Imaging at MD Anderson and lead investigator on the studies.

It turns out that a nontoxic fragment of tetanus toxin can bind to this pathway and be transported up the nerve. Dr. Schellingerhout realized that an image-enhancing agent could be attached to this fragment and transported along nerves as well, essentially hitching a ride and making the path visible.

“Our experiments showed that that we could hijack the retrograde transport mechanism by using this tetanus toxin fragment to carry imaging agents into nerves, bypassing the shielding effect of the blood-brain barrier,” he explained. It is the protective wall formed by the blood-brain barrier that makes delivering therapies and imaging agents to nervous system components so difficult.

“Most would agree that our imaging technologies for peripheral nerve structures could benefit from a major improvement,” Dr. Schellingerhout continued. “We’re just not that great at imaging peripheral nerves. We can use magnetic resonance (MR) to show nerves near the spinal cord, but that’s about it.

“Contrast that with cardiovascular imaging, for which effective imaging technologies developed owing to the successful application of contrast agents. Thanks to those imaging technologies, we can do a vast range of diagnostic and therapeutic procedures such as angiograms, computed tomography angiograms, endovascular procedures, and so on. A whole industry grew out of these imaging techniques, and because we do such a good job of imaging vessels, we can help thousands of people each day.”

If nerves could be imaged in a similar manner, people with blindness, deafness, paralysis, impotence, diabetic foot ulcers, neuropathies, and other nerve-related problems could benefit. “History teaches us that improved diagnostic ability has always led to improved therapies and eventually to better outcomes,” Dr. Schellingerhout said. “Many nerve-related diseases are currently regarded as without cure, but with proper contrast agents and imaging, we may be able to improve our understanding of these diseases to the point where we can offer effective therapies. ”

Scope of the problem

The need for effective nerve imaging in human patients is as vast as the number of ailments caused by injured or diseased nerves. Unfortunately, advances in neurography, or the imaging of nervous system components, have been slow. Unlike blood vessels, into which compounds can be injected for transport, the nervous system consists of solid tissues with no built-in channel for transporting agents.

What this means for imaging is that there is no way to distribute a contrast agent throughout the nervous system. And without a contrast agent, the ability of current imaging technologies like MR and computed tomography to distinguish nerves from surrounding tissue is greatly restricted—particularly as nerve bundles become smaller the farther they are from the brain and spine.

In surgery, whether for cancer or other conditions, nerves are often inadvertently damaged or cut because of visualization difficulties or the nerves’ proximity to other structures that must be disturbed. For example, 75% or more of men who undergo prostatectomy for the treatment of prostate cancer suffer postsurgical impotence resulting from nerve damage during surgery. “Visualizing the nerve bundle is actually not a problem for the expert surgeon,” explained John W. Davis, M.D., an assistant professor in the Department of Urology who conducts prostatectomies using robotic-assisted techniques. “However, multiple blood vessels crossing from the nerve bundle to the prostate must be divided and clipped during prostatectomy, and it is thought that the stretching and traction on the bundle causes injury, even if the nerves are not cut.

“Can a surgeon do a better job of preserving potency if the actual nerve fibers can be seen distinctly from their surrounding bundle of blood vessels? Further study will be required, but the idea is certainly attractive,” continued Dr. Davis, who is not involved with Dr. Schellingerhout’s work. “Perhaps this method of neurography could show the surgeon where the nerve fibers are closest to the prostate gland and where they are not, such that the surgeon could prioritize time and techniques more appropriately. We may even learn more about the variability of nerve fiber anatomy.”

Photo: Dr. Dawid Schellingerhout
“Improved diagnostic ability has always led to improved therapies. With proper contrast agents and imaging, we may be able to improve our understanding of nerve-related diseases to the point where we can offer effective therapies.”
 — Dr. Dawid Schellingerhout

The other mainstays of cancer treatment, chemotherapy and radiation therapy, can also cause nerve injuries with significant consequences for the patient. Certain chemotherapies, particularly platinum-based agents, can induce severe, painful neuropathy. Radiation can cause such conditions as brachial plexopathy (occurring in some patients receiving treatment for thoracic and breast tumors) when nerves in or adjacent to the treatment area are damaged by radiation (although the peripheral nervous system is relatively radioresistant).

Finally, cancer itself often directly invades or interferes with nerve tissue adjacent to the primary tumor. Furthermore, the spine and brain are common sites of metastasis for numerous cancer types. Yet little can be done to visualize the physical effects of tumors on nerves, particularly small nerves, or to deliver therapies to tumors that directly involve nerves.

Beyond cancer, the medical need for nerve imaging is widely apparent. For example, diabetics often suffer neuropathy that prevents them from feeling their feet. Because of insensate feet, many of these patients develop infected foot ulcers that can be very difficult to cure, sometimes requiring surgery and even amputation. “Unfortunately, diabetic neuropathy can currently be treated only by improving control of the underlying diabetes and stopping its progression,” Dr. Schellingerhout said. “Current knowledge suggests that the damage already done is irreversible. As with the damage to nerves caused by cancer and cancer therapies, we need to be able to visualize the nerves to better decipher the mechanisms at work in causing the damage. Having a means to study the retrograde transport pathway in nerves is almost certain to yield new insights into the causes and potential cures for these neuropathies.”

Hijacking the tetanus toxin

The retrograde transport pathway has long been known as the mechanism by which growth factors move along peripheral nerves to the nerve cell bodies in the brain and spine. Work done previously to understand tetany revealed that tetanus toxin also makes use of the retrograde transport pathway to gain access to the spinal cord. Further work in deciphering functions of the various parts of tetanus toxin revealed that a fragment of the toxin can be transported without the toxic effects of the intact toxin. “Thus, this nontoxic fragment can be labeled with useful compounds and can deliver them efficiently along the nerves,” Dr. Schellingerhout said.

In a report published last fall in the journal Molecular Imaging (Schellingerhout et al., v. 8, 2009), Dr. Schellingerhout and colleagues showed that the nontoxic fragment labeled with a fluorescent imaging contrast agent was specifically and quickly taken up by the sciatic nerve in mice and delivered to the spinal cord. The compound was injected into muscle and could subsequently be seen on imaging illuminating the nerve tissue along which it had traveled.

If this approach can be refined and applied to humans, it could allow nerve mapping and image-based study of nerve physiologic processes, Dr. Schellingerhout said. “This could significantly advance our capabilities in surgical planning and diagnosis of nerve disease,” he explained. “We are currently gathering more data and seeking funding to make neurography in humans a reality.”

For more information, contact Dr. Schellingerhout at 713-792-3817.

Other articles in OncoLog, April-May 2010 issue:

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