I was invited to speak at the 5^th International Symposium on Experimental Spinal Cord Repair and Regeneration about various therapies discussed in my PN “Healing Options” series. Held on March 27-29 in Brescia, Italy, the Symposium was hosted by University of Brescia’s Dr. Giorgio Brunelli.

Believing that the development of new therapies for spinal cord injury (SCI) requires global and multidisciplinary cooperation, organizers invited scientists with diverse viewpoints from throughout the world.  As in the previous symposium, a highlight was the participation of Dr. Rita Levi-Montalcini, the 1986 Nobel Laureate in Medicine for discovering nerve growth factor over 50 years ago. Following are summaries of a few presentations:

Neuromonitoring:

A keynote lecture was given by Dr. Milan Dimitrijevic (Texas), an internationally recognized neurophysiologist whose investigations on spinal-cord conduction have greatly contributed to our understanding of SCI. He noted that the spinal cord is much more physiologically complex than originally thought; however, rather than making functional repair more challenging, this complexity generates opportunities for new rehabilitation strategies.

Dimitrijevic discussed how various interventions after acute SCI - such as surgical stabilization and reconstructions - could be monitored by recording conduction above and below the injury site. By using such neuromonitoring, a surgeon can have valuable information on where spinal-cord integrity is being preserved.

Through knowledge gained from such monitoring, it may be possible to initiate physiological-like electrical stimulation of the non-injured conducting axons to prevent effects of disuse and secondary lesions.

In chronic injuries, neuromonitoring could assess the efficacy of various function-restoring interventions. For example, the neuromonitoring of bridging tissue transplants could provide information about whether the transplants are filling the gap, integrating with surviving tissue, decreasing scar tissue, reducing cavity formation, staying where placed, and increasing migration of blood vessels or cells that facilitate axonal regeneration.

Rerouted Nerves:

Brunelli, the symposium organizer, reviewed his research on surgically rerouting human peripheral nerves (i.e., those outside of the spinal cord and brain) around the injury site to reestablish functional neuronal connections. For example, he has restored some function by redirecting the wrist’s ulnar nerve and connecting it to nerves that control leg functioning below the injury site. After this procedure, a patient with a complete spinal-cord transection could stand up and walk short distances.

In another procedure carried out in a woman with a complete thoracic transection, the peroneal nerve (to the leg) was used as a bridge directly from the spinal cord above the injury site to the nerves of the gluteus and quadriceps muscles. After two years, she was able to walk 30-40 meters with a walker.

Because the second procedure represents a direct peripheral-nerve-to-spinal-cord connection, it challenged traditional beliefs on how neurons control muscle function. Specifically, in the previous symposium, Levi-Montalcini was troubled by the implications of Brunelli’s work because upper motor neurons (nerves within the spinal cord) and lower motor neurons (nerves that leave the cord to connect to muscles) use different neurotransmitters (chemicals released from a neuron ending that interacts with an adjacent neuron or muscle cell). Hence, theoretically, the muscle should not be triggered due to neurotransmitter incompatibility.

Because scientists pay special attention to the suggestions of Nobel laureates, Brunelli and collaborators have since shown that this procedure indeed restores function in rats in spite of this putative incompatibility. Specifically, they have demonstrated that the target muscles are genetically reprogrammed, producing receptors that are responsive to the neurotransmitters released by the upper motor neurons that have grown to the muscles through the peripheral nerve bridge. 

Radiation:

Dr. Nurit Kalderon (New York) has treated acutely injured rats with radiation, which destroys nascent scar-tissue that blocks neuronal regeneration. Although the spinal cord attempts to repair itself soon after injury, the decay process takes over after the third week. However, when x-rays were directed to the transected spinal cord during the third week, the cord continued to repair.  Once the wound was healed, severed neurons grew across the site, restoring some function.  Because x-rays destroy obstructive cells, spinal-cord repair can continue.

Kalderon carried out additional studies in rats injured by contusion, which more closely resembles most human injuries. Before radiation, surgery was performed to reduce secondary damage caused by swelling and fluid buildup.  Starting 12 days postinjury, the lesion was radiated daily for 10 days at a level proportionate to that clinically used to remove human cancer. Analysis indicated significant tissue repair. 

Activity-Mediated Neurorehabilitation:

Dr. Humberto Cerrel Bazo (Italy) discussed the use of activity–mediated training - such as functional electrical stimulation (FES) - to maximize function after SCI. His talk, as well as others, referred to the spinal cord’s “central pattern generator,” which can sustain lower-limb repetitive movement, such as walking, independent of direct brain control.

Cerrel Bazo noted that we are learning much more about 1) the plasticity (adaptive mechanisms by which the nervous system restores itself) of the sensorimotor nervous system above and below the injury site (i.e., brain-spinal-cord-motor unit), and 2) the residual activity of muscles, bladder, bowel, etc. amenable for enhanced function through new circuitry or artificial means.

He reviewed how a sacral-sparing assessment procedure (gauges anal sensation and control) within 30-days of injury is useful for predicting future functional recovery.

Through FES training, Cerrel Bazo has shown promising, plasticity-associated outcomes, which, in turn, suggests intriguing possibilities about the integration of different systems above and below the injury site. FES may enhance residual potential in people with chronic SCI by generating a movement pattern useful for standing, stepping, and cycling.

However, if residual activity remains dormant over the long term, awareness to support activity may be lost. A properly stimulated sensorimotor nervous system may generate activity useful for the functional integration of different systems. In this sense, FES, the awareness-learning process, and training mediated-activities may open communication pathways between areas above and below the injury site.

Macrophage Therapy:

Drs. Eti Yole, Nachson Knoller, (Israel), and Sir Jacques Brotchi (Belgium) summarized Proneuron Biotechnologies’ efforts to use activated macrophages (a white blood cell) isolated from patient’s blood to minimize neurological damage after acute SCI. Although healing immune cells are scarce in the “immune-privileged” central nervous system, Proneuron has circumvented this limitation by incubating the patient’s macrophage-containing blood with skin tissue. The isolated macrophages are then surgically implanted into the spinal cord within 14 days of injury. By mediating protective immune responses, these activated macrophages promote functional recovery.

Phase 1 clinical trials showed no adverse treatment effects. Functional improvement was measured using the American Spinal Injury Association (ASIA) assessment standards. Of the eight patients treated (2 cervical and 8 thoracic injuries), three improved from ASIA A to C (complete injury to partial motor and sensory recovery). Of the remaining ASIA A patients, three showed improvements in sensory scores and nerve conduction. Proneuron has initiated a much larger phase II clinical trial that will recruit 61 patients at five treatment sites: Sheba Hospital (Israel), Craig Hospital (Colo.), Mt. Sinai (N.Y.), Kessler Rehabilitation (N.J.), and Shepherd Center (Ga.).

Conclusion:

As reflected by symposium presentations, the once considered insurmountable barriers to restoring function after acute or chronic SCI are gradually being eroded in many ways. More importantly, over time, there has been a cumulatively huge shift in the attitude of the inherently conservative scientific community. Namely, SCI is no longer automatically a life sentence of paralysis without parole but a neurological disorder amenable to function-restoring therapies. This shift in the scientific collective consciousness by itself will greatly accelerate the development of real-world therapies.

Adapted from article appearing in Paraplegia News (For subscriptions, call 602-224-0500) or go to www.pn-magazine.com).

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