OLFACTORY-TISSUE TRANSPLANTATION FOR SCI: PORTUGAL CLINICAL TRIALS

Part 1 of this article discussed olfactory tissue’s remarkable regenerative potential and the efforts of various scientists throughout the world to harness this potential by transplanting it into the injury site of people with chronic spinal cord injury (SCI). Part 2 discusses the pioneering work of one of these scientists, Portugal’s Carlos Lima.

Olfactory Tissue:

Olfactory tissue, which covers about one-inch of the upper nasal cavity, contains many cells with regenerative potential, including renewable neurons, progenitor stem cells, and remyelinating olfactory ensheathing cells (OECs). Olfactory neurons are comfortable residing in the central and peripheral nervous system; because they are the body’s only surface neurons, they readily regenerate from a pool of progenitor stem cells. In addition, OECs can produce insulating myelin sheaths around both growing and damaged spinal cord axons, secrete various neuronal growth factors, and produce structural and matrix macromolecules that lay the tracks for axonal elongation.

Carlos Lima:

A 48-year old neuropathologist at Lisbon’s Egaz Moniz Hospital, Lima obtained medical training in Portugal and Germany. In addition to olfactory-tissue physiology, he is an authority on the neuropathology of HIV infection and brain disorders similar to mad-cow disease.

Lima seemed destined to work on olfactory processes. For example, before he was a medical student, Lima was a rock-and-roll singer, and, with prescient foresight, composed “Nose, Nose, Nose,” a song based on a poem written by eighteenth century Portuguese Poet Manuel Bocage.

Lima’s guitar still stands out among home-office computer equipment, and it was only the pleading of his exam-studying son that prevented Lima from giving an impromptu rendition of the song during my visit with him. The incident reminded me again that scientific inspiration reflects the soul’s creativity just as much as the mind’s intellect.

Lima’s scientific epiphany came 15 years ago when, after reading about olfactory tissue’s unique neurological properties, he immediately envisioned its potential for bridging injured spinal cords. Since then, he has unwaveringly directed his research toward this goal, carrying out extensive studies in animals as well as human cadavers.

Lima emphasizes that the project is a multidisciplinary collaboration that also includes Pedro Escada, an ear-nose-and-throat specialist who collects the patient’s olfactory tissue, Pratas Vital or Hasse Ferreira, neurosurgeons who implant this tissue into the patient’s spinal cord, and other Egaz Moniz Hospital specialists (Photo: Escada, Vital, Ferreira & Lima).

Possessing a panoramic vista of the Tejo River estuary, the Egaz Moniz Hospital has a historical association with neurological innovation, including being named after a 1949 Portuguese Nobel Laureate, who developed cerebral angiography for visualizing brain blood vessels.

Patients:

Based on Lima’s extensive preliminary research, the hospital’s ethics committee approved the human clinical trials. Patients were subjected to various neurological, neurophysiological (i.e., neuronal conduction), magnetic resonance imaging (MRI), bladder-functioning, and psychological assessments before and after treatment.

Assessments included the “gold-standard” ASIA (American Spinal Injury Association) impairment scales for measuring SCI-related sensory and motor impairment. With these scales, patient improvement due to a specific intervention can be assessed in a consistent fashion and more readily compared to other studies. Patients were excluded if they had psychological disturbances, multiple spinal cord lesions, confounding medical conditions, arm or leg denervation, or severe spinal cord atrophy.

From July 2001 to the beginning of 2003, Lima’s team has operated on four female and three male patients. Three were quadriplegics and four paraplegics. Six of the seven had ASIA-classified complete injuries. Ages ranged from 11-32 (averaging 22), and the time between injury and surgery varied from ½ - 6 ½ years. Spinal cord lesions ranged from 1-6 cm (1 cm = .39 inches) in length, although Lima now believes that the lesion optimally should be less than 2-3 cm. Most injuries were contusion injuries, similar to those sustained in car accidents.

Surgery:

The surgery consists of harvesting olfactory tissue from the patient’s nasal cavity, preparing it, and implanting it back into his or her spinal cord injury site. The procedure takes 4-6 hours depending upon injury level and extent of injury, presence of fixation plates or screws, etc. The patient is discharged from the hospital after 4-7 days.

The critical procedure is the collection of about one fourth of the patient’s olfactory tissue through unique procedures that maximize the harvesting of that tissue and minimize the collection of closely associated nasal respiratory tissue. Although Lima’s experience indicates that small amounts of contaminating respiratory tissue are innocuous, it nevertheless lacks olfactory tissue’s regenerative components. Because olfactory tissue can diminish over time, patient age is important.

In contrast to other researchers who have started to implant isolated OECs into patients with SCI, Lima uses whole olfactory tissue for transplantation without attempting to separate cellular components. He believes that more than one cell type is needed to maximize regeneration in the injured cord, including, in addition to OECs, neurons in different developmental stages, and precursor stem cells.

Because the graft is taken from the patient, immunosuppressive drugs are not needed to avert tissue rejection. In addition, patients regain smelling ability within several weeks.

The neurosurgeon exposes the cord’s injury site with a laminectomy and then myelotomy (cutting open the cord’s membrane coverings). Although it is impossible to remove all of the scar tissue at the injury site cavity, the scar’s top and bottom stumps are taken off so that the cord is visible, and in between, holes are made in the scar.

As the cavity is being prepared, Lima dissects the isolated olfactory tissue into 20-30 pieces while it is immersed in a small amount of the patient’s cerebrospinal fluid. The pieces are then implanted into the cavity. Lima estimates that a 1 cm² cavity filled by this tissue will contain approximately 400,000 stem cells and 4 million each of mature neurons, immature neurons, and other supporting cells.

Outcomes:

Although preliminary results are promising, Lima emphasizes that much follow-up work is needed to document long-term benefits and any delayed side effects. Because only a short-time period has ensued since surgery for many patients, benefits associated with neurological regeneration are not expected to fully accrue for some time. Although Lima underscores that patients should have realistic expectations and not anticipate an all-encompassing, restoration-of-function panacea, he believes that even modest restored function can have profound quality-of-life benefits.

Using the ASIA standards, six of the seven patients regained some sensation and muscle control within a month of surgery. Because the seventh patient had a second undetected lesion, he did not improve.

Lima suggests that this initial recovery may be due to bridging and remyelination of available axons and also perhaps due to some post-surgical cord decompression. Improvement should gradually continue with time as neurons or their axons further regenerate and grow (~ 0.1 cm/day), remyelinate, and make new connections.

This gradual improvement is demonstrated by Lima’s first patient, a 21-year old female who sustained a C7-T1 contusion-type injury six months before surgery. She regained some sensory recovery about one month after surgery, voluntary abdominal muscle control at two months, some gluteus and leg adductor muscle control, including standing without leg braces after about nine months, and recently some bladder control.

Overall, MRIs indicate substantial filling of and continuity in the lesions by the grafts, and electrophysiological assessments document voluntary muscle control.

Lima’s patients have had access to only modest post-surgical rehabilitation. He believes maximal restored function will require much more aggressive rehabilitation.

What Patients Say:

Luís, 29, sustained a 4-cm-long, clinically complete, T4-5 injury two years ago while helping a friend paint walls. After misplacing a foot, his life turned upside down. When a friend told him about Dr. Lima’s work, he immediately volunteered to be a candidate.

“There was much uncertainty, but I had nothing to loose,” he remembers.

Luís started noticing improvements two or three weeks after his August operation. He first regained sensitivity immediately below the injury site. Then came control of abdominal muscles and recently abductor muscles, essential for equilibrium when standing.

“Now I can feel the cold, and even get goose pimples. Day by day, I rediscover my capacities,” he says smiling broadly with a big smile. “And to accomplish it, I am ready to do whatever it takes.”

Florbela, 32, sustained a 2-cm-long, C6 injury in a car accident six years ago. Her restored function demonstrates the procedure’s potential for those with more long-term injuries. Specifically, within several months of her surgery, she recovered abdominal muscle control, left-leg sensitivity, and, most recently, some grasping ability, which occurred at home with her husband. She enthusiastically notes “We have recorded everything with the digital camera; I want everybody to see it”. 

American Patients:

At the time this article was written, two American women with C6 injuries from 2001 auto accidents were being scheduled for olfactory-tissue transplantation. They are considered superb candidates due to their youth, excellent physical health, and commitment to rigorous rehabilitation.

To help disseminate this function-restoring surgery, Lima is attempting to develop a collaboration with an U.S. hospital, in which Americans will travel to Portugal for olfactory-tissue transplantation, and Portuguese patients will travel to America for rehabilitation.

Conclusion:

At a 1995 congressional reception focused on SCI, a colleague with high-level quadriplegia characterized the state of SCI research by paraphrasing a famous Martin Luther King speech. He believed that after a long trek in the wilderness, we have climbed the mountain and for the first time can see in the distance the Promised Land of restored function; some may complete the journey, and some may not.

Times have changed. This Promised Land is no longer a mere vision hovering on the horizon. With groundbreaking physicians and scientists guiding the way, the first pioneers with SCI are beginning to step, in some cases literally, into this Land. Whether it is someone like Luís and Florbela mentioned above, the Shanghai motorcycle driver Huocheng who can now walk and control bladder and bowel function because of a nerve-transfer surgery (PN, April 2002), actor Christopher Reeve, who through innovative rehabilitation therapy can now initiate never-expected movements (TIME, September 23, 2002), or world pole-vault record holder Brian Sternberg who regained considerable life enhancing function decades after injury through omental transposition (PN, March 2001), an increasing number of such pioneers are in the future. It is a growing reality coalescing in bits and pieces, including the first olfactory-tissue transplantation carried out by Dr. Carlos Lima’s team.

Acknowledgements:

The author is grateful for photos provided by “Visão,” magazine, assistance provided by PN magazine and SERONO Biotech, Portugal, and the liaison efforts of James Kelly, Texas.

About the Authors:

The authors are Laurance Johnston and Sara Sá, a journalist for Visão, Portugal’s national news magazine.

Adapted from article appearing in Paraplegia News, March, 2003 (For subscriptions, contact www.pn-magazine.com).

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