Peripheral nerve injury: A review and approach to tissue engineered constructs.

[antiquity]

Anat Rec 2001 Aug 1;263(4):396-404
Peripheral nerve injury: A review and approach to tissue engineered constructs.

Evans GR.

Division of Plastic Surgery, The University of California, Irvine, Orange, CA 92868.

Eleven thousand Americans each year are affected by paralysis, a devastating injury that possesses associated annual costs of $7 billion (American Paralysis Association, 1997). Currently, there is no effective treatment for damage to the central nervous system (CNS), and acute spinal cord injury has been extraordinarily resistant to treatment. Compared to spinal cord injury, damage to peripheral nerves is considerably more common. In 1995, there were in excess of 50,000 peripheral nerve repair procedures performed. (National Center for Health Statistics based on Classification of Diseases, 9th Revision, Clinical Modification for the following categories: ICD-9 CM Code: 04.3, 04.5, 04.6, 04.7). These data, however, probably underestimate the number of nerve injuries appreciated, as not all surgical or traumatic lesions can be repaired. Further, intraabodominal procedures may add to the number of neurologic injuries by damage to the autonomic system through tumor resection. For example, studies assessing the outcome of impotency following radical prostatectomy demonstrated 212 of 503 previously potent men (42%) suffered impotency when partial or complete resection of one or both cavernosal nerve(s). This impotency rate decreased to 24% when the nerves were left intact (Quinlan et al., J. Urol. 1991;145:380-383; J. Urol. 1991;145:998-1002). Copyright 2001 Wiley-Liss, Inc.

[joseph]

From what I understand most SCI injurys come with some peripheral nerve damage just below the level of injury, meaning after there is a cure for the central nervous system or (spinal cord) there will still be a need for repair of the peripherial nerves. Maybe Dr. Young can talk about that a little.Whats the progress for that extent of nerve replacement? How will that happen for SCIs,and when will it be a good time to do it.

[Wise Young]

Many people with traumatic spinal cord injury may have had additional injury to the nerve roots or the peripheral nerves. In addition, there is a very large group of people who have suffered brachial plexus avulsion and lumbosacral plexus avulsion where the network of peripheral nerves emanating from the spinal roots in the cervical and the lumbosacral regions respectively have been damaged. For these people, not only is recovery often minimal but they suffer from severe neurogenic pain due to the deafferentation (loss of sensory input to the spinal cord).

The work of Carlstedt and many plastic and orthopedic surgeons has generated quite a bit of excitement in the field. Carlstedt who is at the Royal National Orthopedic Hospital at Stanmore in London reported successful reimplantation and subsequent regeneration of motor axons into avulsed brachial nerves into the spinal cord. He stuck the nerves directly into the spinal cord and motor axons from the spinal cord grew into the peripheral nerves and reinnervated muscles. Interestingly, he also reports that people in whom this kind of regeneration occurred also reported that they had reduced pain. It is unclear why this occurs since most or all of the regenerating axons are motor rather than sensory.

Professor Giorgio Brunelli took this procedure the ultimat step when he applied it to people with spinal cord injury. He took a nerve from below the injury site, bridged it, and stuck it into the spinal cord above the injury site in several people. This procedure apparently produced reinnervation of muscles below the injury site and last year several news reports showed video pictures of patients who were ambulating (albeit awkwardly) in walkers. Please note again that such procedures should result in only motor innervation and not sensory inputs into the spinal cord.

In any case, the take-home lesson for me is that the spinal cord axons are just itching to grow. If you provide a path for the axons to grow, they will take that path. I was also very interested in how long after injury these procedures could be carried out. Brunelli did it in patients who are several years or more after injury. In response to my question at a recent meeting, Carlstedt said that he preferred to do the reinnervation within 3 months after injury and that the chances of success with the operation may diminish after that point.

Wise.

[joseph]

I love when they that it works and they even tried it on patients a few years out but then they say it may not work. For my son that would help restore his triceps, wrists and hands.At what point during full treatment for healing in SCI would you project this procedure to take place?

[kilgore]

Why can't you attach one set of peripheral nerves into the proximal stump, another set into the distal stump, then connect the two sets of peripheral nerves? The peripheral axons die, but don't they regenerate?

[antiquity]

If a SCI'ed person does not experience neuropathic pain, does that mean their peripheral nerves have not been damaged?

[Wise Young]

Kilgore and Seneca,

Wonderful questions. Let me try to provide an answer to these questions... with the hope that others will chime in.

1. Peripheral nerve regeneration. Kilgore, peripheral nerves provide a better environment for axonal growth than the central nervous system. This has been shown over and over again now in many experiments and in practice. Peripheral nerve surgeons (neurosurgeons, orthopedic, and plastic surgeons) have long reconnected peripheral nerves and find that about 10% of the motor axons in the peripheral nerve will regenerate and reinnervate the muscles and sensory axons will also grow back into the muscle and skin. The motoneurons reside in the gray matter of the spinal cord. The sensory neurons reside in the dorsal root ganglia that are just outside the spinal cord. If the cut to the peripheral nerve is on distal (the term distal always refers to the direction away from the central nervous system and, in the central nervous system, it refers to the direction away from the brain) side of the dorsal root ganglia, you can reconnect a cut or damaged nerve and expect some growth of the axons across the site and down to the peripheral organs. If there is not enough length of the peripheral nerve to reconnect, one can always use another peripheral nerve segment as a bridge. However, if the cut occurs between the dorsal root ganglion and the spinal cord, this causes degeneration of the central sensory axons. The dorsal root ganglion generally will not grow back into the spinal cord or, if they do grow into the spinal cord, they often will not grow up the spinal cord to the brain.

2. Neuropathic pain and peripheral nerve damage. Deafferentation or loss of sensory input to the brain leads to plastic changes of the brain and spinal cord. These changes are what causes neuropathic pain. So, for example, deafferentation from diabetes, brachial plexus avulsions, nerve root compression, transverse myelitis, multiple sclerosis, limb amputations, or spinal cord injury are all associated with neuropathic pain. The degree of neuropathic pain depends on the degree of deafferentation. Peripheral nerve transections have the highest incidence of neuropathic pain. The degree of neuropathic pain also depends on the response of the spinal cord to the injury. Injury to a peripheral nerve or the spinal cord causes a massive induction of cytokines and neurotrophins in the spinal cord. This response of the spinal cord to the injury causes extensive sprouting of axons, both sensory and motor. The former may lead to aberrant (abnormal) connections of the sensory axons and neuropathic pain. The latter may lead to spasticity.

There is still much that we do not understand concerning neuropathic pain. For example, Carlstedt from the Royal National Orthopedic Hospital at Stanmore reports that when he inserts a peripheral nerve into the spinal cord and motor axons grow into the nerve and reinnervate with muscles, patients are reporting a lessening of their neuropathic pain. Since he is sticking back the nerves into the spinal cord and presumably the cut end of the nerve is distal to the dorsal root sensory ganglia, this suggests that only motor innervation is occurring without any sensory component. If so, why should the patients be having less pain? Carlstedt suggests the startling idea that neuropathic pain may be somehow related to paralysis. Another possibility is that some sensory neurons in the spinal cord may be sending axons out into the nerves and may be receiving signals from the periphery but this would really be out-of-the-box possibility that nobody had considered before. A third possibility is that when motoneurons are active, they somehow inhibit sensory activity. The last possibility is the most likely and most interesting. It may also explain why electrical stimulation of the spinal cord reduces neuropathic pain in people. The spinal cord never ceases to amaze me with its richness and diversity.

Wise.

[pejman]

Dr. Young, Regarding your statement "The dorsal root ganglion generally will not grow back into the spinal cord or, if they do grow into the spinal cord, they often will not grow up the spinal cord to the brain", why don't damaged sensory root nerves have the ability to regrow into the spinal cord and up to the brain?

You had mentioned previously that the application of neutrophins to sensory root nerves may aid their regeneration into the cord and up to the brain. Any hope or progress on this? What are the obstacles?

b.Pejman

[Wise Young]

There are two obstacles to peripheral axonal entry and growth up the spinal cord. The first is the so-called PNS-CNS barrier. This is the interface between the peripheral and central nervous system. Axons in the spinal cord cannot grow out the dorsal root and vice versa because astrocytes form a tight boundary between the peripheral nerve and the spinal cord. This barrier forms where Schwann cells meet the astrocytes. The second barrier is presumably axonal growth inhibitors such as Nogo expressed by central myelin in the dorsal column, the same inhibitor that presumably blocks axonal growth in the spinal cord.

Several recent studies suggest that this barrier can be overcome by neurotrophins administered to the spinal cord, by a previous injury to the peripheral portion of the nerve, and by drugs that increase cAMP levels of the dorsal root ganglia. These treatments have generated quite a lot of excitement. It is also well-known from animal studies as well as pathological studies of human spinal cord that the PNS-CNS barrier breaks down when there is substantial loss of astrocytes at the injury site and Schwann cells invade into the injury site. Peripheral axons have been described to invade into the spinal cord in such circumstances.

Wise.

[pejman]

Dr. Young, Thanks for your explanation.

Here is another question that has always puzzled me. When people experience siatica involving excruciating radiating pain down the leg. What portion of the root nerve is being compressed? (the sensory above ganglion, sensory below ganglion, or the ganglion itself?) And why is it that this compression in most cases results in "only" pain and no numbness? (I realize that in certain cases both symptoms are present) What factors detemine whether the pain will result in being permanent (chronic)? It is very puzzling to me why the compression can result in such severe pain when we know that pinching other peripheral nerves only results in numbness.

I have also noticed that doctors recommend decompression surgeries mostly in cases of motor nerve compression that result in permanent weakness. But, isn't sensory numbness permanent also? They do not seem to be concerned with that. And, when it comes to pain, they say that if the pain can be tolerated, it won't be permanent. Why?

b.Pejman

[Wise Young]

Excellent questions. In most cases, a nerve root injury from a slipped disc for example, damage the nerve between the spinal cord and the dorsal root sensory ganglia. In other words, the injury is to the central branch of the dorsal root ganglionic neuron.

The cause of the pain is not clear. There are many many studies of this phenomenon in the past six years since it was discovered that rats develop allodynia (hypersensitivity to touch) if their peripheral nerves were ligated; this has become almost the standard model of neuropathic pain.

Let me first describe the changes that occur with a peripheral nerve damage. Peripheral nerve injury not only damages the axon but causes changes in the dorsal root sensory ganglion and the spinal cord. Although the mechanisms by which the injury causes these changes are still not clear, the changes are well documented.

1. A peripheral nerve injury induces the DRG neurons to turn on many genes that are associated with regeneration. These genes apparently not only stimulate the distal and damaged axon to grow but the central axon to grow as well. Neumann & Woolf recently reported this phenomenon (see below).

2. A peripheral nerve injury also causes inflammatory responses in the spinal cord. Several studies have shown that peripheral nerve injury induces the production of inflammatory cytokines and neurotrophins in the spinal cord. These then probably stimulate aberrant sprouting of axons in the spinal cord, possibly contributing to allodynia and pain, as well as changes in neurotransmitter levels in the spinal cord.

The threshold for surgery depends in part on MRI/CT findings. If a big bulging disc is clearly compressing on a root, most neurosurgeons will decompress the root even if the only symptom is numbness. On the other hand, if there is just a small disc that they think might go away by itself, they will frequently wait until there are motor symptoms. Please note, however, that there is a limit on how long one can wait. Several recent studies suggest that the symptoms are irreversible if one waits longer than 6-9 months.

Many surgeons are reluctant to operate just to relieve pain when there are no neurological symptoms. The reason is that the surgery frequently does not alleviate the pain and may even aggravate the pain. This is particularly true when a person has chronic pain and arthritis where multiple causes of pain may be present, including neuropathic pain. An experienced surgeon should be able distinguish between cases where the pain is due to an acute episode of compression versus those that are related to more chronic pain.


• Neumann S and Woolf CJ (1999). Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron. 23 (1): 83-91. Summary: Regeneration is abortive following adult mammalian CNS injury. We have investigated whether increasing the intrinsic growth state of primary sensory neurons by a conditioning peripheral nerve lesion increases regrowth of their central axons. After dorsal column lesions, all fibers stop at the injury site. Animals with a peripheral axotomy concomitant with the central lesion show axonal growth into the lesion but not into the spinal cord above the lesion. A preconditioning lesion 1 or 2 weeks prior to the dorsal column injury results in growth into the spinal cord above the lesion. In vitro, the growth capacity of DRG neurite is also increased following preconditioning lesions. The intrinsic growth state of injured neurons is, therefore, a key determinant for central regeneration. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=10402195> Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129, USA.

[pejman]

Dr. Young, I am not sure if you are familiar with a book by Dr. Sarno. His explanation of sciatic pain and numbness in most cases is based on oxygen deprevation to the peripheral nerves rather than root nerve compression and damage. The reason for the oxygen deprevation being that the unconsious mind restricts the supply of oxygen to certain nerves and muscle tissues in order to distract the mind from such emotions as anger, stress, and tension. It sounds off-the- wall...but I have not seen any other concrete explanation of why the nerve compression can result in such pain...or why sometimes pain and sometimes numbness or both.

Also, the 6 to 9 months time window that you are referring to is what I based my own surgery on (actually, I had read it to be a 3 month window). However, after 5 weeks of compression, I have permanent damage to sensory and motor nerves. I had no pain but numbness and weakness.

b.Pejman

[Wise Young]

Sarno is from NYU where I spent 20 years as a fellow faculty member. I have a number of friends who went to his seminars and really swear by his methods. His theory is interesting but seems very speculative. On the other hand, very little is known about the cause of back pain, pain associated with root compression, and pain in general.

Recent studies suggest strongly that chronic pain is associated with inflammation and the cytokines and neurotrophins released by inflammation may contribute to the pain and its persistence even after the original cause may be gone. Other studies suggest that inhibition of sensory input is a critical component of sensory perception and if the inhibitory component is damaged or diminished, pain is a common manifestation.

Chronic pain and acute pain differ from each other. Likewise, nociceptive pain (the pain associated with painful input) and neuropathic pain (the pain that occurs spontaneously without painful input) differ in both manifestation and therapy.

Wise.

[Chris Chappell]

You mentioned Dr. Brunelli and his procedure for peripheral nerve growth which was carried out on sci patients. Where and when did this take place? Is it something currently available?

Thanks

[kilgore]

Chris:
All Brunelli did was connect nerves above your injury to muscles below, which means that you have to borrow nerves from something you might not want to part with. As a C5, I don't see much point in that, and it leaves nasty scars up your arms and legs.

Look at:
http://www.dracmanet.it/fondazione/

[Wise Young]

I just posted some news reports of Brunelli's procedures in the Trials Forum (http://carecure.org/forum/showpost.php?p=250018)

[BirdeR]

It's an irresistible dream: for a person paralysed after an accident to walk again.

But what happens if hope becomes an unrealistic obsession?

One Italian surgeon is pioneering radical new treatment which he claims will one day help his patients walk.

Critics say that rather than a miraculous breakthrough, the controversial operation is just raising false hopes.

In the first of two special reports on the victims of spinal cord injuries, Andrew Slorance went to meet Professor Giorgio Brunelli at his clinic near Bologna - to find out for himself:

Many hundreds of people in the UK will suffer a spinal injury this year. Most will walk away, but one in ten will have severed the spinal cord, and will not walk again.

One in 20 of those will commit suicide within five years, making suicide second only to respiratory failure as the highest cause of death among spinal cord injury victims.

The only therapy available for victims is rehabilitation to help them to learn to live life in a wheelchair. Patients spend an average of nine months in a rehabilitation unit, learning everything from scratch; even the smallest of tasks will have become a struggle of incomprehensible frustration.

Most victims of spinal cord injury do not believe they will walk again and the therapy received during rehabilitation does not encourage them to consider it probable. But for some, the only way to keep going is to hold on to a tiny ray of hope.

Much has changed in the treatment of spinal cord injuries since I was a patient in 1983. At the age of 14, I fell 50ft from a tree, breaking my back and severing the spinal cord. The rehabilitation I experienced took the hardline approach and the unit was run like a military camp. I was told that I would need to use a wheelchair for the rest of my life and that the sooner I dispelled any thoughts of walking again, the better. In spite of this, 17 years on, I still carry hopes of walking.

Research into spinal cord injury has made encouraging progress in recent years, although most doctors say that a treatment that would return functional walking (a level of walking that would be considered natural) is still years away.

Until recently, progress has been confined to the lab, but now an Italian surgeon, Professor Giorgio Brunelli, has taken his controversial research into the operating theatre.

As part of a team for Channel 4 News, I went to meet Brunelli at the Montecatone Rehabilitation Centre near Bologna, where he was to perform a new experimental operation during our visit.

Angelo Colombo, his most recent patient, had been paralysed five years ago after falling from scaffolding. He had severed his spinal cord at lumbar level, leaving his hand and arm function unaffected. Brunelli offered him experimental surgery in an attempt to restore some motor function to his legs, using a procedure called an ulnar nerve transfer.

This is based on the principle that while all the nerves above a spinal injury, and all the muscles below an injury, remain intact, the communication between them has been cut off. Professor Brunelli planned to reroute a nerve from above the injury to a muscle below it. The ulnar nerve, one of the main motor nerves running from the spinal cord down the arm to the hand, is ideal for the procedure because of its length.

Brunelli disconnected the nerve from Angelo's hand, leaving the other end connected to the spinal cord. He then removed it from the arm and rerouted it down the chest wall connecting it to the quadriceps muscle in the leg. This is open surgery, which results in significant scarring on both right and left sides. Reconstructive surgery was carried out to try to restore the lost motor function to both hands.

In time, Angelo's brain adapted to the new nerve mapping so he could move his legs on command. Until then, his brain had treated his quadriceps as though they were his hands and when he thought about moving his hands, his legs would move. Brunelli told us that the procedure had been successful but that Angelo had not been doing enough exercise recently, so his walking was not as good as it could be.

Angelo, wearing supportive splints around his ankles, was ready and waiting to demonstrate his newly restored ability to walk. I did not believe that I was about to witness functional walking, but I was hoping I would be proved wrong. Under instruction from Brunelli, Angelo pulled himself from his wheelchair to his feet and, using a walking frame, began to make his way across the gym.

I felt for Angelo as he struggled to move one leg in front of the other. I had seen more effective walking by patients using full-length callipers. The sweat was pouring from Angelo's brow as he came to the end of the demonstration

six metres and two minutes later. I asked how he felt about the operation, given that he had sacrificed some hand dexterity and sensation for a very limited ability to walk. I suggested that he could have achieved the same results using callipers and avoided the dreadful scarring.

His response was that the operation had been a tremendous boost to his mental state. He rolled up his trouser leg to above his quadriceps muscle and demonstrated the restored movement. As he flexed his hand, his quadriceps clenched in unison; being able to move his leg at all was fantastic, he said, and over time his brain had learnt the new nerve mapping. Now if he thought about moving his leg, he could do so.

Gigilola Centurelli, another of Brunelli's patients, was having a variation of the ulnar nerve transfer the next morning. She had been in a traffic accident only four months earlier and was still in rehab. I was concerned that she had not had enough time to adjust to her circumstances, and therefore was not in a position to make an informed decision whether to undergo experimental surgery.

Gigilola was bound to try anything offered to her, no matter how well-advised she was that the operation was experimental and the outcome uncertain. It would be impossible for her not to have huge hopes that the operation would restore her ability to walk.

Gigilola told me that she wanted the operation and felt that, no matter what the outcome, she could not be worse off than she was now - and if it was God's will, then she would walk again. I asked her about her family and what they thought about the operation, and as she began to tell me, she broke down in tears.

It was evident to me that Gigilola was pinning her future on the operation by Brunelli.

This was also to be a nerve transfer, but the nerve used this time would be the sciatic nerve, which would mean that non-paralysed muscles would not be affected. The sciatic nerve has many more motor fibres than the ulnar nerve so, when rerouted, could supply more muscles, therefore potentially achieving more movement and an improved ability to walk. The outcome of Gigilola's operation will not be clear for several months.

Brunelli admitted: "This is the first time I have performed this operation on a human being. Gigilola is a volunteer patient and has been warned that though we get beautiful results when operating on monkeys, the result with her may not be as good. We cannot perform miracles."

At the moment Brunelli assesses the suitability of patients himself, though he says he may seek an examination by psychologists in the future.

Professor Martin Ferguson-Pell, ASPIRE chair in disability and technology at University College London, shared my concerns that the operation on Gigilola might have been premature.

"What Brunelli is doing is controversial. It is very important to look at the whole picture and make sure the patient understands exactly what to expect. At the moment procedures such as these provide a very limited degree of movement, and they don't, for example, restore bladder or bowel function. It is important to look at the whole picture. As far as I can tell, it is unlikely that this technique will result in people coming close to recovering from spinal injury and being able to do the things they would do in normal life. But then for some people, just being able to stand up is very important."

Between the rehabilitation unit we visited in Italy and those in the UK there is an enormous difference in the attitudes towards walking. In the Italian rehabilitation unit, paraplegics could be seen walking using splints and frames. All the patients I spoke to said they were certain that they would walk again and are actively encouraged to think this way. Every patient was optimistic about his future.

Reporter: Andrew Slorance


This article also appears in The Times