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