"And then the nerves are joined up..."

Part of a recent explanation as to how a hand transplant is carried out read: 

“Once blood is circulating to the limb, the remaining nerves, tendons and muscles are attached, before the team finally close the skin.”

Understanding how tendons and muscles can be attached is reasonably straightforward, but how is it possible for nerves to be attached and made to function? 
How does nerve repair actually work?

Professor Simon Kay, the Consultant Plastic Surgeon who carried out the first hand transplant in the United Kingdom in 2012, talks about the history of research into nerve transfers and how the process is far more complex than commonly realised.

Nerves are usually seen as trunks of white fibres that connect the brain and the spinal cord with the muscles and sense organs of the body.  They carry the brain’s commands to the muscles to contract and so cause movement, and to return information from the sense organs on qualities such as heat, cold, touch and pain. Each nerve trunk contains thousands of fibres each dedicated either to movement or sensation as they travel down the limb towards their specific muscles or sense organs.

Nerves and their repair have long fascinated, yet puzzled surgeons. The almost unbelievable biology through which a nerve regenerates has led in equal measure to despair and sometimes magical thinking.

In 1828 a French researcher Marie-Jean Flourens working in Paris published an extraordinary experiment that would seem impossible were it not for the fact that its unexpected results have since been confirmed in other ways.  Flourens operated on a cockerel (before the discovery of anaesthesia, sadly) cutting the nerves supplying movement to the muscles on the top and then the bottom surface of the wing. He immediately repaired one nerve to the other and vice versa.  Of course, the bird was immediately disabled, but gradually recovered function and subsequently even flew.  Flourens then went back, exposed the nerves, and in an elegant bit of physiology showed that each nerve was now animating its opposite muscle.  But yet the bird could fly!

This astounding experiment stretches my own belief as Flourens was operating without anesthetic, in a small animal with tiny nerves, using only rudimentary suturing technology.  In addition, the anatomical aspects are highly questionable. But this experiment endures in the nerve surgeon’s imagination because, since then, it has been established that a nerve to one muscle may be cut and then joined to the stump of another nerve which had previously served to animate a completely different muscle, and subsequently through that junction between the two different nerves, function recovers in that muscle. For example, when the nerve giving movement to the biceps muscle is injured beyond repair, a small nerve passing to the hand normally moving the little finger may be diverted and joined to the damaged biceps nerve with subsequent recovery of movement in the biceps. The biceps is then being activated by a nerve previously destined to control the muscles in the hand. When the brain then tells the little finger to move, since its nerve is now joined to the biceps, it is the latter that moves instead.

Most people now know that nerves send information from the brain and spine to muscles by conducting electrical impulses. This has led many (including some surgeons) to think of them as analogous to electric wires, and to think that repair of a divided nerve involves joining these wires back together.  But we know that each nerve (for example the median nerve that passes through the wrist region to the hand) contains many thousands of microscopic nerve fibres, each of which reaches a specific muscle and is activated only when the brain wishes to use that muscle. When we join cleanly cut nerve stumps back together, we cannot possibly accurately restore all these thousands of fibres, and so it seems mystifying and almost magical that they recover at all.  So how does it happen?

Well, nerve fibres are more complex and smarter than wires! They don't conduct electricity the way wires do, instead they push a wave of electrical charge (hence “nerve impulse”) down the outside of a tube that has a surface adapted to that task. Inside the tube a separate process carries material to and from the cell body (which lies in or close to the spinal cord, and which constantly works to provide the chemicals and nutrition necessary for the whole nerve fibre to function). The wave of electrical charge is somewhat like the wave that we can send along a rope with a flick of the wrist: nothing materially actually travels, but the wave of positive charge ripples along the surface of the tube, (known as an axon, a word we use from hereon for these single microscopic nerve fibres).

This axon is an incredibly fine and long extrusion of the nerve cell body extending to the muscle or sense organ that is the target of that nerve cell. When the nerve trunk has been cut, the part of this fine axon beyond the injury is cut off from the cell body and so dies, as it no longer receives the sustenance that emanates from the cell body and is normally transported inside the tubular axon. Then something truly remarkable happens: the end on that part of the axon still connected to the cell body sends out lots of little exploratory fronds which are looking for the remnants of the now dead axon beyond the cut. These fronds explore by touch and by chemically “smelling” until they find the cut-off stump of an axon.  At this point they start to grow into the trace remnants of that axon and regenerate along it, claiming it for their own cell body and eventually reestablishing an electrical link from spinal level to the distant muscle or sense organ. This is nerve recovery.

This mechanism of nerve healing through guided regeneration is found throughout the animal realm and is considerably more complex and even more wonderful than the simple description above. But it is not perfect, and failures occur. For instance, any cut nerve trunk contains axons destined to innervate a wide variety of muscles and sense organs, some very small and highly specialised. Few of the self-repairing axons find their original tube remnants to grow down, and some find none. This is bound to limit the value of recovery, but again some curious events seem to occur to deal with this. 

Firstly there is some redundancy in nerve-muscle systems which allows a muscle to build itself up even though its nerve connection has been reduced after recovery.  This is behind the common experience of body building of course.

The central nervous system (CNS) then steps in and recognizes mismatched fibres, and either abandons that fibre or retrains itself to recognise the new hard-wired arrangement of that fibre. When a motor (movement) fibre hooks up with the stump of another motor fibre serving a different muscle, the CNS learns the new arrangement and adapts to it usefully. Similarly if a sensory axon hooks up with an axon previously destined from a different receptor the CNS adapts itself.  This quality of relearning the new arrangement of the brains connections is termed “plasticity” and is similar to other forms of learning, especially in being more effective in youth.  Children deal with reordering of their peripheral nerve inputs far more effectively and intuitively than adults, just as they learn a new language more easily.

And so it is with the more extensive and intentional nerve transfers performed by surgeons connecting the CNS to different parts of the body’s periphery. Flouren’s prescient demonstration in 1828 swapping the nerves to the wing of a cockerel was the first example of nerve transfer, but others followed and in 1911 another surgeon, Kennedy (in Glasgow), presented examples in animals of nerve transfers around the facial region. For instance, he showed that a nerve that normally moves the tongue can be transferred to move the muscles of facial expression.  In humans nerve transfers gradually became more common, and in German textbooks of the early twentieth century several transfers are described that are still useful today.

In my own area of nerve surgery in children, nerve transfers are commonplace in the treatment of birth palsy (so called Erb’s palsy, resulting from trauma during birth). The most remarkable of these to my mind is called an intercostal transfer. In this procedure the tiny nerves that activate the small muscles between the ribs are dissected free and joined to a destroyed nerve, usually the one that controls elbow bending. It is astounding how rapidly a child “learns” through cerebral plasticity that by activating the nerves to just three rib muscles (out of a total of twenty four rib muscles) it can bend its arm powerfully.  Especially astounding, because none of us is conscious of activating individual rib muscle in order to breathe, is so how the brain separates the intention to activate just these three nerves amongst so many, in order to now move the elbow.

And so by transferring the function of a surplus (or less important) nerve to a damaged but important nerve we can now treat previously irreparable nerve injuries. In recent reports of use in cerebral palsy or paralysis, the concept of rearranging nerves in this way (rather than the clunky rearrangement of muscle as is the time-honoured standard treatment) has allowed much smaller interventions to give greater benefits. There is no doubt this new application of Flourens’ apparent discovery 200 years ago will continue to expand.  He was a remarkable man who went on to make many other discoveries (including anaesthesia), and I wonder whether he might have foreseen how his elegant experiment would change the treatment of nerve injuries as it has?

Professor Simon Kay OBE  FRCS DSc

Leeds 2019