Nerves and Nerve Injuries: Vol 1: History, Embryology, Anatomy, Imaging, and Diagnostics

textbook.

Part I

History, Histology and Development of the Peripheral Nerves

Chapter 1

History of the Peripheral and Cranial Nerves

James Tait Goodrich¹,*; Michel Kliot²    ¹ Division of Pediatric Neurosurgery, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA.

² Peripheral Nerve Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

* Corresponding author: James.Goodrich@Einstein.yu.edu

Abstract

This chapter reviews developments in the practice of treating injuries and tumors of the peripheral and cranial nerves. Starting with the Edwin Smith Papyrus, we explore the treatment of nerve damage from antiquity to the mid-twentieth century. Up until the post-Renaissance era, distinguishing a nerve from a tendon or ligament was not easily done, and the concept of repairing an injured or severed nerve only came into fashion in the latter half of the nineteenth century. Although attempts were made to remove tumors and perform surgical repairs of the nerves, the outcomes were often not favorable, and in many cases, the surgeries left patients with even more painful outcomes. In this chapter we discuss the surgical concepts surrounding various historical nervous system repairs, highlighting the techniques that succeeded and failed. We also introduce key personalities in the field and their contributions, including a number of historical illustrations, many of which may be new to students of this subject.

Keywords

History of peripheral nerve injuries

History of peripheral nerve surgery

Causalgia

Peripheral nerve tumors

History of surgery

No surgical treatment of peripheral nerves can be intelligently undertaken without an eye on their anatomical and physiological connections with the central nervous system. Nerves cannot be considered as independent peripheral structures, as are muscles and tendons, but rather as peripheral parts of the central nervous system, in close association and intimate relation with the latter. The surgical treatment of peripheral nerves is closely allied to the surgery of the brain and spinal cord and forms the third division of the surgery of the nervous system.

Stookey (1922)

The earliest known written record of injuries and tumors of the peripheral nerves is the Edwin Smith Papyrus, which was written about 1700 BC. Among the case studies presented in the Papyrus, one stands out as a likely case of a neurofibromas on the chest (Case 45). The writer describes round masses on the chest (Sanchez & Meltzer, 2012). The described masses were multiple in number, hard to the touch, sometimes appeared elsewhere on the body, and did not produce secretions or pain. The masses were clearly differentiated from any type of infection, and when discussing the treatment of the masses, the writer comments, It is nothing/there is no treatment/remedy. This last comment is similar to the treatment recommendations many surgeons offered over the next 3500 plus years.

After the time of the Edwin Smith Papyrus, surgery and other forms of medicine became more formalized with the writings from the Alexandrian schools of medicine, which developed in Asia Minor. The early anatomical writings of the Alexandrian schools (300 BC-AD 300) show that physicians and surgeons often anatomically confused nerves and tendons. In the treatment of nerve injuries such as avulsion and laceration, the suturing of the severed ends was commonly discouraged due to the more unbearable pain that often occurred after the surgical repair.

A pioneer in the Alexandrian schools of medicine was an anatomist (some consider him to be the Father of Scientific Anatomy) and physiologist by the name of Herophilus of Chalcedon (335-280 BC) (Marx, 1838; Von Staden, 1989). Herophilus had access to condemned criminals for anatomical studies. So, he was one of the first to provide anatomical differentiation between nerves and tendons, and he attributed the concept of sensation to nerves. Rufus of Ephesus (fl AD 50) further uncovered the differences between nerves and tendons and their underlying anatomical characteristics (Rufus of Ephesus, 1554, 1567). Rufus did most of his anatomical studies on apes and other lower animals. He was the first to describe the decussation of the optic nerves. In his early medical writings, Rufus detailed a clearer anatomical distinction between nerves and tendons but still often confused the two. The anatomical distinction of nerves arising from the brain first appeared in his writings. The concept of a nerve having both motor and sensory capabilities also first appeared in some detail in Rufus’s writings on the anatomy of the body (Rufus of Ephesus, 1554, 1567).

A distinguished surgeon and anatomist of the second century AD was an individual by the name of Galen of Pergamon (AD 121-201). Galen entered the study of medicine at the age of 17 and eagerly studied anatomy. An early anatomical subject of Galen’s was a robber who had been killed by the locals and then cleaned of the soft tissues by birds. Following his medical studies, Galen rapidly gained prominence as a physician. He had the good fortune to live under two of the greatest Roman emperors, Antonius Pius (AD 136-161) and Marcus Aurelius (AD 161-180). As physician to the gladiators of Pergamon and Rome, Galen had access to a plethora of human material, particularly subjects requiring attention for traumatic injuries. This extensive surgical experience, together with his scientific studies, enabled Galen to make a wide range of contributions to surgery and in particular issues dealing with peripheral nerves (Galen of Pergamon, 1576-1577). Galen concluded that repairing a severed nerve might lead a patient to develop epilepsy, leading him to discourage nerve repair unless it was absolutely necessary. Yet, Galen was one of the first to purposefully experimental transect a nerve to see the result. In oxen and pigs, he sectioned the recurrent laryngeal nerve and recognized that hoarseness was a consequence (Figures 1.1 and 1.2).

Figure 1.1 Title page from Galen’s collected works. At the bottom of the page is a scene of Galen doing a dissection on a pig for a recurrent laryngeal nerve transection, which he describes as causing hoarseness in the animal.

Figure 1.2 Enlarged dissection image showing Galen positioning the pig, surrounded by students and other famous figures in medicine and surgery. In this scene Galen is getting ready to section the recurrent laryngeal nerve. He reports that the voice is not totally destroyed when one nerve is cut, only weakened. If you cut both branches of the recurrent laryngeal nerve, the voice is totally lost.

In discussing the nerve dissection, Galen describes the following:

An if you do that, then you well see that when the injury has affected only one of the nerves, that is, one of the two great nerves or the recurrent nerves, the animal now retains one half of its voice. But if the injury has affected both nerves then the animal becomes completely voiceless, except that there remains a certain rattling sound which is produced when it gasps.

Chapter XIV.7, Galen of Pergamon (1962)

Nor was this all. Galen provided the first recorded attempt at identifying and numbering the cranial nerves, demonstrating 11 of the 12 nerves. Unfortunately, by combining several, he arrived at a total of only seven. Galen discarded Hippocrates's notion that the brain is only a gland, and he claimed it was responsible for voluntary action, sensation, and the information carried through the spinal cord and out the nerves—a considerable conceptual advance for the time (Figure 1.3).

Figure 1.3 A collection of surgical instruments from the Roman period, including a series of scalpels, forceps, and various probes and dissectors. The coins in the center are Alexander the Great tetradrachms dating from the fourth century BC. From the author’s personal collection.

The Byzantine era (AD 324-1453) began in AD 324 with the seat of the Roman Empire moving to Constantinople under the governance of Constantine the Great (AD 272-337). The Byzantine era was a complex period for surgeons who were continuing to better define human anatomy using cadaveric dissections and trauma that occurred from accidents and wars. Although anatomical knowledge was improving, surgeons still were not eager to suture or repair injured nerves. One of the great surgeons of the early Byzantine era was Paul of Aegina (AD 625-690). As indicated by his writings, Paul rarely considered repairing a peripheral nerve. In the majority of cases, Paul treated a nerve injury with purging or bleeding. He then placed a concoction of pharmaceutical formulations, often including pigeon dung, on the wound site (Paul of Aegina, 1844-1847; Paulus Aegineta, 1533, 1534). Paul of Aegina also cautioned against placing sutures too deep and causing further injury to the nerve. In addition, Paul introduced the concept of agglutinatives to glue the nerves together, although what he actually used is not detailed in his writings (Paul of Aegina, 1844-1847; Paulus Aegineta, 1533, 1534).

When the nerves are wounded or pricked, they experience great inflammation and pain owing to the great sensibility; and therefore fever and convulsions supervene upon them, and in some cases delirium, owing to the continuity of the nerves with the brain. [In discussing nerve repairs Paul notes the following]. When the wound is transverse there is a greater danger of convulsions, but everything relating to the cure is in this case the same, except that while the wound is recent some have used sutures and certain of the agglutinative applications; but the sutures must not be applied very superficially lest the part below remain ununited, but more deeply, taking care however that the nerve be not punctured by the needle.

Section LIV: On the Wounds of Nerves; Paul of Aegina (1844-1847)

Paul of Aegina’s writings enormously influenced surgeons through the Renaissance. After the great Greek and Roman periods of medicine, the intellectual centers of medicine shifted to the Arabian and Islamic cultures, and their major influence extended from about AD 750 to 1200. Academically, medicine in Europe during this period remained quiescent and unimaginative. Most of Europe was overrun and ruled by barbarians (Huns, Goths, and Norsemen). Meanwhile, rather than developing new ideas for medical and surgical treatment, the Islamic schools of medicine were satisfied to codify the surviving manuscripts from the Greek and Roman schools. Due to their almost incredible zeal, the best of Greek medicine was made available to Arabic readers by the end of the ninth century. But a rigid scholastic dogmatism became characteristic of the Arabic-speaking learning centers, as copyists of the great works of antiquity translated from Latin, Greek, and Hebrew into Arabic and then systemized the knowledge. The Islamic schools included a number of prominent individuals, such as Avicenna (Abu ‘Ali al-Husayn ibn ‘Abdallah ibn Sina, 980-1037). Avicenna was a famous Persian physician and philosopher of Baghdad, and he was a strict disciple of Paul of Aegina. Reflecting the teachings of Paul, Avicenna mostly advocated the medical or pharmaceutical treatment of nerve injuries. In the rare cases in which a nerve needed repair, he advocated a primary repair of the nerve, but it is not clear whether the nerve was just placed in continuity or if the nerve was actually approximated and possibly sewn (Avicenna, 1564).

Albucasis (Abu Al-Qasim, Abu I-Qasim uz-Zahawi; 936-1013) is considered the most prominent surgeon of the Islamic schools. He wrote extensively on various surgical topics, and his writings document the surgical practices of the time (Albucasis, 1519, 1973). Albucasis was also a disciple of Paul of Aegina, having adopted his principles on nerve repairs. Following the earlier writings of Galen and Paul of Aegina, he recommends that in most cases peripheral nerve injury repairs should be avoided due to the risk of increased inflammation and seizures. Albucasis typically made his sutures from cotton and silk. For special cases when he needed a fine suture, he used the hair of a woman. As for needles, he fabricated them from various metals, adding either a round or triangular sewing end. In very special cases, he had the needle fabricated from a mixture of gold, however. Albucasis does not directly address the actual repair of a nerve injury in his work on surgery, but if a repair was needed, he likely would have advocated the technique offered by Paul of Aegina.

The Islamic era of surgery gave way to the Middle Ages when Europe began to develop universities for advanced education. A number of interesting surgical figures emerged during this period from the twelfth to early-sixteenth centuries. Roger of Salerno (fl 1170) was a prominent medieval-era surgeon and surgical leader in the Salernitan tradition (Schola Medica Salernitana), and he practiced in what is now southern Italy. A pioneer in the techniques of managing nerve injury, he argues in his writings that the surgeon should consider a reanastomosis of severed nerves. He further points out that, during the repair, the surgeon should pay particular attention to the alignment of the nerve fascicles. Additionally, Roger advocates not only suturing the nerves together but also adding a touch of hot cautery to the ends of the nerves. The use of hot cautery in wound care appeared earlier in the Islamic schools for the treatment of surgical cuts and injuries (de Chauliac, 1478; Roger of Salerno, 1519).

Guy de Chauliac (?1298-1368) was a leading European surgeon of the Middle Ages, if not the most prominent one, having studied at Montpellier, Paris, and Bologna, and receiving his Magister in 1325. de Chauliac later became the resident physician of the papal household in Avignon, France, and his Chirurgia Magna became the standard surgery text of his time, remaining in use for nearly 300 years (de Chauliac, 1923; Haighton, 1795). The writings of Guy de Chauliac clearly show that he was an innovator in peripheral nerve injury and repair of nerves. Guy de Chauliac states that injured or severed nerves should be treated like any of the other soft tissues. Following this view, he directed surgeons to perform a primary suture repair of injured nerves and associated tendons. With interesting insight to these injuries, he also advocates that any foreign material or debris should also be removed from within the nerve and surrounding tissues (de Chauliac, 1923; Haighton, 1795).

Lanfranco of Milan (fl 1290-1296), who is considered to be the founder of French surgery, left Milan, Italy due to politics and moved to Lyon, France where he produced his classic manuscript on surgery in 1296. Copies of his work circulated throughout Europe until the first mechanically printed edition appeared in 1490 (Lanfranco of Milan, 1490). Lanfranco left Lyon for Paris where he further developed his career and is remembered as an advocate for bedside teaching and skillful lecturing. Lanfranco also became a strong advocate for surgeons becoming university educated, moving away from the concept of the itinerant barber-surgeon. In his surgical writings, Lanfranco recommends direct suture repair when the nerve has been severed. Lanfranco argues that all wounds should be carefully addressed and the surgeon should be meticulous in closure. Lanfranco specifically notes that the needle and suture in the repair must be placed superficially to reduce pain and further injury to the nerve.

With the introduction of the Renaissance and more powerful military weapons employing gunpowder, traumatic injuries became even more severe and complex to treat. Active during this period, Ambroise Paré (1510-1590) was a prominent French surgeon who learned many of his surgical skills during the multiple military conflicts so common in Europe at the time, and he produced one of the earliest clinical descriptions of what we now call causalgia (Paré, 1634). Although Paré clinically described this painful disorder, the word causalgia was not coined until 1864 when it was introduced by S. Weir Mitchell (1829-1914) from American Civil War clinical studies. Mitchell named the syndrome causalgia based on the Greek causos (heat) and algos (pain), in order to indicate a severe burning pain from an injured nerve (Mitchell, 1872).

Paré worked as a surgeon for King Charles IX (1550-1574) who had developed a severe case of smallpox. The king was treated by Paré using a then standard medical practice that included venesection and multiple blood-lettings. As a result of a blood-letting, King Charles developed an iatrogenic nerve injury and subsequently contractures in an arm that later developed the symptoms of causalgia. In patients with this type of result, Paré would sometimes advocate severing the nerve to eliminate the pain. Paré also provided an early description of phantom limb syndrome (Paré, 1634).

A most clear and manifest argument of this false and deceitful sense appears after the amputation of the member; for long while after they were complaining of the part which is cut away. Verily it is a thing wondrous strange and prodigious, and which will scarce by credited unless by such as have seen with their eyes, and heard with their ears the Patients who have many months after the cutting away of the Leg grievously complained that they yet felt exceeding great pain of that leg so cut off.

Paré (1634)

Another Renaissance era surgeon was Gabriele Ferrara (1543-1627), a Catholic monk, who produced a richly detailed description of a primary repair of a severed nerve (Artico, Cervoni, Nucci, & Giuffre, 1996; Ferrara, 1596). In his description of the surgical repair, Ferrara describes first gently separating the severed nerve from the surrounding injured tissues. Ferrara would then approximate the nerves and suture the ends together using split tortoise tendons as his suture material. The tendon material was soaked in red wine and a mixture of rosemary and rose oil prior to placement. The red wine likely provided some then unappreciated wound sterility. Ferrara clearly advocates for a very gentle surgical technique of not putting too much traction on the nerve endings. Ferrara also points out that placement of too many sutures can lead to further injury of the nerve. Once the repair was complete Ferrara would place the limb into a splint for immobilization and confine the patient to bed rest until the nerve healed (Artico et al., 1996).

In reviewing writings of surgeons, in particular those with military backgrounds, support for direct primary repair seems to have gone back and forth; some were in favor of a primary repair and some were not so enthusiastic. Most of the debate formed around the potential for worse pain after the repair, a concept dating back to the Alexandrian and Roman schools of medicine. In cases of traumatic nerve repair in which severe pain did develop postoperatively, the surgeon had to consider going back in and cutting the nerve for pain relief.

The nineteenth century brought a renewed interest among surgeons in the treatment of nerve injuries and tumors of peripheral nerves. By this time, better dissection practices had left surgeons clearly more informed about the anatomy of the human body. Nerves were better recognized as to their functions, and they were no longer confused with tendons and ligaments. A prominent surgeon who greatly contributed to the study of peripheral and cranial nerves and neurosciences in general was Sir Charles Bell (1774-1842). Bell was among the first to experimentally study and detail the differentiation of the motor and sensory components of cranial and spinal nerves. Bell’s studies on the fifth and seventh cranial nerves were positively brilliant. In Operative Surgery, Bell details an interesting case of a shipman who took a bad fall, sustaining a serious injury to the leg (Bell, 1814). Initially the seaman had no complaints, but he went on to gradually develop a severe painful burning sensation at the base of the foot. To relieve the pain, the seaman placed the foot in either very cold or hot water, sometimes alternating between the two. Initially, he was treated with mercury, a common therapy at the time. The patient then developed severe weight loss, becoming a skeleton. Bell thought the lesion was a tumor of the popliteal nerve because the swelling there was very painful to the touch. Bell initially considered surgery but felt the patient was too thin and too ill to undergo surgery. The patient died within a week of Bell’s consultation. Bell did an autopsy and found a traumatic neuroma of the tibial nerve. Bell comments that, if the tumor had been noted earlier and the lesion resected, the patient would have had a much better quality of life—a lament by surgeons still heard today.

Postoperative pain in peripheral nerve surgery remained a serious concern for nineteenth-century surgeons. The concern was significant enough that many surgeons still avoided peripheral nerve surgery in the first half of the nineteenth century. An opponent of peripheral nerve repair was George J. Guthrie (1785-1856), an English surgeon employed by the Duke of Wellington, with extensive military experience. Guthrie was only 15 years of age when he passed the examination for the Royal College of Surgeons. Guthrie also held the position of President of the Royal College of Surgeons, England for three terms. Guthrie’s military career took him to the United States and the Spanish campaigns of 1811 and 1812, in addition to the Battle of Waterloo. Guthrie was a surgeon of high integrity who constantly argued for improvement in the medical and surgical care of soldiers. Based on his military experience, Guthrie advocated not repairing a totally severed nerve. Guthrie presented his views on nerve injury and repair in an influential monograph on gunshot wounds (Guthrie, 1827). In this monograph Guthrie describes the treatment of nerve injuries and notes that what we now call causalgia can occur when ligating the ends of severed nerves. These findings led Guthrie to argue that the best course of action is to avoid this type of surgical repair.

Joseph Swan (1791-1874) was another nineteenth-century anatomist and surgeon with an interest in nerves and especially peripheral nerves (Swan, 1834). In his pioneering work, A Dissertation on the Treatment of Morbid Local Affections of Nerves, Swan discusses a number of the pathological conditions that can occur in a peripheral nerve (Swan, 1820). These conditions include traumatic injury, tumors, and inflammation of the nerve. One of the most common traumatic nerve injuries that Swan reports is damage due to venesection or bleeding, an extremely common practice for many medical diseases. During the venesection, the bleeding fleam (a handheld sharpened knife-like device to open a vein) often injured a nearby peripheral nerve. Following up on earlier surgical views, Swan argues only the rare case of venesection-related injury requires surgery. Like Swan, other contemporary surgeons continued to argue that a surgeon had to either take the nerve with the lesion or amputate the limb—the other option (Swan, 1820). Swan includes in his discussion the issues of pain and, more importantly, the principles of healing of injured nerves. Swan also provides an early clinical finding to what we now call the Tinel sign (Jules Tinel 1879-1952) (Tinel, 1917). Swan reported the following clinical description:

When a tumour is forming in the substance of a nerve it causes very violent pain, which sometimes affects the whole nerve in which it is contained. The pain is very much aggravated by any pressure made on it, and when it is moved. It is generally moveable from side to side only, as the upper and lower extremities are confined by the nerve.

Swan (1820)

Swan was among the first of the nineteenth-century surgeons to argue that divided nerves that are surgically repaired heal the best. Swan interestingly proffered a surgical opinion that surgery actually provided better results than no surgery at all (Swan, 1834). Part of Swan’s surgical treatment included the application of leeches and evaporating lotions to the injured parts, while placing those parts at rest (Swan, 1820).

Swan comments on divided nerves and their ability to heal:

Many experiments have been made by physiologist, to prove that when a nerve is divided, all sensation and motion are lost in the parts to which it was distributed, and that after the reunion of the divided parts it performs its functions as well as before the division.

Swan (1820)

One of the earliest illustrations of a partially divided nerve appears in Swan’s 1820 monograph (Swan, 1820). Swan comments that, in experimental studies, when a nerve is divided, the ends retract. If the nerve is only partially divided, the intact fascicles hold the nerve in position, but the cut portions still retract. This concept is illustrated in Figure 1.3. Swan’s book can be considered one of the pioneer monographs on peripheral nerve injury and treatment. In addition to the 25 clinical case studies contained in the book, Swan provides an additional 22 experimental studies on rabbit nerve injuries and repairs, clearly making the monograph an early landmark study on peripheral nerve injury (Figures 1.4–1.6).

Figure 1.4 Title page from Swan’s brilliant dissertation on morbid conditions in peripheral nerves.

Figure 1.5 Swan’s illustration of a partially divided peripheral nerve with some of the fascicles still intact and retraction in the cut fascicles.

Figure 1.6 Swan’s illustrations of the facial nerve innervations in a cadaver dissection. This is a very early and elegantly detailed anatomical description of facial nerves.

William Wood (1783-1858) was an English surgeon and a president of the Royal College of Surgeons Edinburgh, in which he was also a fellow. He published a provocative paper in 1829 on 24 cases of various neuromas drawn from the literature and his personal experience (Wood, 1829). In this paper, Observations on Neuromas. With Cases and Histories of the Disease, Wood notes that neuromas are tumors formed by an enlargement in a diseased nerve, but he incorrectly concludes that the tumor arises from the connective tissue of the nerve and not the nerve itself. Wood attributes the origin of the word neuroma to Louis Odier (1748-1817) of Geneva, Switzerland, who first used it in a monograph he published in 1811 (Odier, 1811). Odier called neuromas tumours formed by diseased enlargements of the nerves. Wood also details cases in which patients were found to have multiple neuromas. Wood felt that there was no good medical treatment for neuromas, and the best treatment was their surgical removal. Wood details the surgical findings in some cases involving the resection of a nerve tumor or traumatic neuroma, and he notes that patients can recover substantial nerve function after surgery. Wood comments:

This disease (i.e., neuroma), although fortunately not of very frequent occurrence, is an extremely interesting one, both on account of the importance of the functions performed by the parts affect by it, and of the difficulty which is occasionally experience in determining when it is sage and prudent to attempt a cure by the extirpation of the diseased parts along, and when it is essentially necessary to have recourse to the removal of the affected limb.

Wood (1829)

Wood points out that these tumors can sometimes grow quickly and be aggressive and therefore be made the subject of operation, at an early period of its progress, when the circumstances are all more favourable for obtaining a perfect cure, than afterwards (Wood, 1829). Wood states that pain during the surgery can be relieved by cutting the proximal or upper part of the nerve prior to removing the neuroma: by this means, the pain of the operation, which is often very severe is considerably diminished. This is an operation which has been proved to be a perfectly safe one, and often been practiced with complete success (Wood, 1829).

Alfred L.M. Velpeau (1795-1867) was a nineteenth-century French surgeon who published a series of surgical lectures in 1841, arguing that repairing a peripheral nerve injury or removing a tumor (neuromatic tumor—nérvomes) was a reasonable surgical treatment (Velpeau, 1841, 1845). Velpeau notes that the size of these neuromas can range from the size of a wheat grain to the size of a newborn child’s head (Velpeau, 1845). Velpeau comments that neuromas are often extremely painful, and patients come to the surgeon wanting it extirpated, which is done quickly. Velpeau points out that operating on a superficial neuroma is significantly different than operating on a deep neuroma on a large nerve. Velpeau also appreciates that the neuroma or tumor can be diffusely integrated (he uses the term confounded) into the fibers of the nerve. Velpeau advocates that, when operating on a peripheral nerve injury or tumor, the surgeon should do a generous resection of the nerve and then allow the nerves to regenerate and connect. In his book on operative surgery, Velpeau provides an extensive discussion in a section called Neuromas, in which he details the surgical resection of neuromas. In most cases the neuroma is resected and the cut nerve endings approximated, and in a number of cases, this approach provided for good neural regeneration with return of nerve function. Velpeau concludes a chapter on neuromas with the following comment:

The facts which I have related under the article on Excision of nerves, and those which have been considered in this chapter, prove that the consequences of such an operation rarely compromise the life, that they do not always alter the functions of the limb to an incurable extent, and that very frequently in fact the phenomena of sensation and motion which had been believed to be permanently destroyed, are ultimately more or less perfectly re-established.

Velpeau (1845)

Coming from a nineteenth-century general surgeon, this was clearly a most poignant and futuristic comment on peripheral nerve surgery. A cautionary comment on nerve resections was offered by a nineteenth-century physician and pathologist Rudolf Virchow (1821-1902) (Virchow, 1858). In 1864, Virchow commented that, in his opinion, the longer segments of resected or removed nerve segments (greater than 10 cm in length) rarely showed any reasonable signs of regeneration (Virchow, 1864). This comment made over 125 years ago is still very relevant today.

In the mid- to late-nineteenth century, surgeons continued to debate the risks and benefits of an end-to-end anatomosis of cut peripheral nerves. The arguments went back and forth. Some insisted that the needle repair only further injured the nerve, leading to infection, septicemia, neuritis, and traumatic nerve damage from passing the needle. Others in the medical community asserted that the mere opposition of the cut nerves could lead to good return of function, and still others, including S. Weir Mitchell, argued that such was not the case (Mitchell, 1872). To illustrate the relative effectiveness of repair, Anthony A. Bowlby, a fellow of the Royal College of Surgeons and a surgical pathologist at St. Bartholomew's Hospital, London, reported on 20 cases of primary suture repair with only two cases showing any sort of reasonable return of function (Bowlby, 1889). Bowlby observed that nerve injuries are signalized by the destruction of the myeline, the multiplication of the nuclei, and the loss of continuity of the axis-cylinder. Bowlby went onto postulate there might actually be trophic factors in the nerve and surrounding tissue that encourage more active regeneration in some cases. Bowlby also commented that the surgeon often had to wait up to 2 or 3 years before evaluating the final results.

Experimental studies published in 1795 by William C. Cruickshank (1745-1800) revealed that nerve regeneration did in fact take time, in some cases requiring years to complete (Cruikshank, 1795). Cruickshank cut the vagus nerve in a dog and then followed it over time to record its regeneration. Cruickshank was among the first to report actual observations of nerve regeneration in an experimental situation. He described the regenerating nerve as similar in color and structure to an uncut nerve but with bulbous endings. His experimental findings led Cruickshank to postulate that a severed nerve could actually regenerate, a phenomena not previously visualized or reported. When Cruickshank originally submitted his findings for publication, the concept of regeneration did not bode well with the journal editors. Similar findings on nerve regeneration were presented by John Haighton (1753-1823), a physician and physiologist who lectured at St. Thomas Hospital, London. The Cruickshank and Haighton papers were published in the same issue of the Philosophical Transactions in 1795 (Haighton, 1795).

Augustus V. Waller (1816-1870) (Waller, 1850, 1852a, 1852b, 1852c, 1852d), Wilhelm His (1831-1904) (His, 1890), Louis-Antoine Ranvier (1835-1922) (Ranvier, 1872, 1878), and others later showed that regeneration was based on the downward growth of fibers from the cell body. These findings contradicted the conclusions of the reunionists who asserted that the proximal and distal ends of the cut nerve rejoined or formed a complete nerve through reunion. Interestingly, Waller’s original work on degeneration or what we now call Wallerian degeneration helped settle these arguments (Waller, 1852a). Following his research, Waller reported findings that showed regeneration occurring at the proximal end of the nerve, just above the area where the nerve was cut. Waller clearly described the changes that occurred in the regenerating nerves and noted there was not a reunion of the proximal and distal ends of the cut nerve but rather a regeneration from the proximal element or cell body downward (Waller, 1850).

A classic nineteenth-century monograph on peripheral nerve injures and their treatment was authored by S.W. Mitchell, G.W. Morehouse, and W.W. Keen from Philadelphia (Mitchell, Morehouse, & Keen, 1864). These three gentlemen staffed the Turner Lane Hospital in Philadelphia, set up by the US Surgeon General (William Hammond) to treat the enormous amount of battlefield injuries from the American Civil War (1861-1865). In their book Gunshot Wounds, the authors present 43 cases of wounds of large nerves detailed with thorough clinical histories and findings. Mitchell describes his American Civil War experience in a local Philadelphia hospital, as follows:

No sooner did this class of patients begin to fill our wards, than we perceived that a new and interesting field of observations was here opened to view… Among them were representatives of every conceivable form of nerve injury, from shot and shell, from sabre cuts, contusions and dislocations. So complete was the field of study, that it was not uncommon to find at one time in the wards four or five cases of gunshot injuries of any single large nerve. It thus happened that phenomena which one day seemed rare and curious, were seen anew in other cases the next day, and grew commonplace as our patients became numerous.

Mitchell et al. (1864)

In a work published 8 years later, Injuries of Nerves (Mitchell, 1872), Mitchell expands his thoughts on the subject of nerve injuries, including more descriptive findings of nerve injuries as well as trophic changes of the extremities, referred sensation, and the psychological consequences of amputation. Although the causalgia had been recognized at least since the sixteenth century, Mitchell was the first to formalize the description under the term causalgia (pain and heat), familiarizing the medical community with a now well-known painful posttraumatic nerve injury syndrome (Figure 1.7). Mitchell writes:

Figure 1.7 Title page from S.W. Mitchell’s seminal work on nerve injuries, based on extensive experience from the American Civil War and work at the Turner Lane Hospital in Philadelphia. Mitchell dedicated this volume to Surgeon General William Hammond.

The skin affected in these cases was deep red or mottled, and red and plate in patches. The subcuticular tissues were nearly all shrunken, and, where the palm along was attached, the part so diseased seemed to be a little depressed, firmer, and less elastic then common. In the fingers there were often cracks in the altered skin, and the integuments presented the appearance of being tightly drawn over the subjacent tissues. The surface of all the affected parts was glossy and shiny as though it had been skillfully varnished. Nothing more curious than these red and shining tissues can be conceived of. In most of them the part was devoid of wrinkles and perfectly free from hair… [Mitchell later comments] Further study led us to suspect that the irritation of a nerve at the point of the wound might give rise to changes in the circulation and nutrition of the parts in its distribution, and that these alterations might be of themselves of a pain-producing nature.

Mitchell (1872)

Mitchell calls causalgia the most terrible of all tortures which a nerve wound may inflict…its favorite site is the foot or hand…its intensity varies from the most trivial burning to a state of torture. The part itself is not alone subject to an intense burning sensation, but becomes exquisitely hyperanesthetic, so that a touch or tap of the finger increases the pain (Mitchell, 1872).

Mitchell discusses nerve injuries and their surgical treatment, which, at the time, included exploration and cleaning the wound of any debris, glass, and other foreign material. Mitchell notes that the ends of the nerves should be brought together, and a splint should be placed on the arm in a relaxed position to prevent traction. In discussing the suture of nerves Mitchell comments:

Sutures in nerve wounds. Where it is plain, from a careful study of the wound and the loss of function, that the nerve trunk has been altogether divided, the surgeon is called upon to decide whether he will leave repair to nature alone, or enlarge the wound and secure coaptation of the nerve ends by the use of sutures. The propriety of this step rests upon the manner in which we answer these two questions: Will any, even the most perfect approximation of nerve ends insure immediate union? And, failing this, will it make likely a more speedy return of healthy function? To the first, we may give a certain reply in the affirmative. [Mitchell adds] As I have already pointed out, all the physiological evidence is against the possibility of immediate useful union. Within a few days the peripheral end of the nerve surely degenerates, and in adult animals many months may pass before it is restored and the two ends reunited.

Mitchell (1872)

As a neurologist, Mitchell most commonly advocates that the best treatment for a nerve injury is the application of electricity to the injured limb, along with splinting and rest, with surgery being the last resort of treatment.

Some Further Historical Concepts Related to Peripheral Nerve Anastomosis

In 1669, Richard Lower (1631-1691) provided the first description of a traumatically divided nerve forming a callous (Lower, 1669). Interestingly, Lower included this observation in a treatise on heart and pulmonary circulation. Lower collaborated with Thomas Willis (1621-1675) in the development of the physiology and anatomy of the circle of Willis and the anastomotic flow of blood (Willis, 1681). Although Lower described his finding of callous formation, he did not recognize the callous as being part of a regenerating nerve. With rare exceptions, earlier writings show that the primary repair or end-to-end suturing of peripheral nerves did not really evolve into a surgical practice until well into the nineteenth century. The previous fears of infections, neuritis, and painful neuralgias kept many surgeons from doing primary nerve repairs. The concept of separate motor and sensory functions in a nerve also did not evolve until the nineteenth century. As we have seen here, the 1800s were characterized by arguments between the reunionists and those who felt that a nerve only regenerated from the cell body down. The surgical pioneers of this era include B. Van Langenbeck who, in 1854, published a report on a primary repair of a median nerve injury (Langenbeck & Hueter, 1854). The cut ends of the nerve were reapproximated and, 1 year later, the patient reported return of full nerve function. In 1895, Thomas Masters Markoe (1819-1901), a professor of surgery and pathologist at New York Hospital, reported a variation on the end-to-end suture by cutting the ends of the nerves at an oblique angle. Markoe devised this technique because he felt it increased the contact surface of the two nerves (Markoe, 1885). Markoe also suggested the use of a round (i.e., atraumatic) needle to avoid further injury to the nerve when passing the needle. The concept of removing the callous or nerve bulb on a regenerating nerve was a late addition to the surgical techniques for nerve repair. A Scottish Surgeon, Alexander Ogston (1844-1929), who was among the first to popularize the concept, published a paper on removing the bulb at the end of a regenerating nerve prior to suture repair. In 1881, Ogston had exposed a large neuroma during an ulnar nerve exploration and made the decision to excise the neuroma prior to the repair (Ogston, 1881). By the time of World War I, surgeons commonly trimmed the nerve back until more normal neural filaments were seen. In 1908, J. Sherren provided a strong argument for nerve anastomosis, particularly as applied to the facial nerve (Sherren, 1908). Sherren reviewed an extensive amount of literature available at that time on surgery of peripheral nerves. A series of illustrations were provided on the various types of anastomoses that can be done. Sherren notes that, in a repair absolute asepsis and gentleness of manipulation are essential to success, the great hindrance to recovery being the ingrowth of fibrous tissue between the ends … In addition, if extensive separation of the nerve from surrounding parts has been necessary, it should be protected from forming adhesions by enclosing the bare portion and the junction in sterile Cargile membrane or foil; this should also be done whenever a nerve has been incised (Sherren, 1908).

A concept little recognized at the end of the nineteenth century was the disabling nature of nerve stretching that often occurred during a primary end-to-end repair. Surgeons of the time commonly freed up the proximal and distal ends of the severed nerves and then stretched them, like rubber bands, sometimes up to several centimeters to close the gap. In his work, Bowlby actually tries to describe to the surgeon the cracking and snapping sounds that occur as the surgeon stretches the nerve ends (Bowlby, 1889). A prominent proponent of nerve stretching was John Marshall (1818-1891), an English anatomist and surgeon. In 1883, Marshall gave the prestigious, endowed Bradshaw lecture on nerve stretching (Marshall, 1883). Nerve stretching had been introduced in the nineteenth century to help treat the symptoms of sciatica and also causalgia. The technique involved exposing the nerve causing the symptoms and then stretching it. Marshall felt this technique stretched the nervi nervorum, an anatomical structure that does not exist in peripheral nerves. Nevertheless, Marshall imagined that pain relief came from the stretching of this structure, which he believed contained nerves that went into the nerve trunks from the periphery. Interestingly, Marshall completed some of his investigative work in collaboration with Victor Horsley (1857-1916), the English surgeon (Horsley, 1884; Sugar, 1990).

Among others, Byron Stookey (1887-1966) clearly noted that nerve stretching was deleterious to regeneration and should be avoided if at all possible (Stookey, 1922). According to Stookey, a surgeon should only take up the natural slack that already exists between the nerve ends. Another contribution to nerve repair came from studies by surgeons in World War I who realized that an additional relaxation could be provided to a repaired nerve by placing the limb in a flexed position, thereby avoiding strain on the nerve anastomosis. At the time, another technique for reducing nerve stretching was to reduce the limb length by removing portions of the long bone, a particularly useful technique when a fracture was present. One of the strongest advocates of this technique was Walter Dandy (1886-1946) who presented some of his findings in a 1943 paper (Dandy, 1943).

The concept of reanimating the face after a facial nerve injury developed toward the end of the nineteenth century. In 1879, Drobnik provided one of the earliest case reports, describing how a traumatically severed facial nerve was anastomosed to the spinal accessory nerve (Drobnik, 1903). Over time Drobnik reported some improvement in facial function. Another pioneer in these techniques was Sir Charles Ballance (1856-1936), who did an anastomosis of a traumatically divided facial nerve to a branch of the spinal accessory nerve as early as 1895 (Ballance, Ballance, & Stewart, 1903; Stone, 1999). The facial nerve was sutured into a gap in the spinal accessory nerve using a fine silk suture. Interestingly, the movement in the face that eventually evolved occurred only when the shoulder was moved. Although not a particularly good result, Ballance’s procedure was an interesting surgical innovation for 1895. Ballance also did a similar type of anastomosis with the glossopharyngeal nerve (Ballance, 1907; Ballance & Duel, 1932). As the results with both nerves were not particularly good, Ballance moved on to placing a nerve graft between the divided nerve. He used a blood plasma glue to hold the graft in place. Ballance felt this technique gave a superior result in facial nerve recovery (Ballance et al., 1903). Ballance did point out that the innervated muscles awaiting innervation would not return to functional status until the regenerating nerve reached its destination, however—Until the nervous connection is restored the muscle makes no attempt at recovery (Ballance, 1919).

In 1901, a monograph by Ballance and Purves Stewart provided one of the most important contributions to the understanding of how an injured nerve regenerates (Ballance & Stewart, 1901). These authors extensively investigated the process of degeneration and regeneration after injury in a peripheral nerve, using the then recently introduced Golgi staining technique. Their monograph includes some of the earliest illustrated pathological specimens dealing with peripheral nerve regeneration (Ballance & Stewart, 1901). The authors conducted studies on the regeneration of a cut nerve that was reunited by suturing, as well as regeneration in nerves that had not been brought into surgical opposition. The use of nerve grafts (both from the same animal and from another animal) for repair was also thoroughly investigated. These investigations involved both animal and human studies. As a result, the monograph provides the origins of the current medical understanding of regenerating nerves and their pathology. This monograph best detailed the degeneration and regeneration of a peripheral nerve with studies that, for the first time, clearly identified the involved pathology and histology (Figures 1.8–1.10; Ballance & Stewart, 1901).

Figure 1.8 Title page from the 1901 monograph on the healing of nerves by Ballance and Stewart (1901) .

Figure 1.9 Illustrations of sciatic nerves divided and then treated with suturing or no suturing ( Ballance & Stewart, 1901 ).

Figure 1.10 Illustrations from nerves that have been both cut and sutured and just cut only, as well as the pathological findings in these repairs ( Ballance & Stewart, 1901 ).

An often unappreciated pioneer in facial nerve injury was Harvey Cushing. In 1903, early in his career, he published a paper on his technique for treating facial paralysis by transferring a spinal accessory nerve graft to the facial nerve (Cushing, 1903). In 1903, W. Korte introduced the technique of hypoglossal-to-facial nerve anastomosis more commonly used today (Korte, 1903).

Further Thoughts on Peripheral Nerve Tumors

The recognition of tumors of peripheral nerves has a long history. Ambroise Paré (1510-1590) first described what he called a neoud of the nerve, a swelling that occurred within the nerve, which represented a nerve tumor (Paré, 1634). The pathological concept of a tumor did not really evolve until the eighteenth century. William Cheselden (1688-1752), a British anatomist and surgeon, provided an interesting eighteenth-century case of a tumor of a peripheral nerve (Cheselden, 1756). Cheselden describes a painful round soft tissue mass within a cubital nerve that expanded out the nerve filaments. To treat this mass, Cheselden performed the then common practice of excising the tumor with the nerve. John Hunter (1728-1793), the English anatomist and surgeon, provided details of a case of a surgical removal of a nerve tumor of the axillary nerve that was loosely adherent to the nerve. Hunter sectioned the nerve with the tumor and then later realized that he could have easily dissected the tumor without injury to the nerve (Home, 1800). This led Hunter, and later his protégée (and plagiarist) Edouard Home, to conclude that, in some cases, a nerve tumor could be dissected off, leaving the nerve in continuity. Another technique described in the literature was to open the tumor capsule and then digitally remove the tumor from within the capsule. Interestingly, though freed of the tumor, the patient involved in this procedure went on to die of complications of wound infection due to the surgery. This type of outcome led contemporary surgeons to continue avoiding surgical resections, thinking that dissection within the nerve was just too dangerous.

Illustrated examples of peripheral nerve tumors began to appear in some of the pathological and surgical monographs in the first half of the nineteenth century. Jean Cruveilhier (1791-1874) was a French anatomist, pathologist, surgeon, and the first chair of pathology at the University of Paris, and he illustrated some interesting examples of what physicians now call a peripheral nerve tumor (Cruveilheir, 1835-1842). Cruveilhier also provided one of the earliest colored illustrations of a patient with neurofibromatosis. His surgical and pathological atlas was a remarkable advance in pathology due to the detailed pathological descriptions that he provided. Within this monograph, the peripheral nerve lesions are beautifully illustrated, but as a pathologist, Cruveilhier provides no discussion of any surgical treatments for them (Figures 1.11 and 1.12; Cruveilheir, 1835-1842).

Figure 1.11 Cruveilhier illustrates several different examples of peripheral nerve tumors. In figure 1 (upper left), he shows an amputated arm and illustrates the nerves with the cut ends remarkably enlarged.

Figure 1.12 Cruveilhier’s illustrations of a patient with what we now call neurofibromatosis.

Charles-Prosper Ollivier d’Angers (1796-1845) was a professor of anatomy and the director of the anatomical museum at the University of Breslau. In his 1837 monograph on spinal cord disorders, he demonstrated an interesting example of a spinal root tumor (Ollivier, 1827). This illustration is one of the earliest illustrated examples of a spinal cord or root tumor. The pathological details of this tumor are minimal, but a review of the image indicates that it was likely a schwannoma or a neurofibroma (Figure 1.13).

Figure 1.13 Illustration from Ollivier d’Angers showing a tumor of one of the spinal roots, likely a neurofibroma or schwannoma.

An early description of multiple tumors of peripheral nerves was provided by Adolph Wilhelm Otto (1788-1845) in 1831 (Otto, 1831). Otto’s described these tumors as sarcomatous and cancerous swellings within the nerve. Otto’s description is likely the first of a patient with neurofibromatosis. Otto states the following:

…this especially occurs in sarcomatous and cancerous swellings of the nerves, in which the whole nerve is here and their swollen, hardened, knotty, discoloured, and degenerated in a greater or less degree throughout both its sheath and medulla.

Otto (1831)

As a Dublin surgeon interested in forensic medicine, Robert William Smith (1807-1873) provided an early detailed monograph on pathological disorders and tumors of peripheral nerves in 1849 (Smith, 1849). Smith’s writing detailed numerous clinical examples of traumatic neuromas, tumors of the nerves including both single and multiple lesions. Building on Otto’s work, Smith’s description of multiple tumors of peripheral nerves is also considered an early detailed description of neurofibromatosis. In the clinical treatment of nerve tumors, Smith argues against any form of surgical removal of just the tumor, and in line with earlier surgical thinking, he recommends dissection of the whole nerve and tumor as one pathological specimen. Throughout his career, Smith continued to argue that enucleating the tumor would only lead to an inflammatory disease and a worse outcome, following a concept first introduced by Joseph Swan in 1821. L. Michon carried the surgery one step further, reporting on his operation on a sciatic nerve tumor in which he not only removed the tumor but also sutured the resected nerve endings together (Michon, 1849).

In 1882, Fredrick D. von Recklinghausen (1833-1910), a professor of pathology at Könisgsberg, published a classic monograph detailing the multiple tumors of peripheral nerves characterizing what is now referred to as neurofibromatosis type 1 or von Recklinghausen disease (von Recklinghausen, 1882). He based his findings on two interesting cases, an adult male and a female patient with multiple skin nodules covering the entire body. In his monograph von Recklinghausen provided some of the earliest detailed pathology illustrations of cross-sectioned peripheral nerves that contain neurofibromas. The accuracy of his drawings is so good they can still be used today as teaching examples of neurofibromas (Figures 1.14 and 1.15).

Figure 1.14 One of the earliest, if not the earliest, photographic illustration of a patient with neurofibromatosis from von Recklinghausen’s classic work on neurofibromatosis.

Figure 1.15 Illustrations of some of the pathology of nerves with neurofibromas from von Recklinghausen’s book on neurofibromatosis.

Classification of the Different Grades of Peripheral Nerve Injury and Introduction of Electrophysiological Techniques for the Assessment of Nerve Injuries

At the beginning of the twentieth century, early neuroscientists, such as the Spaniard Santiago Ramon y Cajal (1852-1934) and Paul Weiss (1898-1989), applied modern experimental approaches, both in vivo and in vitro, to better understand chemical (trophic and tropic) and mechanical factors in the local environment of peripheral nerves that influence their growth and regeneration (Ramon y Cajal, 1909-1911, 1928, 1952-1955; Weiss, 1939). The breadth of Ramon y Cajal’s life is reflected in the enormous scope of his scientific work. As a child he was very independent minded and quite unruly, resulting in his having to attend many different schools. His precociousness, ingenuity, and resourcefulness can be seen in his imprisonment at the young age of 11 years old for destroying a neighbor’s gate with a homemade cannon. In addition to intellectual pursuits such as painting, he excelled as a gymnast and, later in life, prided himself on carrying around a very heavy cane. Ramon y Cajal attended the medical school of the University of Zaragoza where his father taught anatomy. He then obtained a doctorate at the University of Madrid, before holding professorships in the Department of Anatomy at the University of Valencia and then simultaneously at the University of Madrid and the University of Barcelona. He was the director of several institutes and was a founder of the Laboratory of Biological Investigations, which was later renamed the Cajal Institute, in Madrid, Spain. In 1906, Cajal shared the Nobel Prize with Camillo Golgi (1843-1926) in recognition of their work on the structure of the nervous system. Ironically, Cajal used Golgi’s own stain to refute the reticular theory of neuronal connectivity and support the neuronal doctrine, which became one of the central tenets of modern neuroscience. He also discovered the axonal growth cone by which axons extend during both development and regeneration. His artistic talent and amazing capacity for synthesizing microscopic observations are clearly evident in his many beautiful illustrations gracing his publications (Ramon y Cajal, 1909-1911, 1928, 1952-1955).

Paul Weiss (1898-1989) was also of European origin, having been born in Vienna, Austria just before the turn of the last century. Weiss grew up with a background in music, philosophy, and poetry. After serving as an artillery officer in World War I, he started studies in engineering at what is now the Vienna University of Technology. Weiss then made an academic change and majored in biology with a minor in physics. Like Ramon y Cajal, he was drawn to study neural development and regeneration. After moving to the United States in 1930, Weiss had a very productive scientific career at Yale and the University of Chicago, and he ultimately became one of the first professors at Rockefeller University. Weiss did seminal studies, developing tissue culture techniques that permitted experimental manipulation of the microenvironment of cells and thus more rigorous study of cell proliferation and process outgrowth (Weiss, 1939).

During the twentieth century, two other prominent, prolific, and multitalented physicians made important contributions toward providing a better understanding of the pathological alterations occurring in human peripheral nerves following traumatic injury. The distinguished English orthopedic surgeon Sir Herbert Robert Seddon (1887-1964) classified such alterations in an article published in Brain in 1943, titled Three Types of Nerve Injury (Seddon, 1943). Seddon was the first to develop a classification of traumatic nerve injuries based on involvement of specific anatomical components of the nerve, and this classification helped determine both treatment as well as prognosis (Seddon, 1942). The first two grades of nerve injury, neuropraxia, which involves damage to the Schwann cell insulation of axons, and axonotmesis, which involves damage to the axon but not the surrounding endoneurial structures supporting axonal regeneration, result in recovery of function without a surgical intervention. The third and most severe grade involves damage to the axon-surrounding structures that prevents axonal regeneration and therefore requires a surgical repair for recovery of function. It was not until 1972 that Seddon’s magnum opus, Surgical Disorders of the Peripheral Nerves, was finally published (Seddon, 1998). In this classic book, Seddon devotes an entire chapter to his care of, and relationship with, Sir Winston Churchill.

Sir Sydney Sunderland (1910-1993) later expanded Seddon’s logical classification system for peripheral nerve traumatic injury. Born in Brisbane, Australia, Sunderland proved to be an excellent athlete and student as a boy, and he won several prestigious scholarships. He obtained his MD degree from the University of Melbourne where he eventually became the dean. Along the way, Sunderland worked at many prestigious institutions, including Oxford, where he collaborated with the famous neuroanatomists Wilfrid Le Gros Clark (1895-1971) and Pio del Rio-Hortega (1882-1945). Sunderland also worked at the Montreal Neurological Institute with Wilder Penfield (1891-1976), a highly innovative neurosurgeon and neuroscientist. Sunderland eventually became head of the Peripheral Nerve Injuries Unit in Heidelberg, Victoria, where all Australian servicemen sustaining nerve injuries during World War II were sent for treatment. There, he began his long-term and meticulous studies on nerve injuries, using the most up-to-date neurosurgical and neuropathological techniques in combination with careful and detailed serial clinical examinations. Sunderland was able to personally study the natural history of 365 patients who sustained traumatic nerve injuries over a 10-year period. On the basis of his clinical and pathoanatomical studies, he subdivided Seddon’s 3-tier grading system of traumatic nerve injuries into a five-grade system by further separating neurotmetic injuries on the basis of finer anatomical distinctions. Sunderland’s wealth of clinical experience and wisdom was collected in his book entitled Nerve Injuries and Their Repair: A Critical Appraisal (Sunderland, 1991).

After the refinement and broad clinical application of nerve and muscle stimulation and recording techniques, in the form of electromyography and nerve conduction velocity studies, clinicians could finally distinguish milder neuropraxic injury from the more severe axonotmetic and neurotmetic nerve injuries. These studies have origins that date back to the work of Francesco Redi (1626-1697) in 1666 on the muscle of electric eels, followed by the work of Luigi Galvani (1737-1798) in 1791 published in De Viribus Electricitatis in Motu Musculari Commentarius (Galvani, 1791; Redi, 1687). More recent developments, such as the invention and application of oscilloscopes, amplifiers, and stimulating and recording electrodes, have made electrodiagnostic studies a mainstay in working up patients with peripheral nerve injuries, both inside and outside the operating room.

Even as late as World War I, nerve injuries were repaired often under tension. In order to span gaps and avoid the use of nerve grafts, surgeons often placed limbs in extreme positions of flexion. Unfortunately, these repairs often resulted in poor clinical results. It was not until World War II that nerve injuries and surgical repairs were