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Milestones in Oculofacial Plastic and Reconstructive Surgery: The Discovery of the Levator Palpebrae Superioris and Its Subsequent History

Purpose: This review aims to substantiate attributions of priority for the discovery and first description of the levator palpebrae superioris (LPS) muscle to Matteo Realdo Colombo [Columbus] (1516–1559), and to describe the history of this muscle from ancient to modern times. Methods: Relevant chapters on eyelid and eye muscles in Colombo’s De re anatomica (1559) were translated, and the work was further analyzed from a historical perspective. Literature on the anatomy of human eyelid and orbital striated muscles was reviewed from the publication of the Fabrica (1543) by Andreas Vesalius (1514–1564) through modern times. The discovery of the LPS was viewed in relation to other milestones along the road that led to the establishment of the subspecialty of oculofacial and orbital plastic surgery. Results: The first description of the LPS appeared in De re anatomica (1559) by Colombo who correctly identified the LPS as a retractor of the (upper) eyelid and the orbicularis oculi as its protractor. The current lack of recognition of the priority of Colombo’s description of the LPS stemmed from his lifelong rivalries with other anatomists, improved descriptions of the orbital muscles by Gabriele Falloppio (1523–1562) that soon followed, and historical controversies over other anatomical discoveries. Conclusions: Colombo discovered the LPS and described the antagonistic functions of retractors and protractors of the eyelid, just a portion of his broader contributions to anatomy. Colombo’s discoveries of such ophthalmologic and oculofacial plastic surgical importance should be added to the ongoing reappraisals of Colombo by medical historians.

T he discovery of the levator palpebrae superioris muscle (LPS) is considered to be one of the major milestones along the road to establishing oculofacial plastic and reconstructive surgery as a subspecialty. 1 The discoverer of the LPS, Matteo Realdo Colombo [Realdus Columbus Cremonensis] (1516-1559) and his book De re anatomica (1559) 2 containing its first description have gone almost unrecognized in the ophthalmic literature. From the writings of Galen (129-210) 3 and through those of Andreas Vesalius (1514-1564), 4 upper eyelid elevation was incorrectly described as an action of a portion of the orbicularis oculi muscle. Debunking this concept, Colombo became the first to establish the relationship of the LPS and the orbicularis oculi as "antagonists." 5 In current terminology, the opposing actions of opening and closing of the upper eyelid classify the LPS as its "retractor" and the orbicularis oculi as its "protractor." 6,7 Colombo was imprecise on some important points. He erroneously described the LPS as taking its origin "from the optic nerve like the rest of the eye muscles" rather than separately from the lesser sphenoid wing. Colombo also provided the first, albeit incomplete and confused, European description of the anatomy and functions of the superior and inferior oblique muscles, though he made the following two errors: he numbered the superior oblique with the LPS ascribing the action of eyelid opening to both; and, while correctly recognizing supraduction of the eye as an action of the inferior oblique, he incorrectly described both the origin and insertion of the inferior oblique as being on the eyeball. Two years after Colombo's De re anatomica, Colombo's contemporary, Gabriele Falloppio (1523-1562 published improved descriptions of the oblique muscles in his book, Observationes anatomicae (1561). 8 Both Colombo's and Falloppio's works contained refutations of a retractor bulbi muscle in humans (Fig. 1). (Supplemental Digital Content 2, available at http://links.lww.com/IOP/A261: Subdividing anatomy; describing networks of growing complexity.) Ignorance of Colombo's priority for the discovery of the LPS became entrenched through the judgments of twentiethcentury historians such as Julius Hirschberg (1843Hirschberg ( -1925 9 and Sir Stewart Duke-Elder (1898-1978) 10,11 Conflation of biographical details eventually arose wherein Falloppio was inaccurately described as "Vesalius' pupil, friend, and successor to the chair of anatomy in Padua" 12 or simply as Vesalius' "student and successor." 13 Actually, Falloppio was neither Vesalius' pupil nor his friend. It was Colombo who had been the (star) pupil, (short-lived) friend, and (immediate) successor of Vesalius.
Historical misattributions and biographical conflations about the LPS, Columbo, and Falloppio appear to have had their original source in the decades-long rivalry between Colombo and Vesalius that endured beyond their lifetimes. In the shadow of the heroic figure of Vesalius, and poisoned by mutual animus, the trail to Colombo's ophthalmologic discoveries became obscured. Negative characterizations crept into the narrative as did the unfounded charge of Colombo's "plagiarism" for his independent discovery of the pulmonary circulation. Charles Singer (1876Singer ( -1960 erroneously suggested that Colombo's omission of illustrations from De re anatomica was in "opposition" to Vesalius' emphasis upon them. 14 Elsewhere, in a review of the "Vesalian" school of Renaissance anatomy, he noted, "In the first line comes Realdus Columbus (1516-1559), of whose attainments very different estimates have been formed." 15 A recent reappraisal of Colombo places him in an enlightened role as a key figure in the "revival of Alexandrian anatomy." 16 24 Years later, in the introduction to De re anatomica, Colombo affectionately recalled his apprenticeship to "Ioanni Antonio PLATO, known as Lonigo," the capitalized sobriquet alluding to the surgeon's frequent reference to Plato in his lectures. The lectures undoubtedly included Plato's teleological descriptions of the human body in service to the soul, divided into three natural regions: the head, housing the immortal soul; the upper thorax as the seat of the mortal soul; and the lower (subdiaphragmatic) body, as a "manger" for the animalistic or lowest soul. In 1540, Colombo left Venice and his apprenticeship with Lonigo and went to Padua. He served as a lecturer in Aristotelian philosophy, "a very junior and poorly paid position," 25 which was then emphasized at the university under Marcantonio de' Passeri [Genua] (1491-1563). Colombo's transition to being a student of medicine served as an appropriate entrée to a future academic career. He remained a philosopher although deemphasizing abstract and spiritual Platonic notions in favor of more empirical Aristotelian and Alexandrian methods. As a student of medicine and anatomy, he was a classmate of the anti-Aristotelian philosopher, Bernardino Telesio (1509-1588), 26 and of the English scholar and Galenist, John Caius (1510-1573), the second founder of Gonville and Caius College of Cambridge with whom he competed for students. 27,28 Caius had a falling out with Vesalius over disputes about Galen's methodology and mundane philological issues.
Colombo's friendship with Vesalius, like that of Caius, would likewise turn sour. Before Colombo suffered the same fate, he had been a favorite of Vesalius, chosen as the assistant for public dissections in 1541. Harvey Cushing (1869Cushing ( -1939 identified Colombo in the foreground of the famous frontispiece of the Fabrica-the bearded man standing prominently in the foreground of the frontispiece to the right of the dissecting table, staring at the dog stepping on his foot and raising his index finger as if to give a warning. 29 O'Malley suggested this individual represents Marcantonio de' Passeri [Genua] mentioned above. 30 The individual appears to be balding though not yet completely bald. The antique garb evokes Aristotle or an heir to his philosophy and methods. Before the falling out between Vesalius and Colombo, the Senate of Venice intervened to deny Colombo's university appointment to its second chair of surgery, probably upon an appeal by Vesalius. This was the chair that Vesalius simultaneously held along with the first, with pecuniary benefits from both positions. 31 Perhaps Colombo was not so sad to see his teacher leave Padua in 1542, to publish the Fabrica in Basel, and to seek a position in the court of Emperor Charles V (1500-1558). At that time, Colombo dutifully assumed Vesalius' teaching duties lecturing and dissecting in public. Before his departure to England in the summer of 1543, John Caius was among those who watched Colombo's dissections. 2 Later in 1543, Colombo received a formal but temporary appointment as a chair of anatomy and a permanent appointment to one of the two chairs of surgery.
Colombo's second teaching appointment was at the newly reopened Studio of Pisa (1545-1547), resulting in a loftier salary and the prestige of the patronage of the Duke of Tuscany, Cosimo I de' Medici (1519-1574). Vesalius had performed a public dissection in Pisa at its reopening in 1543 but, according to Colombo's student, Juan Valverde de Hamusco (1525-1587), Colombo likewise visited Pisa to perform dissections in 1544, the second academic year of the studio. While Vesalius may have been Cosimo's first choice for the position of chair of anatomy and surgery, Colombo was a highly desirable second choice. He was given the authority to use the text of his own choosing. 16 Perhaps, he used the Fabrica to point out its errors. Upon permanently departing Pisa, he was replaced by Gabriele Falloppio.
The third and last of Colombo's teaching appointments was his longest, over a decade at the Studio della Sapienza in Rome (1548-1559). This was the papal university reestablished by Leo X (1475-1521), the pope who had issued the Papal Bull of 1520 condemning Martin Luther (1483-1546). Colombo's appointment at the Sapienza by Pope Paul III (1468-1549) placed him at the heart of the Counter-Reformation.
For a time in their lives back in Padua, Colombo's relationship with Vesalius was amicable. In the first edition of the Fabrica, Vesalius referred to Colombo as "my friend Colombo, skilled professor at Padua, most studious of anatomy." Falloppio, on the other hand, was never a student of Andreas Vesalius, a correspondent certainly but not his friend. He studied medicine in Ferrara where he was a classmate and perhaps a friend of Franciscus Vesalius (the younger brother of Andreas), and a student of the anatomy professor, Giambattista Canano (1515-1579). Falloppio earned his medical degree at Ferrara in 1548 and his three professorial appointments were at Ferrara The rivalry between Colombo and Vesalius began during an unexpected and brief return of Vesalius to Padua around December 1543. Vesalius was irritated to learn of the very public and brusque criticisms by his former student. Colombo was not prepared for Vesalius' visit and reportedly hid himself from public view. Among his public criticisms, Colombo had proclaimed that the retractor bulbi of ruminants and other lower animals does not exist in humans. The ironic and mocking insinuation was that Vesalius had erred, just as Galen had centuries before, by basing a description of human anatomy upon dissections performed on animals. Vesalius countered that Colombo had boastfully erred in claiming an imaginary discovery of a direct venous connection between the spleen and the stomach. In a letter known in English as The China Root Epistle (published October, 1546), Vesalius attacked Colombo, referring to him as an illiterate, boastful dabbler who had learned a smattering of practical anatomy with his help. 32 Elsewhere in the epistle, Vesalius conceded to the reappraisal of the retractor bulbi saying, "I am compelled to admit that Galen needs to be corrected in describing the use of the muscle he enumerates so casually." The China Root Epistle was published with a dedicatory preface by Franciscus Vesalius to Duke Cosimo I de' Medici. At that time, Colombo was well established at his new post at the University of Pisa, recruited by this same powerful and wealthy benefactor. In August 1547, Cosimo granted Colombo's request to pursue his research in Rome though the duke required that he still attend to the studio and his winter lectures in Pisa. The following spring, Colombo beseeched his benefactor to let him remain permanently in Rome to continue his work, stating that he was receiving assistance from "the leading painter in the world" and further supervising other painters. With Cosimo's acquiescence, Colombo remained permanently in Rome beginning in 1548. He taught at the Sapienza for the next decade, occupied with private dissections, writing, and arranging for the illustration of a textbook that would feature his own discoveries and document the errors of his predecessors.
Cosimo was certainly aware that the "leading painter" and friend of Colombo was Michelangelo Buonarroti (1475-1564) whose drawings, paintings, and sculpture had long displayed anatomic insights. Near the center of The Last Judgment (Sistine Chapel, 1536-1541), Michelangelo had purportedly emplaced his self-portrait on the meticulously flayed skin held by Saint Bartholomew, a symbol of that saint's martyrdom. 33 Colombo provided Michelangelo with cadavers for the two of them to dissect together, sometimes also in the company of Michelangelo's disciple and second authorized biographer, Ascanio Condivi (1525-1574). Capparoni implied that Colombo's supply of cadavers to Michelangelo was part of a quid pro quo, having received a promise from Michelangelo to supply illustrations for his book. It was a promise that was not fulfilled. 34  Another issue of concern to Colombo was censorship by the Church that had adopted Galen's writings as an official canon and scrutinized anti-Galenist writings with suspicion. 35 Before Colombo, former Galenists turned anti-Galenists, had fallen into disfavor with the Catholic Church and the Reformed ("Calvinist") Church, respectively, for reasons that likely extended beyond issues of anatomy: Vesalius by virtue of his service to Emperor Charles V whose troops had sacked Rome in 1527; Miguel de Villanueva Years after Colombo's death, and even years after the death of William Harvey (1578-1657), Colombo became linked with a previous description of the pulmonary circulation in Servetus' Christianismi restitutio (1553), a mainly theological work published six years before De re anatomica. This "linkage" was made (most now believe erroneously) by medical historians and biobibliographers in the nineteenth and twentieth centuries, based upon similarity of concepts between Servetus' and Colombo's respective works, and which were developed independently from the earlier, Medieval work of Ibn an-Nafis (1213-1288). As stated in the introduction, such accusatory linkages may be repeated from one generation of historians to the next. Rather, conditions and the spirit of discovery in Renaissance Europe were ripe for the independent discovery of the pulmonary circulation and ultimately the general circulation as well; its further elaboration by Colombo's student, Andrea Cesalpino (1519-1603) in Quaestionum Peripateticarum (1571); and its elaboration and embrace by the scientific community with Harvey's famous monograph, De motu cordis (1628). (Supplemental Digital Content 6, available at http:// links.lww.com/IOP/A265: The pulmonary circulation: Ibn an-Nafis, Servetus, Colombo, Cesalpino, and Harvey.) Like Harvey many years later, Columbo was concerned about his reputation and legacy as a "discoverer" but also the reaction of an entrenched Academia. Colombo was particularly concerned with carefully planning an anti-Galenist work from the heart of the Counter-Reformation. Galenists were still thriving in Rome and in universities throughout Europe. In the smaller, learned circles of anatomy, a notable event in the summer of 1555 was the publication of the second edition of the Fabrica, wherein the deletion of Colombo's name would have been noticed by those aware of the rivalry. The previous first-edition praise that Vesalius had lavished upon Colombo as "amicus studiosissimus" was gone. However, the erroneous description and illustration of a human retractor bulbi were repeated in it, and in copies of Vesalius' Epitome which was also reprinted in 1555 without significant revisions.
The foregoing review of Colombo's life to this point and his intersections with various contemporaries serve as a prologue for a general description of his sole literary output, De re anatomica libri xv (1559). Among the fifteen books, the LPS is described in Book 5 (De Musculis), Chapter 8 (De Palpebrarum Musculis) which is translated below. The two final books are also particularly interesting: Book 14 (De Vivasectione) describes Colombo's experimental methods that led to his famous discovery of the pulmonary circulation. An English translation was provided by Boisliniére. 37 Together Book 14 and Book 15 (De iis quae raro in Anatome conspiciuntur) [Those Things Rarely Found in Anatomy] reveal a separation of the subject matter from the main chapters on normal anatomy. Moes and O'Malley stated, "Colombo recognized the desirability of subdividing the field of anatomy which had grown immensely in a very few years" but also suggested that inclusion of the final Book 15 may have been a posthumous "afterthought" of his sons. 18 Before his own death, Vesalius weighed in on the (now deceased) Colombo's description of the LPS. After personally receiving confirmation of Colombo's discovery of the LPS from Falloppio in 1561, Vesalius responded with a friendly letter that was never delivered as Falloppio also died while the letter was en route with an aristocratic courier. In this epistle, Vesalius admitted that the LPS had been discovered in Rome by his rival though he did not credit Colombo by name. It reveals Vesalius' previous doubts about the retractor-function of the orbicularis oculi and his unclear postulations about other orbital structures that might instead have this action. Written "from the royal court in Madrid, 17 December 1561," the epistle was sent to a publisher in Venice after failing to reach Falloppio before his death. The Examen (1564) came to publication soon after Vesalius, returning from a Jerusalem pilgrimage, had perished on the island of Zante. 38 (Supplemental Digital Content 8, available at http://links.lww. com/IOP/A267: Vesalius' tacit acknowledgment of Colombo's discovery.)

DE RE ANATOMICA LIBRI XV
On June 1, 1559, Colombo signed a prefatory dedication of De re anatomica to Pope Paul IV. However, both Colombo and the pope would die that summer while the book was still being printed in Venice-Colombo in late June and the pope in mid-August-and so the task of preparing a new dedication fell to his sons, Lazaro and Febo [Lazarus and Phoebus] who appear to have resided in Rome. 39 The flourishing book trade of Renaissance Italy was particularly centered at that time in Venice where Colombo's book would be published by Nicolò Bevilacqua (active 1554-1573). A second printer, Vincenzo Valgrisi (active 1540-1572), participated at some point as his colophon (printer's mark) appears on the last printed page of the work. 40 Colombo's third son, Epiphanio (d. 1564) who appears to have resided in Padua, may have helped facilitate the printing in Venice. Alone or with his brothers in Rome, perhaps Epiphanio Colombo served as a liaison for the production of the frontispiece or, after his father's death, had a hand in securing privileges for subsequent editions that were published elsewhere in Europe. (Supplemental Digital Content 9, available at http://links.lww.com/IOP/A268: The frontispiece of De re anatomica.) In 1897, James Moores Ball of St. Louis noted that a colleague in Sing Sing, New York owned the first issue printed with Colombo's own dedication to Paul IV and stated, "… in another exemplar, similar to my own, the dedication has been written by the two sons of Columbus and is addressed to 'Pio IIII., Pont. Max.' this pontiff, on the death of Paul IV, on August 18, 1559, became head of the Church." 37 In actuality, Columbo's sons were confronted with the longest hiatus between papacies in the sixteenth century, the papal conclave lasted from September 5 until December 25, 1559 when Pius IV finally ascended to the papal throne.
Before his death, Colombo had arranged for the production of an elegant frontispiece, having it designed and executed with great care and probably at great expense (Fig. 2). The organization of De re anatomica libri v is outlined in Table 1 "I have no doubt that our investigation concerning the muscles of the eyelids is going to delight all, because the treatments conducted by others do not much agree with the truth of the matter itself. I, on the other hand, to the extent that I was able, took pains so that they might be described as truthfully as possible. The muscles of the eyelids, therefore, are six in number, three, obviously, on each side. Of these, two are situated outside the eye-sockets, while the rest are situated inside, right next to the muscles of the eyes, and on account of this, all anatomists who wrote before me have been deceived to reckon that these serve not the eyelid, but the eye. The orbicularis, therefore, having fibers that are also circular, are first born in the canthus, in a suture common to the head and the upper maxilla, with a sharp beginning; and they get broader upwards, towards the forehead, in which place they get fused together with the muscles of the forehead. After that, going toward the ear, the closer they approach the lesser canthus, the broader they get, and they turn about downward around the socket, so that they end up with a sharp end right next to their beginning. They have been made to close the eyelids, and contract them forcefully, and in order to protect the eyes from external harm. These Vesalius divided up in four; however, at that part where he drew back the flesh, they are fleshier than in the rest of their tract. Second will be two muscles straight, broad, fleshy in the upper region of the eyes, having arisen in the interior of the socket from the visual nerve, like the rest of the eye muscles. These muscles end up with a rather broad end in the topmost part of the eyelid. They have been made to draw the eyelid upward, and open the eye. The third group of muscles is of a slender shape, and slim, born out of the same place. These end up slantwise, toward the great canthus, in the eyelid, almost with a slender tendon. In several people, a portion of this tendon is sometimes inserted into the cornea. In these people, it appears that it assists in the movement of the eye upward. However, they have been created above all for this function, that is, to draw the eyelid, and open the eyes; which function, and position, because it is the same in animals too, I cannot fail to wonder how Galen, Vesalius, and the rest of the Anatomists have numbered these four muscles which serve the eyelids among the muscles of the eyes, deceived, perhaps, by the fact that they are situated inside the socket of these."

THE LPS FROM COLUMBUS TO MODERN TIMES
Early written descriptions of the LPS were summarized in 1734 by Bernhard Siegfried Albinus (1697-1770) 42 in his book entitled, Historia Musculorum Hominis. 43  Liver and Veins 7 Heart and Arteries 8 Brain and Nerves 9 Glands 10 The Eyes 11 The Viscera 12 Formation of the Fetus 13 Coverings of the Human Body 14 Vivisection 15 Things Rarely Seen in Anatomy credit, the term, levator palpebrae superioris was adopted by the Nomina Anatomica in 1955 and its successor, the Terminologia Anatomica in 1998. In conclusion, biobibliographical methods have been used to establish Realdo Colombo as the individual who first described the LPS, to make the case that he was its discoverer, and to clarify various distortions in historical accounts that developed over time. This reappraisal of Colombo and his De re anatomica will hopefully guide the future inclusion of the discoverer and his work in catalogues of antiquarian collections and biobibliographic sourcebooks, [50][51][52] and, most importantly, in recording his discovery among the milestones and histories of ophthalmology and oculofacial plastic surgery. (Supplemental Digital Content 13, available at http://links.lww.com/IOP/ A272: Anatomy of the LPS among milestones of oculofacial plastic surgery.)