Theodor Karl Gustav von Leber: The Sultan of Selten.

Theodor Karl Gustav von Leber (1840–1917)[1]

“There is nothing insignificant in the world. It all depends on the point of view” – Johann Wolfgang von Goethe

The German ophthalmologist Theodore Karl Gustav von Leber was born on the very unique date of February 29 in the year 1840 in Karlsruhe.[2] Son of a Professor of Romance Languages, Theodore, as a child, collected rare plants, flowers, and butterflies during his walks with his father through the woods.[3] Eventually, he developed interest in chemistry, but, on the advice of Professor Robert Bunsen, he chose to study medicine instead, which had better prospects financially.

It is hard to find a good mentor, and to find more than one is almost unheard of. Theodore Leber was a pupil of Herman Ludwig Ferdinand von Helmholtz and Dr. Carl Ludwig and later an assistant to Herman Knapp in Heidelberg, Richard Liebreich in Paris, and then Albrecht von Graefe in Berlin. As a medical student, Leber won a contest sponsored by Helmholtz to establish the relationship between muscle performance and fatigue.[3] Leber enjoyed his tenure with Knapp in 1862. In a letter to his brother, Leber writes enthusiastically about their work, “There are examples of ladies being operated on by famous ophthalmologists and later marrying them. Even the famous von Graefe couldn’t resist this temptation! Chelius did it the other way round. He first married his wife and then operated on her. This, however, does not seem to work so well, she still has a horrible squint!”[4] However, he was drawn more toward physiology than ophthalmology, that quenched his desire of basic research.[3]

In 1863, he chose to go to Vienna to work with Dr. Carl Ludwig in the Department of Physiology, where he was working on a technique of injection of a dye, alcian blue, and glycerine to study the vascular anatomy. Theodor Leber wrote to his father, “I found in Prof. Ludwig an always friendly and cooperative teacher with sensitive and hard criticism, a master of experimental physiology.”[1] Leber studied the vascular anatomy of the eye [Fig. 1]. At the Heidelberg Ophthalmology Conference on September 4, 1864, a 24-year-old Leber presented his talk on “The Blood Vessels of Human Eye,” which caught the attention of the greats – von Graefe, Liebreich, Donders, and Helmholtz. Richard Liebreich invited him to become his assistant in Paris while von Graefe was eager to publish Leber’s work in the Archiv für Ophthalmologie (he eventually published it the following year).[4] Since his initial description, only minor changes have been made in Leber’s original drawing, demonstrating his accuracy and precision. Professor Ludwig, however, discouraged him from pursuing physiology because of the scarcity of positions. That is when he decided to follow a more dedicated path to ophthalmology.[3]

Figure 1

Leber's drawings: (a) Circulation of the globe. (b) Blood vessels of the anterior segment of the eye, including the sclera, limbus, conjunctiva, ciliary body, and iris. (c) Anterior segment of the choroid seen from the inner side. (d) Posterior part of the choroid close to the optic nerve. (e) Posterior segment of the sclera, including the optic nerve head[4]

Leber accepted Liebreich’s invitation and arrived in Paris in 1864. Although he worked enthusiastically, their interests differed. Liebreich concentrated on the surgical aspect and the second edition of his Atlas of Ophthalmoscopy. Leber, on the other hand, was more interested in the experimental aspect. However, this allowed engaging and elaborate discussions in meetings at Liebreich’s home in Champs Elysées. In a rare coincidence, Leibreich and his colleagues’ names started with ‘L’ and the invite for Liebreich’s birthday read (in German), ‘Langes, leichtes, leidloses, lustiges, liebereiches, leuchtendes Leben lache liederreichem Liebreich! Laqueur, Leber, Loewenberg’. The alliteration cannot however be emulated in the English translation which read, ‘A long, light, harmless, funny, rich of love-filled, bright life with laughter [may occur] for Liebreich, rich of songs! Laqueur, Leber, Loewenberg’.[5] While in Paris, Leber had the opportunity to witness the surgery of Countess Montijo, the mother of Empress Eugénie, by Dr. Liebreich – iridectomy for her glaucoma. He later described Napoleon as modest and with an affable countenance, qualities scarcely mentioned in historical texts.[5]

In 1867, at the behest of von Graefe, he moved to Berlin. While working with von Graefe, Leber collected 18 cases of optic neuropathy from five families. “Amaurosis is due to a neuritis of the trunk of the optic nerve, which initially manifests itself as retrobulbar neuritis. The visual defects always occur quite suddenly in the shape of a fog, that becomes increasingly dense over the following days. This progressive stage of the disease lasts two to four weeks. The visual defect usually consists of the occurrence of a central scotoma, while the peripheral visual field is either completely free or only comparatively insignificantly affected. Color blindness occurs regularly. When they were asked, the patients always claimed they could see better in the evening or when the sky was cloudy. In all cases both eyes were affected, but usually with a slight lag in time, and to a different degree. The ophthalmologic findings are only rarely completely normal, more often there is a slight opacity of the rim of the papilla, and hyperemia of the vessels, or even a distinct slight neuro-retinitis. It should be stressed that in this stage, the arteries are not constricted as they usually are in optic neuritis, but normal or even dilated. Patients suffer from migraine, headaches, palpitations. The age when the disease became manifest ranged from 13 to 28 years.” It is remarkable that Leber recognized the atypical inheritance pattern of Leber hereditary optic neuropathy (prevalence 1/27,000 to 1/54,000 in Europe, 1 in 113,300 in Australia, and 1/526,000 in Serbia, OMIM #308905), known today to be mitochondrial in origin, and palpitations indicative of the associated cardiac syndromes of Wolff–Parkinson–White and Lown–Ganong–Levine.[67] Following the death of von Graefe, Leber succeeded him as professor extraordinary of ophthalmology and Director of the University Eye Clinic in Göttingen in 1871. While in Göttingen, Leber reported a fungal infection causing hypopyon keratitis and did extensive research on inflammation. His description of chemotaxis in his treatise, “The origin of inflammation and the effect of substances producing inflammation,” went beyond the realms of ophthalmology and was recognized and renowned in physiology.[5]

In 1873, Leber contested the generally accepted theory that the Descemet’s membrane was responsible for controlling the infiltration of fluid from the anterior chamber into the corneal stroma. He conducted a simple experiment using freshly excised corneas from horses and cattle, mounting them over a U-shaped glass tube that was filled with mercury, and the space just under the cornea was filled with water. He measured the pressure exerted by water on the cornea by varying and measuring the height of the mercury column. He demonstrated that the fluid penetrated corneas where the endothelium had been stripped off at pressures of 10–15 mmHg, whereas in corneas with an intact endothelium, a pressure of 30–40 mmHg was required to produce stromal edema. Since then, more sophisticated methods have only confirmed his findings of the functions of the corneal endothelium. However, his results laid the foundations for understanding the pathophysiology of Fuchs’ endothelial dystrophy, glaucoma, and corneal graft failures.[3]

Theodor Leber, in 1877, described an unusual retinal dystrophy and called it “Angeborene Amaurose durch Retinalatrophie,” characterized by profound vision loss, nystagmus, and severe retinal dysfunction very early in childhood, with a non-recordable electroretinogram, high hypermetropia, photodysphoria, keratoconus, and cataracts. He recognized the inherited nature of the disease that is known today as Leber congenital amaurosis (prevalence 1/50,000 to 1/33,000 live births, OMIM # 204000), the role of consanguinity, and the phenomenon of a child sticking fingers into the eye socket and pressing and manipulating the eyelid, applying pressure on the globe or making fanning movements with the fingers to provoke an impression of light, but gave it no special designation. In 1939, Franceschetti coined the term “oculo-digital phenomenon.” The sign, also called the Franceschetti–Leber phenomenon, is a general symptom of poor vision in childhood.[267]

Leber also described a then unrecognized condition in a paper in 1880, describing the case of a 28-year-old female suffering from recurrent redness of the eye since childhood. “The conjunctiva shows on most of its surface a conspicuous thickness and yellowish-red color due to a close network of bundles of dilated lymphatic vessels, recognizable by their rosary-shaped curves, and by the characteristic look of the network they form. These vessels are filled with a red, slightly jelly-like material. The abnormality extends to the fornices, but does not affect the tarsal conjunctivae. Their color is much lighter and more yellowish than that of blood vessels of the same size, which leads to the conclusion that the lymphatic vessels are not filled with pure blood, but with a mixture of lymph and blood. Neither in the parts of the conjunctiva affected by the abnormality nor in its other parts is there any discharge. The cause of the “local bleeding,” however remains unclear, as the anatomic examination could not establish any abnormalities of the blood vessels, and no explanation could be found in other parts of the body either.” He called it lymphangiectasia hemorrhagica conjunctivae.[4]

Leber became the Director of Eye Clinic at Heidelberg in 1890, where he remained till his retirement in 1910.[2] He continued to publish and in 1912 described a condition with multiple retinal aneurysms.[4] “There is a group of cases where miliary aneurysms are combined with a severe illness of the retinal tissue. The main cause for the development of the retinal degeneration is probably a circulatory dysregulation caused by a disease of the small vessels. The changes affect mainly or exclusively the small bifurcation points close to the capillaries, while the larger bifurcation points on the papilla and around it usually appear normal under ophthalmoscopic examination. The disease mainly affects the small arteries, although sometimes the veins are also involved. All cases with the same manifestations I could find are male juveniles aged thirteen to twenty-six.”[4] Although he found them to be different from the retinal telangiectasia reported by Coats in 1908, Reese later concluded the two diseases to be the same, that is, Coats disease (prevalence <1/1,000,000, OMIM # 300216).[67]

In 1916, he described another uncommon condition with von Hippel, characterized by unilateral optic disc swelling, loss of vision, and a macular star, and called it Leber’s stellate neuroretinitis. “Cases are affected by the presence of numerous foci of infiltration, whose number far exceeds the number of hemorrhages, and especially by the occurrence of the well known macular star, comprised of the small white dots. Sometimes there is a pronounced hyperemia, edema, and swelling of the papilla, as well as a spread of the edema to the retina. Vision is often only moderately reduced. This process is presumably an inflammation mainly of the optic nerve. So far, we have no specific explanation for the macular star.”[2]

Alfred Theodor Leber, his nephew, had a unique Indian connection that few know about. Alfred Leber is regarded as the pioneer of tropical ophthalmology. He discovered the eye involvement in filarial infection (Leber fundus). Alfred Leber was reported missing following an expedition to New Guinea in 1913, just before the World War I commenced. He remained in the neutral Dutch East Indies during the war. In the Second World War, he was arrested and shifted to Dehradun Camp in India. There, he started training doctors. After his release in 1946, he became the Director of Department of Ophthalmology in the Prince of Wales Hospital in Bhopal. In 1952, he was appointed the Professor, Dean, and Director of the Institute of Ophthalmology at the Muslim University of Aligarh.[8]

In 1896, Theodor Leber was honored with the von Graefe medal, the highest award of the German Ophthalmology Society.[4] In his address, he considers himself as a physiologist rather than an ophthalmologist, “I have had much fortune and success as an eye doctor, but, nevertheless, I am not a genuine ophthalmologist. The research, which I believe to be my best, belongs to the field of biology, and the eye just served as an extremely suitable object for research. What stimulates me to do research work are the rules of the living organisms. What satisfied me is to acquire information on the nature and connection of pathologic conditions.” Strangely, the graduation report of young Leber read, “Theodore will study natural sciences.”[3] Theodore Leber passed away in 1917, within a few weeks of his teacher, Liebreich. His last publication was an obituary for Liebreich, which was published in the same volume as his own obituary written by von Hippel, who firmly commemorated his place as one of the greats of ophthalmology, “Whoever were to write the history for the last fifty years of our science, would have to place Leber in the center of his considerations.”[4]

“Eventually, my eyes were opened, and I really understood nature. I learned to love at the same time” – Claude Monet

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Conflicts of interest

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