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Exfoliation Syndrome: A Historical Perspective

Tarkkanen, Ahti, MD

doi: 10.1097/IJG.0000000000000901
Exfoliation Syndrome

The discoverer of exfoliation was John Lindberg of Helsinki, Finland. He conducted his research as a young ophthalmology resident with the aim of elucidating 2 types of age-related degenerations of the iris and presenting it as an academic thesis. To this end, he had to construct a slit lamp, because they were not commercially available. During this investigation, he paid attention to greyish flakes and fringes on the anterior lens capsule and the pupillary border, which had not been previously described. His material consisted of 202 patients. The findings were recorded by time-consuming skillful drawings. His conclusions that the condition was age-related and often linked to chronic glaucoma and cataract are still valid today. The work was accepted as an academic thesis at the University of Helsinki in 1917.

Department of Ophthalmology, University of Helsinki, Helsinki, Finland

Disclosure: The author declares no conflict of interest.

Reprints: Ahti Tarkkanen, MD, Helsinki University Eye Hospital, Haartmaninkatu 4C, Helsinki 00290, Finland (e-mail: ahti.tarkkanen@kolumbus.fi).

Received January 25, 2018

Accepted January 26, 2018

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JOHN LINDBERG AND HIS ORIGINAL DISCOVERY

Personal

John Lindberg (1884 to 1973) was born in St Petersburg, Russia. At that time, Finland was a semiindependent Grand Duchy of Imperial Russia, and the border between the countries was open. His father, an engineer, was a managing director of a machine factory manufacturing large bridges and boilers of steel. In 1890, the family moved back to Finland. St Petersburg was Lindberg’s home town, and it was easy for him to return there for training in ophthalmology and research.

Lindberg graduated from the Medical School of the University of Helsinki in 1914. He had already decided to become an ophthalmologist. He had worked as a nurses’ aide at a private eye hospital and volunteered as an intern at the Helsinki University Eye Hospital. The chair of ophthalmology had been founded at the University of Helsinki in 1871 as the first one in the Nordic countries.

Immediately after his graduation in 1914, Lindberg started his residency at the Helsinki University Eye Hospital. The following year, he moved to St Petersburg for a continued residency at the Imperial Ophthalmic Hospital. This hospital had been founded in 1816 as one of the first eye hospitals in the world. The professors had always been of German extraction. Since 1915, the chair had been held by Ernst Blessig (1859 to 1940), who had succeeded his father as the chair after his ophthalmology training in Berlin, Göttingen, Erlangen, and Heidelberg, Germany, and St Petersburg. Because of the Russian revolution, Lindberg returned to Finland in 1917 and received a licence to practice ophthalmology.

Lindberg completed his training as a postgraduate scholar in the period spanning from 1920 to 1921 at the University Eye Hospital of Freiburg, Germany, headed by Theodor Axenfeld (1867 to 1930). He also paid shorter visits to many eye hospitals in Continental Europe, Scandinavia, and the United States. He consistently attended the Annual Conference of the German Ophthalmological Society in Heidelberg and the Scandinavian congresses.

As a clinician, Lindberg worked from 1923 to 1928 as chief ophthalmologist in the Eye Hospital of the city of Wiborg, the capital of Southern Karelia. He was the sole specialist for a population of 150,000 people. Trachoma and ocular trauma were the prevailing conditions. The time-consuming treatment of trachoma consisted of pressing and rolling of the tarsal follicles as well as using silver nitrate and zinc sulfate baths. After this period, he returned to the Helsinki University Eye Hospital, and, in 1937, he was appointed director of the newly established Helsinki City Eye Department. He became known as a skillful clinician and surgeon as well as a devoted teacher and administrator. He retired from this post at the age of 65 and from his private practice at the age of 75.

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Research

As a resident (Fig. 1), Lindberg started a research project with an academic dissertation as a goal. He had read papers by Axenfeld,1 who had described 2 types of age-related iris degenerations. The first was characterized by hyaline degeneration of the pupillary border and the second by an independent pigmentary atrophy and depigmentation of the iris pigment epithelium. These changes were thought to account for the poor pupillary dilatation in old age. It was also supposed that the changes could be related to increased intraocular pressure. Lindberg’s aim was to further elucidate these observations. Blessig suggested that Lindberg enroll elderly patients of the same age group with and without cataract.

FIGURE 1

FIGURE 1

The methods or research consisted of determination of visual acuity, iris color, transillumination of the iris using Sachs’ lamp, and biomicroscopy of the anterior segment of the eye.

Because slit-lamp biomicroscopes were not commercially available, Lindberg had to construct 1 and learn how to use it. Gullstrand had received a Nobel Prize in medicine in 1911 for his research in physiological optics of the eye. Lindberg studied his monograph carefully. He happened to find a Zeiss binocular microscope that was assembled to the new unit. The findings were recorded by hand-drawings (Fig. 2). The work was time-consuming. The study and drawing of the findings of a single patient could take several hours. Lindberg’s material consisted of 202 patients.

FIGURE 2

FIGURE 2

While working on his project, Lindberg became interested in new findings that had not been previously described. He had noted greyish flakes and fringes at the pupillary border and on the anterior lens capsule. These could also form a membrane or a round disc on the anterior lens capsule. He decided to change his subject of research and concentrate on these new findings. He concluded that age was 1 decisive factor. The flakes became more prevalent with increasing age. They were common in patients with senile cataract but could be found also in control patients aged 55 years or more. In his material, Lindberg had 60 patients with chronic glaucoma. Flakes were present in 50% of them.

Lindberg presented his doctoral thesis as a monograph2 written in Swedish in 1917. His conclusions on exfoliation are still valid today. A posthumous English translation was published in 1989.3

While working as a research scholar at the University Eye Hospital in Freiburg from 1920 to 1921, Lindberg met a Swiss ophthalmologist from Basel, Alfred Vogt (1879 to 1943). Lindberg gave him a copy of his monograph and explained the new findings. Two years later, Vogt published a case report suggesting that exfoliation was a complication of glaucoma filtering surgery.4 In 1925, he proposed that exfoliation was related to a new type of glaucoma5 and in 1930 that glaucoma was caused by exfoliation.6 Lindberg was not cited in any of these papers.

At the 1921, Nordic Congress of Ophthalmology in Stockholm, Sweden, Lindberg met a Norwegian ophthalmologist, Birger Malling (1884 to 1989), to whom he also handed his thesis and explained the new findings in the anterior segment. Two years later, Malling published 2 papers7,8 in which he reported that exfoliation was present in 33 of 81 (40%) patients with “compensated glaucoma.” According to him, exfoliation was a feature of chronic iridocyclitis combined with glaucoma in old age. Lindberg was not cited here either. Lindberg was aware of the situation but as an extremely modest person he did not ask for a rectification.

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EARLY THEORIES ON THE ORIGIN AND NATURE OF EXFOLIATION

Numerous theories on the subject were expressed. Vascular changes of the uvea with exfoliation being a sort of exudation was suggested by several authors. Further sources were pigment epithelium of the iris, aqueous, Descemet membrane, the zonule, lamina vitrea of the Bruch membrane, vitreous, and the lens capsule. Chemically altered aqueous could produce precipitation on the lens capsule. It was also thought that aqueous had a degenerative effect on the lens capsule with exfoliation as the result. In 1957, Ashton9 expressed his opinion on the ciliary epithelium being the primary site. This view was accepted by several authors. Dvorak-Theobald10 studied histologic sections of 3 eyes that had clinical exfoliation. In reality, she described “pseudocapsular exfoliation,” accretions of unknown material as deposits, mucopolysaccharides, and tyrosine, on the anterior lens surface and other structures of the anterior segment. She proposed that the condition be called pseudoexfoliation to differentiate it from true exfoliation. Today, 70 years later, there are no reasons to make this differentiation because patients with true exfoliation of the lens capsule are no longer common.

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EARLY VIEWS ON EXFOLIATION AND GLAUCOMA

Early observers had paid attention to the frequent occurrence of exfoliation in glaucomatous eyes. The relations, however, were unsettled for a long period of time. The opinions varied from a cause-effect relationship to mere coincidence. Among others, Hörven11 thought that glaucoma was a direct result of exfoliation flakes blocking the aqueous outflow pathway. Thus exfoliative glaucoma would be classified as a secondary glaucoma. This view was challenged by Trantas12 who proposed that glaucoma would result by coincidence. The role of pigmentation of the chamber angle was also emphasized. In a series of 418 patients with exfoliation, 61% had glaucoma.13 The same magnitude came out in a literature search of about 45 papers.

The incidence of glaucoma in eyes with exfoliation was also studied. Lindberg2 found that 50% of his patients also had glaucoma. In an analysis of 35 early papers on the subject, the percentage found varied from 0% to 93% with an average of 36%. These data did lend support to a causal relationship of exfoliation and glaucoma. The large variations might have represented true variation in the population or merely variations in the recruitment of patients, ability to recognize exfoliation, and definition of glaucoma.

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EARLY VIEWS ON EXFOLIATION AND CATARACT

Lindberg paid attention to exfoliation among patients with nuclear cataract (20%). This raised ideas on exfoliation as the causative element. Ten years later, this finding was confirmed by Busacca14 and by many other studies later. Observations on the incidence of cataract among patients with exfoliation was published from Greece in 192912 with a reported incidence of 71%. In later studies, the numbers varied from 40% to 80%. Today, it is known that cataract is closely associated with exfoliation, and complications of cataract surgery are more common because these eyes have weak and friable zonules.

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EARLY GENETICS

In early years, no data on genetic occurrence of exfoliation were known. Late presentation after the age of 60 made it difficult because of a low life expectancy. However, in the 1960s, papers on familial occurrence were published. Families with exfoliation in successive generations and/or among siblings with glaucoma were found.13 Another larger study confirmed these findings.15 It took another 40 years for the breakthrough in molecular genetics. Two single nucleotide polymorphisms in the LOXL1 gene are strongly associated with exfoliation. The LOXL1 protein functions in the cross-linking of collagen and elastin in the extracellular matrix and is responsible for homeostasis of elastic fibers found as a major component of exfoliation.16

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REFERENCES

1. Axenfeld TH. Über besondere Formen von Irisatrophie, besonders über die hyaline Degeneration des Pupillarsaums [On special types of irisatrophy, particularly the hyaline degeneration of the pupillary border]. Vers Ophth Ges Heidelberg. 1911:s.255–265.
2. Lindberg JG. Kliniska undersökningar över Depigmentering av Pupillarrander och Genomlysbarhaten av Iris vid Fall av Ålderstar samt Normala Ögon hos Gamla Personer [thesis] [Clinical studies on depigmentation of the pupillary border and translucency of the iris in cases of senile cataract and in normal eyes of elderly persons]. Finland: University of Helsinki; 1917.
3. Lindberg JG. Clinical investigations on depigmentation of the pupillary border and translucency of the iris. Acta Ophthalmol. 1989;67(suppl 190):1–96.
4. Vogt A. Weitere Ergebnisse der Spaltlampenmikroskopie des vorderen Bulbusabschnittes, VIII Abschnitt: Über die pathologisch veränderte Iris [Further results of slit lamp biomicroscopy of the anterior segment of the eye]. Graefes Arch Ophthalmol. 1923;111:91–127.
5. Vogt A. Ein neues Spaltlampenbild des Pupillargebietes: Hellblauer Pupillarsaumfilz mit Häutchenbildung auf der Linsenvorderkapsel [A new slitlamp picture of the pupillary border: blue pupillary border with flakes on the anterior surface of the lens]. Klin Monatsbl Augenheilkd. 1925;75:1–12.
6. Vogt A. Neue Fälle von Linsenkapselglaukom [New cases of lenscapsule glaucoma]. Klin Monatsbl Augenheilkd. 1930;84:1–2.
7. Malling B. Untersuchungen über das Verhältnis zwischen Iridocyclitis und Glaukom [Studies on the relation between iridocyclitis and glaucoma]. Acta Ophthalmol. 1923;1:97–130.
8. Malling B. Untersuchungen über das Verhältnis zwischen Iridocyclitis und Glaukom.II. Klinische Versuche [Studies on the relation between iridocyclitis and glaucoma II. Clinical trial]. Acta Ophthalmol. 1923;1:215–231.
9. Ashton N. In discussion to Gifford. A clinical and pathologic study of exfoliation of the lens capsule. Trans Amer Ophthalmol Soc. 1957;55:189–216.
10. Dvorak-Theobald G. Pseudo-exfoliation of the lens capsule. Relation to “true” exfoliation of the lens capsule as reported in the literature and role in the production of glaucoma capsulocuticulare. Am J Ophthalmol. 1954;37:1–12.
11. Hörven E. Exfoliation of the superficial layer of the lens capsule and its relation to glaucoma simplex. Br J Ophthalmol. 1937;21:625–637.
12. Trantas A. Lesions seniles de la capsule anterieure du cristalllin et du bord papillaire [Senile lesions of the anterior lens capsule and of the pupillary border]. Arch Opht. 1929;46:482–491.
13. Tarkkanen A. Pseudoexfoliation of the lens capsule. A clinical study of 418 patients with special reference to glaucoma, cataract and changes of the vitreous. Acta Ophthalmol. 1962;40 (suppl 71):1–98.
14. Busacca A. Struktur und Bedeutung der Häutchenniederschläge in der vorderen und hinteren Augenkammer [Structure and significance of the fflakes of the anterior and posterior chamber]. Graefes Arch Ophthalmol. 1927;119:135–176.
15. Tarkkanen A, Voipio H, Koivusalo P. Family study of pseudoexfoliation and glaucoma. Acta Ophthalmol. 1965;43:679–683.
16. Thorleifsson G, Magnusson K, Sulem P, et al. Common sequence variants in the LOXL1 gene confer suspectibility to exfoliation glaucoma. Science. 2007;317:1397–1400.
Keywords:

exfoliation; pseudoexfoliation; glaucoma

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