Abstract

Kinnier Wilson’s hallmark paper on ‘Progressive Lenticular Degeneration ‘ in 1912 made no mention of the copper-containing corneal rings which were described a decade earlier by Kayser and Fleischer. Their description and practical neurological significance in the setting of Wilson’s disease are described.

Figure 1: Kayser Fleischer ring. From: Walshe JM, ref. 8

The meticulous, time-consuming elicitation of history and neurological signs was the hallmark of the era of classical neurology, which continued until the later part of the 20th century. There was no more exacting exponent than the disciplinarian Samuel Alexander Kinnier Wilson, (1878-1937). Feared and revered in equal measure he dominated Queen Square Neurology for many years. A fine example of his minutely observed clinicopathological observations is still known as Wilson’s disease. The Kayser Fleischer (K-F) ring (Figure 1) although a clinical rarity became recognised as ‘the single most important diagnostic sign in Wilson’s disease.’ [1] Yet herein lies a paradox. Although it had been described a decade earlier, Kinnier Wilson’s famous paper [2] Progressive Lenticular Degeneration did not mention it.

Wilson’s disease is a rare autosomal-recessive disease typically presenting in adolescence. Fifteen to 20 percent of patients present with liver disease, 70% with neuropsychiatric symptoms [3]. Renal tubular defects are common, but seldom a presenting feature. Wilson later noted ‘the K-F ring is inconstant [1]*, though it is now said to be present in over 95% of patients with neurological symptoms and over half of those presenting with liver disease [4]. Rarely, it is found in non-Wilsonian cases of cholestasis and biliary cirrhosis. The underlying cause is a genetic mutation in ATP7B gene on chromosome 13q 14-3 that encodes a plasma membrane copper-transport protein. 

Wilson’s powerful reputation lay in his philosophical, clinical approach to a vexed problem, and in his brilliance as a clinician and writer [5]. A theatrically impressive if self-aggrandising teacher, in his MD thesis (Edinburgh, 1911) – for which he received a gold medal – Wilson described his four patients and two previous cases [2], those of WR Gowers’ tetanoid chorea, 1888; and JA Ormerod’s obscure and fatal nervous symptoms, 1890.  

With no mention of the K-F ring, Wilson’s thesis reported: 

Progressive lenticular degeneration may be defined as a disease that occurs in young people, which is often familial but not congenital or hereditary; it is essentially and chiefly a disease of the extrapyramidal motor system, and is characterised by involuntary movements, usually of the nature of tremor, dysarthria, dysphagia, muscular weakness, spasticity, and contractures with progressive emaciation; with these may be associated emotionalism and certain symptoms of a mental nature. It is progressive, and, after a longer or shorter period, fatal. Pathologically it is characterised predominantly by bilateral degeneration of the lenticular nucleus, and in addition cirrhosis of the liver is constantly found, the latter morbid condition rarely, if ever, giving rise to symptoms during the life of the patient. [6]

With measured disdain, Wilson discounted those instances of pseudosclerosis described by Westphal and Strümpell that were ‘non specific, with no evidence of liver disease, and heterogeneous’ – a view confirmed later by Greenfield [12].

The Kayser-Fleischer ring is a golden to brown annular deposition of copper located in the periphery of the cornea (Descemet’s membrane) in one or both eyes [7]. It first appears as a superior crescent, then develops inferiorly and becomes circumferential [8]. Usually visible to the naked eye with careful inspection, the earliest stage is visible only by slit-lamp and gonioscopic examination. Corneal rings are almost always present in neurological Wilson disease but not always in the pre-symptomatic and hepatic stages of the disease [9].

Kayser 

Figure 2: Kayser’s paper 1902. 

Bernhard Kayser (1869-1954) observed [10] in 1902 the occurrence of an annular ‘congenital [sic] greenish discoloration of the cornea’ in a patient with nervous symptoms attributed incorrectly to multiple sclerosis (Figure 2). Kayser was a student at Tübingen, who received his doctorate from the University of Berlin in 1893. After a varied early career, he became a physician in Brandenburg and Bremen and interested himself in ophthalmology. He edited the essay section of Klinische Monatsblätter für Augenheilkunde. 

Fleischer 

A year later the ophthalmologist Bruno Fleischer (1874-1965) said: I have recently had the opportunity to see two more such cases and to repeatedly examine them in detail. The result is in both cases completely consistent with the Kayser case [11].11 (Figure 3) 

Figure 3: Fleischer’s paper 1903.

Importantly, Fleischer recognised that the ring heralded a neurological disorder associated with cirrhosis, shown at autopsy. Fleischer worked at Tübingen, Geneva, and Berlin, obtaining his doctorate in Tübingen in 1898 where he became assistant and later associate professor of ophthalmology in 1909. In 1920 he secured the chair of ophthalmology at the University of Erlangen.  

The Kayser-Fleischer ring 

The Kayser-Fleischer rings, and less often capsular ‘sunflower cataracts’ accompany a characteristic dysarthria, fixed smile, drooling, rigidity and tremor [12]. Wilson reported:  

With mouth often held open, and a stereotyped smile, or, if not laughing or smiling, a vacant or fatuous look, the patient sits and leans to one or the other side, or back, all four limbs agitated by tremor, mostly quick and rather fine… [5,2]

The tremor becomes coarse, irregular, proximal, with a  ‘wing beating’’ appearance. Dystonia can be focal or generalised. A tremor-rigidity syndrome (‘juvenile Parkinsonism’) should raise suspicion of Wilson’s disease, especially in children. 

Initially the K-F rings were thought to be due to the accumulation of silver, but Gerlach and Rohrschneider [13] in 1934 showed that they contained copper granules. Many case reports followed, confirming both their copper content and Wilson’s meticulous clinical observations. A fundamental discovery was Cumings’ proof in 1948 of copper overload in both brain and liver [14]. In the same year Holmberg and Laurell showed a copper-binding globulin, named caeruloplasmin [15]. Low caeruloplasmin levels (<0.20 g/L) [16] allow the diagnosis of Wilson’s disease [9]. Additional tests include raised 24-hour urinary copper excretion, and high liver biopsy copper content. MR imaging is not diagnostic but typically shows bilateral T2 hyperintensity of the putamen, thalami, and brainstem; and a characteristic ‘giant panda sign.’ 

Early treatment by copper chelation using penicillamine, trientine hydrochloride, and zinc is effective but in about 10-30% causes serious neurological deterioration. Tetrathiomolybdate that inhibits copper absorption from the gut and cellular uptake of free copper is effective and has fewer side effects. When treatment is started, copper is slowly removed from both the lens capsule and the corneal rings: a sign useful in evaluating the efficacy of treatment.  

* He later said:  I have seen the ring only three times. Proc R Soc Med. 1934 Jan;27(3):297-8.

References

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