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From The Archives

Alastair Compston
DOI: http://dx.doi.org/10.1093/brain/awt104 1336-1340 First published online: 24 April 2013

Hepato-lenticular degeneration. By Stanley Barnes and E Weston Hurst. Brain 1925; 48: 279–333. With A further note on hepato-lenticular degeneration. By Stanley Barnes and E Weston Hurst. Brain 1926; 49: 36–60. With hepato-lenticular degeneration: a final note. By Stanley Barnes and E Weston Hurst. Brain 1929; 52: 1–5

The problem is that, following S.A.K. (Samuel Alexander Kinnier) Wilson’s (1878–1937) monograph ‘of outstanding importance’ describing extrapyramidal disease due to gross damage of the lenticular nuclei in association with cirrhosis of the liver (Brain 1912; 34: 297–509; and see Brain 2009; 132: 1997–2001), cases have appeared in the literature that do not conform to the ‘Wilson picture’. Particular confusion arises with examples of pseudo-sclerosis and torsion-spasm. More generally, the relationship between involvement of the brain and liver is unexplained; and the presence of corneal pigmentation known as the Kayser-Fleischer line or zone is unpredictable, and of uncertain significance. Drs (Arthur Stanley) Barnes (1875–1955) and E (Edward) Weston Hurst (1900–80) have observed and followed over time four cases from a single family, all with cirrhosis and one with corneal pigmentation in which post-mortem findings in two individuals are already available. When first presented to the Royal Society of Medicine in January 1924, Dr Wilson is present and agrees that the patients have his disease.

There are eight siblings in the family. Frederick B presents, aged 8, with impaired use of the right arm and leg: movements are slow, clumsy, stiff and slow to relax; his mouth is constantly gaping, with the appearance of a broad smile or grimace when other parts of the body are moved; and he is emotionally unrestrained. Puzzled by the diagnosis, and considering Thomsen’s disease as the best explanation for the apparent myotonia, Dr Barnes, the clinician involved, decides to await events. Later it emerges that Frederick has previously been under the care of the Children’s Hospital in Birmingham with recurrent diarrhoea and an episode of ascites with jaundice. His mother considers that, thereafter, Frederick became ‘stupid, dazed and drowsy’. Re-examination now shows a fatuous facial expression; his limb movements are slow, still characterized by ‘myotonia’ and athetosis when distracted, with rigidity and exaggerated tendon reflexes; his liver is enlarged and the edge hard. Over time, Frederick deteriorates showing increased intellectual and physical impairments and, developing broncho-pneumonia which leads to ‘a blaze of nervous spasm of tetanoid type’, he dies at 4 am on 11 October 1924, aged 11 years. At autopsy there is evidence for advanced multilobular cirrhosis with fibrosis and fatty degeneration of most liver cells. The lenticular and caudate nuclei are shrunken (see Fig. 1). The nerve cells are degenerate with abnormal morphology of those that survive. There is intense overgrowth of the neuroglia with conspicuous nuclear abnormalities, some having the appearance of ‘Alzheimer cells’ (Fig. 2). These changes are most marked in the putamen and, although histological abnormalities are seen in the globus pallidus, other parts of the basal ganglia including the thalamus are normal. Conversely, some cortical neurons are degenerate and morphologically abnormal.

Figure 1

Two sections across the right cerebral hemisphere of Frederick B showing the marked shrinking and dark coloration of the putamen. From Barnes and Weston Hurst (1925).

Figure 2

Drawing illustrating the various types of neuroglial cells seen in Frederick B. The large pale elements (a) represent the so-called Alzheimer cells. Two normal neuroglial nuclei are seen (b). At c is a nucleus showing hyperchromatosis. From Barnes and Weston Hurst (1925).

From the age of 8 years, Phoebe B has suffered recurrent vomiting and haematemesis, an episode of jaundice, ‘hysterical’ behaviour, and difficulty with walking and speaking so that she no longer attends school. Examination shows a vacuous facies with the mouth open, athetosis and fixed dystonic posturing of her rigid limbs. Matters deteriorate over time. In July 1925, during one of many hospital admissions and with much difficulty in view of her movement disorder, Phoebe undergoes ophthalmological examination and Mr (Thomas) Harrison Butler (1871–1945) identifies a Kayser-Fleischer line in the right eye: ‘I noted that when light was thrown obliquely from above upon the iris, so that the light passed through a considerable thickness of the cornea at its lowest periphery, the lower part of the iris had the appearance as though the evening sun were shining upon it; there was a most unmistakeable golden glow … examination with the slit-lamp and the corneal microscope under a magnification of 23 showed that the posterior surface of the cornea was pigmented … yellow towards the centre of the cornea, golden brown at the periphery… in view of the rarity of the zone being observed in Wilson’s disease, and its appearance being so little known in this country, Mr Harrison Butler has kindly made two coloured drawings of the slit-lamp appearance in this case’ (Fig. 3).

Figure 3

The upper drawing represents the anterior aspect of the eye as seen with the loupe, and shows the delicate golden glow upon the lower portion of the iris. The lower portion of the drawing shows the Kayser-Fleischer ring as seen with the slit lamp. The beam of the lamp in passing through the cornea illuminates a sinuous block of cornea generally called the corneal ‘prism’ with a curve mainly convex but reversed at the limbus. The anterior or epithelial surface is to the left and is normal. On the right is the posterior or endothelial surface, which shows a granular pigmentation, brown above (near the limbus) and gradually becoming yellow and fading away towards the centre of the cornea, being no longer perceptible just central to the line where the cornea is seen crossing the inner edge of the iris. The corneal nerves shown on the prism are normal in aspect and are not increased in number (T. HARRISON BUTLER). From Barnes and Weston Hurst (1925).

Elsie B develops recurrent vomiting and jaundice and, when first examined, has an enlarged liver and spleen but no neurological symptoms or signs. Over time her liver disease progresses and Elsie dies from liver failure. At post-mortem there is ‘a healing subacute yellow atrophy rather than an ordinary cirrhosis’ but with nodules in which fatty degeneration and fibrosis are intense. Although her brain is macroscopically normal, there is neuronal degeneration in the lenticular nucleus and overgrowth of neuroglia. Similar changes are present in the caudate nucleus and cortex but not the globus pallidus or thalamus.

Daniel B appears normal when first examined after the diagnosis of Wilson’s disease is made in his older brother Frederick. Later, aged 7, Daniel has episodes of vomiting with jaundice, and starts to regress intellectually with a behavioural disturbance manifesting as mental and physical agitation. He has a vacuous face and tendency to sneer during associated limb movements, with clear evidence for poor intellect, but neurological examination is otherwise normal although his liver is enlarged. Mr Harrison Butler cannot see a Kayser-Fleischer line even with slit-lamp examination.

Drs Barnes and Weston Hurst compare their experience of this family with the cases described by Wilson who had summarized hepato-lenticular degeneration as manifesting ‘generalized tremor, dysarthria and dysphagia, muscular rigidity and hypertonicity, emaciation, spasmodic contractions, contractures, emotionalism … mental symptoms … and a certain facility or docility’. They sense some equivocation in Wilson’s position regarding the issue of ‘tremor’ and turn to an earlier description by (Sir William) Gowers (1845–1915) of a case with movements intermediate between those of chorea and tetany, which Gowers therefore designated ‘tetanoid chorea’. Dr Barnes is so struck by the agonal features of Frederick B that he can see no great distinction from the many cases of tetanus that, as an experienced neurologist, he previously observed. Had it not been for the additional history, he would have diagnosed tetanus with confidence. This leads Dr Barnes to challenge the prevailing view of that condition: ‘the generally accepted theory that tetanus results from an irritation of the lower spinal reflexes is surely untenable … the widespread nature of the spasms and the grouping of the muscles involved strongly suggest a damage at a much higher level … death [occurring] because the extrapyramidal control normally exercised through the basal ganglia and adjacent nuclei … [is] cut off by a paralysis of their activity’. For Drs Barnes and Weston Hurst, their own cases and those of Gowers and Wilson are examples of the same disorder, and they insist on athetosis as the correct designation for the slow writhing movement disorder, arguing that this is quite unlike the rhythmic tremor seen in paralysis agitans or pallidal atrophy described by (James) Ramsay Hunt [(1872–1937): see Brain 1917; 40: 58–148]. Concluding that disease of the putamen results in double athetosis, generalized rigidity and dysarthria, the authors take as their authority (Gabriel) Anton (1858–1933) and Madame (Cécile) Vogt-Mugnier (1875–1962). Although the disorder of speech also differs from that seen in Parkinson’s disease, it is the facial expression of bemused vacuity that so distinguishes these cases from other types of extrapyramidal disease. On the liver, involvement of which usually precedes the appearance of neurological manifestations, Drs Barnes and Weston Hurst consider that the disorder is not a chronic slowly progressive cirrhosis but damage resulting from repeated attacks of acute hepatitis. This leads them to speculate on a sequence in which ‘toxin’ is delivered from the liver to a specific target structure in the nervous system either in small doses over prolonged periods, as in the typical case of Wilson’s disease, or in more of a wave during episodes of hepatic disease resulting in collateral damage to neighbouring structures in the more accelerated examples of hepato-lenticular degeneration, such as Elsie B. One possibility is that the toxin is manganese although the authors acknowledge that the neurological manifestations of manganese poisoning adhere more to the picture of paralysis agitans than Wilson’s disease. Therefore they favour the hypothesis that organisms within the flora of the alimentary tract burst into activity at intervals and pass through the portal system to the liver which suffers acute inflammation and damage allowing microbial toxins to access the nervous system. ‘We wish to stress that … signs of inflammation … [are] completely lacking in the nervous system … the process appeared to be a toxic degeneration with disappearance of nerve cells, accompanied by neuroglial reaction and the production of a peculiar type of neuroglial cell … these changes, though widespread, [are] far more advanced in the putamen than elsewhere’. There has been much speculation on the relationship between Wilson’s disease and pseudo-sclerosis: (Sir Arthur John) Hall (1866–1951) considers these to be the same disease, a view with which Drs Barnes and Weston Hurst have some sympathy, concluding that the two conditions have probably been artificially separated. Perhaps one difference is the more frequent presence of Alzheimer cells. Their interpretation is that toxin sets up a peculiar and diffuse reaction leading to the production of Alzheimer cells in pseudo-sclerosis; whereas in other instances ‘the same or more probably another toxin acting on the neurones and affecting those especially of the neopallidum leads to progressive lenticular degeneration’. But since ‘only the gravest of reasons would be adequate to warrant any alteration of the title of the disease which was so ably evolved from a chaotic conglomeration of cases by Wilson in 1912’ it follows, for Dr Barnes, that the term ‘hepato-lenticular degeneration’ (introduced by Hall) should replace pseudo-sclerosis. Moreover, not only is Gowers’s tetanoid chorea the same condition, so too is dystonia musculorum deformans.

In a footnote to this paper, Dr Barnes mentions that Phoebe B died in September 1925, and that he plans to describe her post-mortem findings in due course. In a second article, he explains how Phoebe became completely bedridden and rigid with tetanus-like spasms, dying with asthenia and starvation through inability to swallow. The putamen and caudate are shrunken—as in her late brother, Frederick—with generalized neuronal loss in these structures (and also the thalamus) and morphological abnormalities in surviving nerve cells. There is neuroglial overgrowth and the presence of Alzheimer cells, findings that extend outside the putamen being also apparent in the external capsule, claustrum and island of Reil. Many of these cells have intracellular inclusions. But the most striking aspect is white matter destruction of the anterior parts of the frontal lobes, and to a lesser extent the parietal cortex, with cavity formation. The areas of damage appear to have developed in three stages: proliferation of neuroglia and small blood vessels orientated along the myelinated fibres; next, an increase in cells associated with splitting and fissures in the myelin sheaths with a spongy appearance extending from white matter up to the cortex; and, finally, less cellular infiltrate but extensive demyelination and preserved axons, with parts of the cortex now involved and showing patchy neuronal loss. Abnormal neuroglia appear as these stages evolve: proliferation of normal appearing cells; rounded and enlarged cells; granular cells containing lipid debris; large cells with an eccentrically placed nucleus and processes forming a reticulum; and typical Alzheimer cells. The liver is much the same as in Phoebe B’s siblings: multinodular changes with fatty infiltration and some fibrosis. Although this case is remarkable for the extensive and confluent involvement of the frontal lobes with cavitation, increased vascularity, neuroglial overgrowth with formation of Alzheimer cells, white matter involvement and relative preservation of neurons, it is the opportunity to study the Kayser-Fleischer zone that most deserves comment. Both corneas are abnormal. The membrane of (Jean) Descemet’s (1732–1810) is darkly pigmented without encroaching on the posterior epithelial covering of the cornea, the limbus or centre of the cornea (Fig. 4). There is no apparent excess of manganese in either the brain or liver; and no special properties resulting from chemical analysis reveal the nature of the pigment.

Figure 4

Section of the cornea showing the pigmentation of Descemet’s membrane. From Barnes and Weston Hurst (1926).

In 1902, (Bernard) Kayser (1869–1954) first described corneal pigmentation in a young male suffering from ‘multiple sclerosis’. A decade later (Bruno) Fleischer (1874–1965) drew attention to the brown line made up of fine dark brownish-green and golden particles most dense at the periphery and becoming less obvious towards the centre of the iris, in two cases of pseudo-sclerosis with cirrhosis. This is confined to Descemet’s membrane extending neither to the angle of the anterior chamber nor to the centre of the cornea. Thereafter, many authors have described the zone of pigmentation in cases of hepato-lenticular degeneration or of pseudo-sclerosis and tetanoid chorea. But the difficulty of detecting the zone in Phoebe B and her siblings in life, other than by expert use of the slit-lamp, indicates that the Kayser-Fleischer zone is helpful when present but its absence carries no particular significance for refuting the diagnosis of hepato-lenticular degeneration. Considering the literature as whole, Drs Barnes and Weston Hurst conclude that of 12 cases of Wilson’s disease in whom adequate examination has been performed, six had the Kayser-Fleischer zone; and it was also present in all 16 examples of pseudo-sclerosis making it not possible to separate the two diagnoses on this basis. In fact, they are in doubt that these are one and the same disease. Three cases in the literature are described as having the Kayser-Fleischer pigmented zone in the context of another condition: Kayser’s original case of ‘multiple sclerosis’ which Dr Barnes now re-diagnoses as hepato-lenticular degeneration; and two others in whom despite the absence of neurological symptoms and signs, the affected individuals had cirrhosis of the liver. Therefore Drs Barnes and Weston Hurst add early involvement of the cornea, before the nervous system may be affected, to the sequence of events whereby liver disease allows delivery of a toxin, normally filtered, to other tissues. Fleischer has also described a quite separate condition of pigmentation associated with conical cornea and due to accumulation of iron, for which the Kayser-Fleischer zone does not stain, and which (to add confusion) has also become known as the ‘Fleischer ring’. So, of what is the pigmentation seen in hepato-lenticular degeneration composed? Fleisher considered silver but discarded this interpretation based on his microchemical assessments. Hall who has investigated this most assiduously believes the pigment to be derived from haemoglobin but not containing iron. Drs Barnes and Weston Hurst can only conclude from analyses on their own case, carried out by Dr H.W. (Harold Ward) Dudley (1887–1935) of the National Institute for Medical Research (Mill Hill, London, UK), that the reactions are not those ‘of any normal body-pigment, or of any pigment found in the commoner pathological conditions, nor are they in accordance with the view that the deposits consist of silver or manganese’.

But the tragedies facing this family from Birmingham (UK) were not over. For in a short final note, Dr Barnes and his colleague describe the fate of Daniel B found to have an enlarged liver at age 6 when first examined at the time his siblings were under medical care for more florid manifestations of hepato-lenticular degeneration. Soon after Daniel has diarrhoea and vomiting with jaundice that recovers but he then fails to thrive and cannot attend school due to mental backwardness. The previously noted choreic or athetoid movements become more apparent during the agonal stages of his final illness. This is brief and characterized by fever, jaundice and recurrent ascites; well-intentioned relief of distressing symptoms with opium brings matters abruptly to an end. Autopsy shows a small liver with fatty degeneration and fibrosis indicating multilobular cirrhosis. Apart from generalized swelling and granular staining of nerve cells with no regional distribution, the central nervous system appears to be unaffected. One cornea shows a few fine pigment granules not confined to Descemet’s membrane and affecting epithelial cells of the posterior surface but with biochemical characteristics closer to those described by Hall as typical of hepato-lenticular degeneration than were apparent in Daniel’s sister Phoebe. The authors speculate that, as did his brother Frederick B, Daniel died due to a wave of toxin, untrapped by the liver, suddenly flooding his nervous system and causing acute athetoid spasms through involvement of nuclei destined to be affected clinically and pathologically had he survived this surge to suffer the later stages of the illness.

Not for many years did the role of copper and careuloplasmin in the pathogenesis of Wilson’s disease became apparent and, with the availability of genetic analysis, the role of mutations in ATP7B in many but not all cases was elucidated. With time the complexities of patterns of inheritance and heterogeneity in mutations underlying the phenotype emerged. In the present issue, Alison Coffey and colleagues describe the molecular genetic findings in 181 cases of Wilson’s disease, confirmed clinically and biochemically, studied in centres throughout the United Kingdom (see page 1476) including the City of Birmingham where Drs Barnes and Weston Hurst studied the unfortunate Family B in the 1920s.

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