A case report and a historical review

The purpose of this report is to present a short review of the history of Wilson’s disease and to describe the first diagnosed case at the Neurologic Clinic of Hospital das Clínicas of São Paulo University Medical School. The topics of the historical review are the first contributions of authors along the second half of the XIX century, the seminal monograph of Samuel Alexander Kinnier Wilson (1912), the landmarks in the investigation of mechanisms of the disease and the introduction of the first effective treatment by John Walshe (1956). The first case studied in our Clinic, in 1946, was a 20 year-old male whose main neurological manifestations were postural tremor (“wing beat”) and dysarthria and could be characterized as WestphalStrümpell form of the disease. Along the discussion of this case difficulties to establish the diagnosis and to treat the patient at that time are highlighted. We conclude with a brief history of the development of researches on Wilson’s disease in our Clinic, with an honor to the pioneer contributions of Horacio Martins Canelas. Key WordS: Wilson’s disease, historical review, copper metabolism. Doença de Wilson: relato de caso e revisão histórica Resumo – Neste artigo inicialmente é feito um retrospecto dos principais marcos na história dos conhecimentos sobre a doença de Wilson, desde as primeiras descrições de casos no século XIX, passando pela magnífica monografia de Samuel Alexander Kinnier Wilson, m 1912, pelas descobertas sobre a causa da doença e chegando à era do tratamento efetivo da moléstia inaugurada por Walshe em 1956. A seguir, relata-se o primeiro caso de doença de Wilson estudado na Clínica Neurológica do HC-FMUSP. o paciente admitido na Clínica Neurológica em 1946, aos 20 anos de idade, apresentava a variante da doença em que predominavam tremor postural e disartria, conhecida como forma de Westphal-Strümpell. Na discussão, são ressaltadas as dificuldades da época para a confirmação do diagnóstico e para o tratamento; além de se realizar um breve histórico do estudo da doença na Clínica Neurológica, com o devido realce para a figura de Horácio Martins Canelas, pela sua participação pioneira nas pesquisas sobre a doença de Wilson em nosso meio. PAlAvrAS-CHAve: doença de Wilson, revisão histórica, metabolismo do cobre. department of Neurology and department of Gastroenterology of São Paulo University Medical School, São Paulo SP, Brazil. received 25 September 2008, received in final form 5 January 2009. Accepted 28 March 2009. Dr. Egberto Reis Barbosa – Rua Sergipe 401 / 311 01243-001 São Paulo SP Brasil. E-mail: [email protected] Wilson’s disease (Wd) is an autosomal recessive disorder of the copper metabolism leading to the accumulation of this metal in different organs and tissues. Hepatic and neurological symptoms are the main clinical features of the disease. Some authors attribute to FT Frerichs the first case report of Wd, in 1861. The patient described by Frerichs was a 9-year-old boy who developed neurological symptoms characterized at the beginning by speech changes and difficulty to control the movements of the limbs. He later developed intention tremor, difficulty in swallowing and died at the age of 10. The autopsy revealed abnormalities compatible with cirrhosis of the liver. Westphall, in 1883, reported the study of two cases which had as the main neurological manifestation a tremor similar to that seen in patients with multiple sclerosis but their necropsy did not show the typical white matter lesions of this disease, well-known at that time. For this reason, Westphall used the term “pseudosclerosis” for this new disease. Strümpell reported in 1898 and in 1899, three other cases of pseudosclerosis and the pathology of the third one revealed the presence of cirrhosis of the liver. Gowers (apud Tyler), in 1888, described the cases of a 10 year-old boy and his sister, in which there were a predominance on the clinical picture of a kind of moveArq Neuropsiquiatr 2009;67(2-B) 540 Wilson’s disease Barbosa et al. ment disorder that was named by the author as “tetanoid chorea”. In 1906, Gowers (apud Wilson), in his new report named “On tetanoid chorea and its association with cirrhosis of the liver” described with more details the neurological abnormalities seen in one of the patients as: “both arms presented slow changing tonic spasm... at times the spasm changed so that the fingers were spasmodically extended; occasionally they were spread out and moved irregularly in a manner resembling athetosis”. This description shows clearly that Gowers referred to what today is called dystonic movements and postures. Illustrating this report there is a photo of the patient where we can see the dystonic postures of the four members. The pathological findings of both cases revealed the presence of cirrhosis of the liver while there were no defined lesions in the brain. ormerod, in 1890, reported a similar case in a 10 year-old child with rapid-onset of neurological manifestations along 3 to 4 months and he described them like this: “weakness of right hand and arm, with cramped position of the fingers, soon followed by difficulty of speech. drawing of the face, then an unnatural gait. Speech gets worse; he seems silly; has some difficulty in swallowing. Gait much worse. lastly some affection of left arm and hand”. The progression was fast and the death came 8 months after the beginning of the symptoms. In this seminal report, we can identify some neurological features that are hallmarks of the disease: the presence of a motor disorder affecting at the beginning, the right hand and arm suggesting dystonia; the early and severe involvement of speech; the facial expression compatible with risus sardonicus; and the quick progression to death in less than a year, as it can occur in the dystonic form of Wd. The necropsy showed necrosis of the external segment of the lentiform nucleus (putamen) and the presence of cirrhosis of the liver. These pathological findings are in agreement with the diagnosis of Wilson’s disease. In this remarkable report, ormerod emphasized the great similarity between his case and those reported by Gowers two years before with the patients described by Homén in the same year (1890). Homén’s report included 3 siblings (two males and a female) with ages at the onset of the disease ranging from 12 to 21 years old, and neurological manifestations similar to those described by ormerod, although with a slower progression. Severe damage of nucleus lentiform and cirrhosis of the liver were also observed by Homén in his cases, despite he thought these were related to syphilis. In 1902, Kayser reported the presence of a greenishbrown ring around the cornea of a 23-year-old man, thought to have multiple sclerosis. In the following year, Fleischer (1903) described the same pigmented ring in a case of “pseudosclerosis” and in another case of multiple sclerosis. In 1911, Wilson presented his monograph describing the “progressive lenticular degeneration” that resulted in the publication of a historical paper in Brain”journal, in 1912, with the title“Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Briefly versions of the same study were published in 1912, in two other journals: the “Lancet” and the “Revue Neurologique” (Paris). In these seminal reports Wilson described four personal cases (three of them with neuropathological study), two referred (but not studied) by Gowers and ormerod and six other cases from the literature (the cases described by Gowers; ormerod and Homén). He emphasized the familial character of some cases and the presence of cirrhosis of the liver, mostly asymptomatic, but claimed that the liver did not contribute to the clinical progression of the disease. Bramwell, in 1916, was the first to realize the importance of liver pathology in Wd, when he described a family in which 4 siblings died of “acute fatal cirrhosis” all between 9 and 16 years of age, and suggested that this cases might have been related to those reported by Wilson 4 years before. Wilson did not see at his first papers a relationship between his cases and the pseudosclerosis of WestphalStrümpell. However, two years later, while writing on “progressive lenticular degeneration”, Wilson mentioned similarities between the two entities. In 1920, Spielmeyer, contesting the ideas of von Hoesllin and Alzheimer concluded that, from the neuropathological point of view, pseudosclerosis and Wd were the same disease. The controversy between the followers of Wilson’s ideas about the unity of the two entities and Westphal, Strümpell and Alzheimer’s school, who considered them as independent, was definitely over in 1921 with the publication of Hall’s monograph. This author, based on the review of 64 cases of literature and studies of four personal cases, demonstrated in a conclusive way the identity between the two diseases. Furthermore Hall pointed out their inheritable character and assembled the two diseases under the name of “hepatolenticular degeneration”. once established the clinical characterization of the disease, the studies started to be orientated toward its ethiopathogenesis. rumpel, in 1913, had already mentioned by the first time the increase of the amount of copper in the liver of a patient with pseudosclerosis. According to Scheinberg and Sternlieb, vogt, in 1929, Haurowitz, in 1930, and Glazebrook, in 1945, demonstrated the accumulation of copper in the liver and in the basal ganglia of patients with Wd. In 1948, some important discoveries brought a great advance to elucidation of metabolic disorders of Wd. In this year Mandelbrote et al. studying the copper meArq Neuropsiquiatr 2009;67(2-B) 541 Wilson’s disease Barbosa et al. tabolism in multiple sclerosis noticed that in the control group, that included patients with other neurological diseases, one patient with Wilson’s disease presented an increase of urinary excretion of copper. In a two-hour period the patient with Wd excreted 41.7 μg of copper, whereas none of the other twelve patients studied excreted more than 18 μg. In the same year Cumings definitely proved the accumulation of copper in the liver and in the brain of patients with Wd. Along the 1950’s the investigation on Wd concentrated on the study of the copper metabolism and on the treatment of the disease aiming to reduce copper accumulation. In 1952, Scheinberg and Gitlin demonstrated the decreased level of ceruloplasmin in patients with Wd and, in 1954, Cartwright et al. reported the increase of serum free copper, not bound to ceruloplasmin, in patients with Wd. The attempts of treatment with copper chelating agents were unsuccessful until the introduction of the penicillamine by Walshe, in 1956, what made possible the long term treatment of the disease, so far always fatal. The efficacy of penicillamine in the treatment of Wd was recognized only after several years. To illustrate this fact in the book published by Boudin and Pepin on Wd, in 1959, this drug was put in the same plane of others therapeutic options that later revealed completely ineffective such as isoniazide and sodium thiomalate. From 1946 to 1961, six cases of the Wd were evaluated in the Neurologic Clinic of the Hospital das Clínicas of São Paulo University Medical School (HC-FMUSP). The first of these cases, evaluated in 1946, is the objective of this report.