692 Journal of Neurology, Neurosurgery, and Psychiatry 1992;55:692-696 Wilson's disease: the problem of delayed J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.8.692 on 1 August 1992. Downloaded from diagnosis

J M Walshe, M Yealland

Abstract approximately half of these will present with To discover the earliest symptoms and neurological symptoms.6 Thus in the United signs of neurological Wilson's disease we Kingdom, with a birth rate ofbetween 600 000 analysed the case histories of 136 patients and 700 000, there will be on average 10 new who were seen between 1955-87: patients patients presenting annually to all the neuro- with hepatic or presymptomatic Wilson's logical clinics in the British Isles. disease were excluded from this series. Little attention has been paid in the lit- Thirty one patients (23%) gave a history of erature to the very earliest neurological symp- an episode of liver damage. The onset of toms and signs of this disease except for brief symptoms ranged from nine to 40 years mention in Scheinberg and Sternlieb's mon- with a median of 16-2 years. The correct ograph.4 While we are largely in agreement diagnosis was made at presentation in with their observations it is our intention to only 43 patients. The mean delay before describe in greater detail this important stage diagnosis was 12-8 months for the others. in the evolution of the illness. The earliest symptoms were dysarthria or In many cases it has been difficult to identify difficulty with the hands, or often both. the very earliest symptoms. Most patients will There was often an associated change in have been seen by a number of doctors, often personality or deteriorating performance of different disciplines (general medical, psy- at school. The four common clinical pic- chiatric and neurological) and have had their tures were Parkinsonian (61 cases), case histories taken on numerous occasions "pseudosclerotic" (33 cases), dystonic (21 before referral. Thus their recollection of how cases) and choreic (15 cases): six cases the illness started will have faded with the were unclassified. Parkinsonian symp- passage of time and will also have been toms were equally common in children influenced by direct questioning dictated by (under 17 years) and adults, a "pseudo- the preconception of the examining physician. sclerotic" picture was much more com- Also, in many cases the later development of mon in adults but dystonic and choreic more dramatic symptoms and signs will have symptoms were seen more often in chil- coloured the patient's view of the disease. dren. Experience suggests that no two We believe that the analysis of so many case

patients are ever the same, even in a histories, all taken by one of us, over a period http://jnnp.bmj.com/ sibship. in excess of 30 years, has enabled us to establish the onset, evolution and varying (_ Neurol Neurosurg Psychiatry 1992;55:692-696) clinical pictures of this disease. There appears to be only one thing which all patients have in More than thirty years of investigation and common, apart from Kayser Fleischer corneal management of patients with Wilson's disease pigment, namely that they are all different. It is has shown that there is frequently an unaccep- therefore unwise to rely on seeing "the typical table delay in establishing the correct diag- picture ofWilson's disease" before making the on September 30, 2021 by guest. Protected copyright. nosis. This is greatly to the disadvantage of the diagnosis. patient not only by prolonging unnecessarily the duration of the illness but also by affecting adversely the prospects for recovery. If too Material and methods much damage is allowed to occur in the brain We selected for study 136 patients (F = 70, University before the initiation of "decoppering" therapy M = 66) presenting with neurological signs Department of to Medicine and the then full restoration of function is difficult from some 250 cases of Wilson's disease Department of achieve despite the remarkable improvements seen between 1955-87, the majority at Neurology, which have been observed in CT scan Addenbrooke's Hospital, Cambridge; patients Addenbrooke's seen were not included. One Hospital, Cambridge, appearances. subsequently UK The mean delay in diagnosis for patients hundred and fourteen cases have been omitted J M Walshe presenting with neurological symptoms in this because the diagnosis was made before the M Yealland series has been in excess of one year. The onset onset of neurological symptoms. Thirty one Correspondence to: of Wilson's its evolution and a of an earlier of Dr Walshe, The Department hepatic disease, (23%) gave history episode of Neurology, The response to treatment has been described liver damage the significance of which was not Middlesex Hospital, London elsewhere.2 It be that Wilson's WIA 8AA, UK might argued appreciated at the time. The clinical picture of so rare to Received 12 August 1991 disease is that failure recognise it hepatic Wilson's disease, its diagnosis and and in revised form soon after onset is not surprising. However, it management of the presymptomatic stage have 20 November 1991. now Accepted 27 November is established that the prevelance in the been described elsewhere.6-8 Eighty five 1991 general population is 30 per million35 and patients came from the United Kingdom and Wilson's disease: the problem of delayed diagnosis 693 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.8.692 on 1 August 1992. Downloaded from 51 from abroad; mostly the Mediterranean oped Parkinsonian symptoms considered countries and the Near East. secondary to phenothiazines. During the next All patients showed the classical biochemical two years she suffered from increasing tremor lesion ofWilson's disease, that is a low serum of the arms and slurring of speech. She was copper, a low caeruloplasmin and a high serum referred to a consultant neurologist who con- "free copper" together with an increased sidered her symptoms to be hysterical. As she urinary output of the metal. They also all had became increasingly disabled she took an Kayser Fleischer corneal pigment, though not overdose ofphenothiazines which was followed necessarily complete rings,9 when first seen by by exacerbation of her tremor. She was then us. referred to a psychiatrist who agreed with the All patients were examined by one of us diagnosis of hysteria. Later she was seen by a (JMW) immediately after referral and the second neurologist who could find no evidence majority were examined by both of us sepa- of organic disease. Six months later a third rately. We relied upon the recollections of the neurologist investigated her and, at that time, patients and the letters of referring physicians an ophthalmologist suggested that she might for information about the earliest stages of the have Kayser Fleischer rings but this was illness. A minority of patients only were seen ignored and again she was said to have no soon after the onset of symptoms. organic disease. Finally her speech defect Wilson's disease has a recessive mode of became so severe that she was rendered mute. inheritance so that it is probable that families At that stage the partner in her father's general will be seen in which more than one sibling is practice suggested the diagnosis of Wilson's affected. If the diagnosis of Wilson's disease disease and she was referred to us. We found has already been confirmed in one sibling there that she had dense, broad, complete Kayser should be no problem in making the correct Fleischer rings, blepharospasm, saccadic eye diagnosis if a second sibling develops similar movements, anarthria, severe action and rest- symptoms. In our series 16 families had more ing tremor of the arms and truncal tremor. She than one affected sibling and in one kinship eventually made an excellent recovery on first cousins developed neurological Wilson's penicillamine. disease. In eight sibships screening studies led Case 2 a civil engineer noticed at the age of to the diagnosis of presymptomatic Wilson's 30 years a change in his handwriting and in his disease in a younger sibling. In three other speech which became quavering and rapid. families a second sibling had early symptoms This was followed by tremor of both arms. A of neurological involvement. In three families diagnosis of multiple sclerosis was made and the diagnosis ofWilson's disease in the propo- he was treated with ACTH. The following year situs was not followed up and a second sibling he developed nodding tremor of the head and developed symptoms at a later date. In one his work was seriously impeded. A consultant family the diagnosis in the elder sibling was neurologist could find no abnormality in his only made after a second sibling developed speech but confirmed the tremor of the head symptoms. and arms, the gait was normal. A cursory In another family the establishment of the examination of the eyes did not reveal the diagnosis ofWilson's disease in an elder sibling presence of Kayser Fleischer rings. A CT brain with neurological symptoms led to the finding scan showed dilatation of the ventricles, more http://jnnp.bmj.com/ that her younger sister, who was being treated marked on the left, and atrophic changes in the for chronic hepatitis, also had the same dis- cerebral and in the cerebellar cortex. The ease. Interestingly, the 43 patients in whom the serum caeruloplasmin was just below the lower diagnosis ofWilson's disease was made at the normal limit for the laboratory. The diagnosis first time of investigation, nine had affected ofWilson's disease was discarded in favour of siblings, whereas in the remaining 93 cases familial tremor. He was seen regularly for only three siblings had Wilson's disease. follow up and during this time there was a The diagnoses made when the patients first change in his personality, he took to drink and on September 30, 2021 by guest. Protected copyright. consulted a doctor fall into four groups: 1) an to hitting his wife who left him. This led to no organic disorder other than Wilson's disease review of the diagnosis or his management. (35); 2) a psychiatric illness (32); 3) a group in After this he attended a neurological clinic in which no diagnosis was made or else the the United States where he was noted to have patient declared fit (26); 4) Wilson's disease head tremor, action tremor of the arms and (43). Incorrect organic diagnoses were as slurred speech. He was also found to have diverse as flat feet, myxoedema, myasthenia broad, dense complete Kayser Fleischer rings. gravis, encephalitis, multiple sclerosis and Par- He improved on treatment with penicillamine kinson's disease. Patients presented to paediat- but developed immune complex nephritis. He ric, general medical, neurological and was referred to us for treatment at this stage. psychiatric clinics. Psychiatric diagnoses were He still had mild head and arm tremor and schizophrenia, depression, anxiety state and very dense corneal rings. He has subsequently hysteria. The type of problems patients suffer made an excellent recovery on trientine. in the diagnostic process are illustrated by two The age of onset ranged from nine to 40 brief case histories. years with a median figure of 16 years, the Case 1 had an excellent academic record median age for the onset of hepatic symptoms, until, at the age of 17 years, she developed "an in those patients who had shown them was 11 acute anxiety state" which was attributed to years (fig). the break-up of her parents' marriage. Follow- We have subdivided the patients into two ing treatment with antidepressants she devel- groups, 65 juveniles (16 years of age and 694 Walshe, Yealland J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.8.692 on 1 August 1992. Downloaded from Age of onset disease. The speech defect could be of greatly 6 varying severity. In a small number of patients Median age = 11-5 years a change in personality was the very earliest Mean delay before diagnosis = 6 12 months abnormality and showed itself as facile laugh- 5 ter, inappropriate and occasionally aggressive behaviour, labile mood, lack of insight and 4 disinhibition. Hepatic The tremor was of varying severity and N = 31 clumsiness of the hands was usually described 3 as difficulty in writing. Problems in walking were not recorded as a first symptom in any patient though it often rapidly followed tremor of the hands. Despite the fact that the neuro- logical lesion is biochemically induced and 2 - therefore affects the brain uniformly, limb symptoms and signs were always asymmetrical in the early stages of the disease. Muscle Z 10 15 20 25 30 cramps and spasms were rare but did occur o 15 Median age = 16-2 years and presumably were responsible for the Mean delay before diagnosis = 12*8 months spontaneous dislocation of the jaw complained of, as a first symptom, by two patients; a third patient had such severe abnormal jaw move- I ments that she needed dental extractions to 10k CNS protect her cheeks from damage by her teeth. I N= 136 Nine patients gave a history of epilepsy, either grand mal or focal fits, early in the illness; in one patient a single grand mal seizure was the only complaint when he was first seen, 5 but examination revealed complete Kayser I Fleischer rings and sun flower cataracts. Epi- lepsy was more common in juveniles (7) than in adults (2). A detailed account of epilepsy in o . . Wilson's disease has already been presented.'0 10 15 2u 35 40 We observed no differences in symptoms Age (years) between the sexes. The and in Figure This shows the age of onset of neurological symptoms in all 136 patients. A total signs, for both juveniles adults, of 31 patients had an earlier episode of liver disease. the four diagnostic categories are shown in tables 1 and 2. These will be described together as most differences seen in the pattern of signs under) and 71 adults (17 years and over). The in the 2 age groups are probably explained by eight major complaints of personality change, the relatively small numbers involved. The one

speech defect, drooling, difficulty in swallow- exception was that a Parkinsonian facies was http://jnnp.bmj.com/ ing, hand tremor, other difficulties with the noted three times more frequently in the hands, abnormal gait and a deterioration in the juveniles than in the adults. In 10 cases no quality of school work, were largely similar in abnormal signs were recorded even though the both groups though dysarthria and drooling patients may have complained of speech dis- were rather more common in the juveniles turbances or tremor. Presumably this was (table 1). Deterioration in school work could because of the intermittent nature of the early result from intellectual impairment, physical movement disorders. Signs in the limbs were problems or both. The combination of a speech always asymmetrical with no preference for on September 30, 2021 by guest. Protected copyright. defect and drooling was found in 86% of either side. As might be expected from the juveniles (56) and 72% of adults (51); despite symptoms the commonest signs were dysar- this -fact difficulty in swallowing was not common in the early stages of the disease. In Table 2 Number (percentage) ofjuveniles and adults both children and adults dysarthria and tremor with different initial signs or clumsiness of the hands were the pre- Juveniles Adults dominant early symptoms. Indeed one or both 65 71 of these nearly always heralded the onset of the Personality disorder 14 (21) 13 (18) Dysarthria 34 (52) 19 (27) Gait abnormal 8 (12) 5 (7) Table 1 Number (percentage) of patients with different Eye movement abnormal 4 (6) 4 (6) initial symptoms Drooling 18 (28) 11 (15) Parkinsonian facies 15 (23) 5 (7) J'uveniles Adults Open mouth 10 (15) 0 (0) Number ofpatients 65 71 Bradykinesia 6 (9) 3 (4) Tongue abnormal 11 (17) 9 (13) Personality change 21 (32) 23 (32) UL tremor* 17 (26) 23 (32) Speech defect 63 (41) 42 (30) UL dystonia* 14 (21) 1 3 (18) Drooling 31 (20) 22 (16) UL spontaneous movements* 8 (12) 0 (0) Dysphagia 14 (9) 7 (5) LL tremorN 2 (3) 6 (8) Hand tremor 48 (31) 55 (39) LL dystoniaN 12 (18) 0 (0) Hand clumsy 32 (21) 20 (14) LL spontaneous movementsN 1 (1) 1 (1) Abnormal gait 34 (22) 18 (13) Liver disease 19 (29) 8 ( 11) Fall in work at school 40 (26) *UL % upper limb. NLL % lower limb. Wilson's disease: the problem of delayed diagnosis 695

thria (53) and tremor of the hands (40 Table 3 Distribution of cases in four clinical types J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.8.692 on 1 August 1992. Downloaded from cases). J'uveniles Adults Total Although patients with dysarthria often had Number ofpatients 65 71 136 abnormal tongue movements these did not Parkinsonian 28 (43) 33 (46) 61 (45) always occur together. Dysarthria varied from Pseudosclerotic 7 (11) 26 (37) 33 (24) slight slurring of speech to complete incompre- Dystonic 14 (21) 7 (10) 21 (15) Choreic 13 (20) 2 (3) 15 (11) hensibility; it could involve disturbances of lip, Intermediate 3 (5) 3 (4) 6 (4) tongue, palate, vocal cord and diaphragmatic movements. The incidence of abnormalities of Percentage totals in brackets. speech was followed by that of Parkinsonian expression and by the change in personality. Disorders of eye movement, though not com- By the time the correct diagnosis was made mon, were seen; six patients were recorded as many of the juveniles had moved into the adult showing nystagmus while two gave a history of group so comparison here is no longer valid. relatively short episodes of diplopia. The com- Predictably the physical signs had become bination of an alert expression of the upper more obvious and widespread with dysarthria face with a rather vacuous open-mouthed and drooling remaining the most common. A lower face, so characteristic of the established striking feature in many patients was a peculiar disease, was recorded in only 10 juveniles and and characteristic laugh on inspiration, (once in no adults. Disorders of lower limb function heard never forgotten). The frequency of were common at this stage; the gait was speech difficulties were closely followed by described as abnormal in eight children but in tremor, dystonia and spontaneous movements none of the adults. of the upper limbs. By this stage difficulty in The distribution ofsigns, no matter what the walking and bradykinesia were much more initial diagnosis, showed few variations among common. Kayser Fleischer rings were noted in the patients. However, personality change was 135 patients and sun flower cataracts in three. noted twice as often in patients who were In one patient, in whom the diagnosis was labelled "psychiatric" as in the other groups, made retrospectively, the rings were not whether juvenile or adult. Kayser Fleischer sought. rings were reported in 21 children and 13 adults in the correctly "diagnosed group" but in no others. In only one patient, diagnosed at Discussion this stage, were Kayser Fleischer rings sought Our findings in 136 patients with neurological with a slit lamp and not seen. When this patient Wilson's disease demonstrate that this diag- was referred to us six months later the rings nosis must seriously be considered in every were dense and complete, despite six months adolescent who complains of a change in chelation therapy. One patient in the "psy- speech and difficulty in the use of the hands. A chiatric" group was reported by an ophthal- change in personality makes the diagnosis of mologist as having Kayser Fleischer rings but Wilson's disease that much more probable. this was ignored by the physician. Evidence of The correct diagnosis at the time of presenta- previous liver disease was most frequently seen tion was made in only 43 patients or less than in the "juvenile Wilson's disease" group. one third; children fared slightly better than In the patients not correctly diagnosed at the adults. For the others there was a mean delay http://jnnp.bmj.com/ first consultation there was a mean delay of 13 of 13 months before the diagnosis was made, months before it was established that they had 35 were diagnosed as having an organic dis- Wilson's disease. Although the symptoms and ease, 32 a psychiatric disorder and in 26 no signs of Wilson's disease are pleomorphic we diagnosis was made or the patients were found that it was possible to place all but six of declared fit. There was no striking difference in the patients into four main clinical types: 1) symptoms between these four groups of

Parkinsonian; 2) "pseudosclerotic"; 3) dys- patients. Whenever the diagnosis is suspected, on September 30, 2021 by guest. Protected copyright. tonic; 4) choreic. The Parkinsonian patients Kayser Fleischer rings should be sought by an showed paucity of expression and movement. experienced ophthalmologist, using a slit lamp. Although the term "pseudosclerosis"'° has The rings or crescents can easily be missed by largely been abandoned we have used it here an inexperienced observer particularly if the because it is the best description of a type of iris is brown. Similarly laboratory errors in the the disease in which tremor closely resembles estimation of copper and caeruloplasmin can that seen in multiple sclerosis and which can be delay the correct diagnosis; experience in the severe enough to be described as "wing- laboratory is as important as in the clinic. All beating". The dystonic patients showed adolescents and young adults with changes in hypertonicity often associated with abnormal personality and disturbances of movement, limb movements which could be grotesque. In particularly involving speech and use of the the choreic group abnormal movements, hands, should be considered as possible exam- which could be choreic or choreo-athetoid ples ofWilson's disease if the sensory nervous were often associated with dystonia. A Parkin- system is not involved. As a screening proce- sonian picture is the most common in both dure we recommend that the serum copper children and adults (table 3). The "pseudo- and caeruloplasmin should be determined and sclerotic" presentation occurs about three the eyes examined for Kayser Fleischer rings times more frequently in adults than in chil- by slit lamp. dren whilst involuntary movements are seen six It is interesting to compare our findings with times more often in juveniles than in adults. the case reports in Wilson's original publica- 696 Walshe, Yealland

tion." He observed, personally, four patients time I fainted. I knew something was wrong so I told my J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.8.692 on 1 August 1992. Downloaded from whose neurological symptoms showed a mum and we mentioned it to the doctor. I was made redundant after 5 weeks just before Christmas on slightly older age of onset than our median age December 22nd 1988. of 16 years, the youngest was 17 and the oldest In January I noticed I was getting worse, started 25 years. Two gave a clear history of an earlier dribbling and also noticed when I walked, I was episode of liver damage. In three patients the staggering about as though I was drunk. When I sat in a onset appeared to have been Parkinsonian chair I gradually started to lean forward as ifI was going while the fourth showed rigidity and "clonic to fall. When trying to ride my bike, I couldn't keep my balance. These symptoms went on for a couple of tremor". One had an earlier and apparently months with frequent visits to the doctor to see what self limiting psychotic episode. was wrong with me. Denny Brown"2 divided his patients into two I then noticed that my hands started shaking and I clinical types, the first he called "pseudo- couldn't stop them. I started to lose my temper, sclerotic" and these were characterised by swearing and throwing things, which was totally out of dysarthria and a flapping tremor of the "wing- character for me. I felt I was being possessed by some evil force and had lost control of my actions. I felt like beating" type, the patients were all over 19 taking an overdose but I couldn't, not after saving a years of age and the illness very chronic. The friend's life after she took an overdose and slashed her second group showed the progressive lenticu- wrists. I just couldn't go through with it. lar degeneration of Wilson and were all In April 1989, I was admitted to hospital by my between the ages of seven and 15 years. The doctor. I was put through all the tests, lumber puncture, first symptom was "almost always related to cat scan, ECG, EEG, magnetic brain scan, but it wasn't until they looked in my eyes that they saw the copper dystonia". Some patients showed a Parkinson- rings and looked up their books to find the name. The ian facies and fine tremor of the fingers. This professor came to the room to tell me and my mum and latter group of patients responded-very badly dad what the disease was and how it was treated. I was to treatment with dimercaprol. In this publica- started on the tablets straight away. The doctors were tion Denny Brown did not comment on the not promising a quick recovery-it would take time, very earliest symptoms except to mention that and I would have good days and bad days. I am still going for check ups to see a specialist in there was often a tendency to inattentiveness at London every so often, but I am getting better every school, an observation in keeping with our own day. findings. I owe my life to my mum for sticking by me and The delay in making a correct diagnosis is putting up with the abuse I gave her, and for pushing another feature of Wilson's disease which has the doctors to help me get better. received little attention in the literature. With I never thought I would see my 20th birthday, it was increasing awareness of the disease over the very special to me." past 30 years the diagnosis is being made more often than previously but the delay recorded in 1 Williams FJB, Walshe JM. Wilson's disease. An analysis of the cranial computerised tomography appearances found this series of 13 months is unacceptably long. in 60 patients and the changes found in response to The source of referral of the patients made treatment with chelating agents. Brain 1981;104: 735-52. surprisingly little difference to this figure, 13f 1 2 Walshe JM. Wilson's disease presenting with symptoms of months (range six to 72 months) for 85 hepatic dysfunction: A clinical analysis of eighty-seven patients. QuartJ Med 1989;70:253-63. patients from the United Kingdom and 12-3 3 Bachmann H, Lossner J, Gruss B, Ruchholtz U. Die months (range two to 60 months) for 51 Epidemiologie der Wilsonehen Erkranjung in der DDR und die derzeitige Problematik einer populationgenetis- patients from abroad. It is impossible to know chen Bearbeitung. Psychiat Neurol Med Psychol (Leipzig) how many patients have died undiagnosed. By 1979;31:393-400. http://jnnp.bmj.com/ 4 Scheinberg IH, Sternlieb I. Wilson's disease, vol XXIII. drawing attention to the earliest symptoms, we Major problems in internal medicine. Philadelphia: W B hope that this article will increase diagnostic Saunders, 1984. 5 Walshe JM. Wilson's disease. BMJ 1984;288:1689. awareness and reduce delays so that patients 6 Walshe JM. Wilson's disease. Handbook of Clinical Neurol- can start their treatment earlier in the course of ogy, vol 5(49). In: Vinken PJ, Bruym GW, Klawans HL, eds. Extrapyramidal disorders. Amsterdam: Elsevier, 1986. the illness and thus have a better prospect of 7 Walshe JM. Diagnosis and treatment of presymptomatic achieving full functional recovery. Wilson's disease. Lancet 1988;ii:435-7. 8 Sternlieb I, Scheinberg IH. The prevention of Wilson's Finally, we have included an extract from a disease in asymptomatic patients. N Engi J Med 1968; on September 30, 2021 by guest. Protected copyright. letter by a patient describing the start of her 278:352-9. 9 Cairns JE, Walshe JM. The Kayser Fleischer ring. Trans illness. She presented to one of us (JMW) late Ophthalm Soc UK 1970;90:187-90. in 1989 and is not included in this series. 10 Denny TR, Berrios GE, Walshe JM. Wilson's disease and epilepsy. Brain 1988;HI:1139-55. "The copper must have been building up all the time in 11 Westphal C. Uber eine dem Gilde der Cerebrospinalen my brain, but no symptoms started to show until I was grauen Degenerationen ahnliche Erkrankung des cen- sixteen years old. I was in my last year at college when tralen Nervensystems ohne anatomischen Befund nebst einigen Bemerkungen uber paradose Contraction. Arch I started to lose concentration and take dizzy spells Psychiat Nervenkr 1983;14:87-134. when I was working in the kitchen. I managed to finish 12 Wilson SAK. Progressive lenticular degeneration: a familial my course and get my qualifications. nervous disease associated with cirrhosis of the liver. I Brain 1912;34:295-509. got a job in the hospital as a general catering 13 Denny Brown D. Hepatolenticular degeneration (Wilson's assistant in the staff dining room. But the dizzy spells disease). Two different components. N EnglJ Med 1964; came back, only this time they were a lot worse as one 270:1149-56.