QJM Advance Access originally published online on July 8, 2005
QJM 2005 98(8):557-563; doi:10.1093/qjmed/hci095
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Prognostic factors in patients presenting with severe neurological forms of Wilson's disease
From the Departments of Neurology and 1Neuroradiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Address correspondence to Dr A.B. Taly, Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, India – 560 029. email: abtaly{at}yahoo.com
Received 23 February 2005 and in revised form 15 May 2005
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Summary |
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 Top Summary IntroductionMethodsResultsDiscussionAppendix: Chu staging2References |
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Background: Wilson's disease (WD), a metabolic disorder, is believed to be potentially reversible, even in its severe form. However, some patients do not respond to treatment.
Aim: To analyse prognostic factors in severe WD.
Design: Retrospective audit.
Methods: A total of 140 patients were regularly followed from February 2002 to May 2004. Twenty-nine (18 males, 11 females) had severe disease, as defined by Modified Schwab and England Activities of Daily Living score (MSEADL) of 
50% or Chu stage of 3. We analysed their clinical, laboratory and MRI features with respect to prognosis.
Results: For the severe form, mean age at symptom onset was 11.5 ± 6.4 years, and at diagnosis, 13.3 ± 7.0 years. Mean Neurological Symptom Score (NSS), Chu stage, and MSEADL were 26.5 ± 8.2, 2.7 ± 0.5 and 24.8 ± 17.4, respectively. Twenty-one patients underwent MRI; 14 had repeat MRI. Following treatment, 14 (group A) had progressive worsening, including death in two, while 15 (group B) had sustained clinical improvement. Baseline demographic, clinical and laboratory features and MRI scores did not significantly differ between the two groups. However, diffuse white-matter abnormalities were more extensive in group A. Full-dose initial penicillamine therapy could have contributed to worsening in four patients. Drug compliance was poor in both groups but resumption of treatment did not benefit patients in group A. Serial MRI showed regression of lesions only among patients with clinical improvement.
Discussion: Severe WD remains a therapeutic challenge, with early diagnosis and treatment are essential. Specific MRI observations, a ‘start low—go slow’ regimen for penicillamine, and compliance may have prognostic significance. In absence of clinical predictors, genetic attributes need to be explored.
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Introduction |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix: Chu staging2References |
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Wilson's disease (WD) is a genetically determined disorder due to a defect in copper transportation. If recognized and treated early, the course of the disease can be modified and most patients have a favourable prognosis. However, despite early diagnosis and treatment, a few patients still have a relentlessly progressive course and premature death. The causes of poor therapeutic response remains unknown. We analysed the prognostic significance of various clinical, biochemical and radiological parameters in patients presenting with severe neurological forms of Wilson's disease.
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Methods |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix: Chu staging2References |
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The study was conducted at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, a tertiary care University teaching hospital in south India, where a large group of patients with WD has been followed for the last three decades. These patients have been diagnosed based on the clinical manifestations, presence of KF ring by slit-lamp examination, low serum copper and ceruloplasmin levels, and increased 24-h urinary copper excretion. Clinical severity and disability status were scored using the Neurological Symptom Score (NSS)1 Chu staging2 (Appendix) and Modified Schwab and England Activities of Daily Living (MSEADL)3 scores.
This study involved 140 patients who were on regular follow-up from February 2002 to May 2004. The patients were considered to have severe disease if at initial evaluation they had a score of 50% on MSEADL score or a Chu stage of 3, or both. Nineteen patients fulfilled both the criteria; eight patients were in Chu stage 2, but their score on MSEADL was >50%. Two patients did not meet both the criteria at initial evaluation; however, during follow-up, they had significant worsening.
The clinical, biochemical and radiological data of 29 patients who met the inclusion criteria were analysed. All these patients were personally reviewed during the study period. The following laboratory tests were analysed for prognostic value: liver function tests, serum copper, serum caeruloplasmin and 24-h urinary copper, renal function tests, haemoglobin, total leukocyte counts and platelet count. Data regarding drug compliance were also noted. During follow-up, 14 patients had progressive deterioration (group A), while 15 patients (group B) showed consistent improvement and attained a score of >50% on MSEADL. All these patients were on de-coppering agents (penicillamine, zinc) and when necessary, symptomatic therapy.
Twenty-one patients (10 group A; 11 group B) had undergone MRI during their first evaluation. The anatomical distribution of abnormalities was noted and grading was done based on severity of changes in signal intensity of focal lesions and associated atrophy if any (0, no abnormality; 1, change in signal intensity with no atrophy; 2, change in signal intensity with mild to moderate atrophy; 3, change in signal intensity with severe atrophy). The structures assessed for grading included caudate, putamen, internal capsule, thalamus, midbrain, pons, medulla, cerebellum, white matter and cortical changes. The grading system provided a composite score of 0–30, with zero indicating normal scan and 30 severe changes. In addition to the grading of the sites, the type of involvement and specific features such as ‘face of the giant panda’, central pontine myelinolysis, pallidal hypointensity were also noted. Serial MRI was carried out in 14 patients (6 group A, 8 group B).
SPSS v10 software was used for statistical analysis. Student ‘t’ test was used for clinical, biochemical and radiological parameters to compare group A and group B. Data were considered significant at p 0.05.
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Results |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix: Chu staging2References |
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Baseline evaluation
Among the 140 patients (83 males, 57 females) on regular follow-up, parental consanguinity was noted in 63 patients, and family history was observed in 33 patients. There was at least one death attributed to WD in 18 families. None of these relatives had received any treatment. All patients were maintained on regular de-coppering agents (penicillamine, zinc sulphate) and other supportive care. There were 29 patients manifesting with severe neurological forms of WD. The profile of these 29 patients was compared with the remaining 111 patients who did not meet the criteria for severe neurological WD all through their course, from initial evaluation to the last follow-up. There were no significant differences with reference to gender, age at onset and diagnosis, delay in diagnosis, consanguinity, family history of WD and biochemical profile between the two groups at initial evaluation (Table 1).
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Among the 29 patients manifesting with severe neurological form of WD, there were 18 males and 11 females. Their mean age at onset of symptoms was 11.5 ± 6.4 years (range 4–36 years) and mean age at diagnosis was 13.3 ± 7.0 years (range 5–40 years). De-coppering therapy was often delayed, with a mean interval from onset of 1.7 ± 1.8 years (range 1 month to 6 years). Parental consanguinity was noted in 17 patients. Ten patients had a family history and there was at least one death attributed to WD in eight families.
The presenting systemic symptoms in patients with severe form of disease were: neuro-psychiatric (n = 19), hepatic (n = 7), musculoskeletal (n = 2) and haematological (n = 1). The predominant manifestations at initial evaluation included: tremors, 16; speech disturbance, 29; dystonia, 22; drooling of saliva, 27; difficulty in writing, 26; decreased scholastic performance, 7; gait disturbances, 28; chorea, 3; seizures, 6; cognitive impairment, 1; jaundice, 8; abdominal distension, 4; anxiety, 4; mania, 3; depressive behaviour, 4; bony deformity, 3; recurrent fractures, 4; bleeding diathesis, 6. Kayser Fleischer (KF) rings by slit lamp examination were documented in all the patients. The mean scores for disease severity at initial evaluation were: NSS 26.5 ± 8.2 (range 12–44), Chu stage 2.7 ± 0.5 (range 2–3) and MSEADL 24.8 ± 17.4% (range 0–70%).
Low serum caeruloplasmin (mean 8.8 ± 7.7 mg/dl, N>15 mg/dl) and raised 24-h urinary copper (mean 275.5 ± 218.8 µg/day, N<70 µg/day) were present in all but four patients each. At initial evaluation, none had evidence of significant hepatic failure (mean serum bilirubin 0.6 ± 0.5 mg/dl, mean serum albumin 3.8 ± 0.5 g/dl).
There was variable involvement of almost all parts of brain on MRI: mild to severe cerebral atrophy, 19; involvement of caudate, 16; putaman, 19; thalamus, 19; midbrain, 16; pons, 12; medulla, 5 and cerebellum, 5; white-matter changes, 12; pallidal hypointensity, 8 and ‘face of giant panda’ sign, 6. The mean MRI score was 10.9 ± 4.8 (range 1–22).
Follow-up
There was no significant deterioration or death among the 111 patients who did not meet the criteria for severe form of WD, during a follow-up period of 7.8 ± 7.5 years. Their clinical severity score showed an overall improvement during the follow up period; NSS improved from 9.1 ± 6.9 to 4.4 ± 4.6, Chu stage improved from 1.8 ± 0.8 to 1.1 ± 0.4 and MSEADL score (%) showed improvement from 82.5 ± 15.5% to 96.1 ± 10.2%.
The follow-up period for the patients with severe disease ranged between 6 months and 20 years (mean 6.2 ± 5.1 years). The mean scores for disease severity at follow-up evaluation were: NSS 18.8 ± 12.0 (range 2–40), Chu stage 1.9 ± 0.9 (range 1–3) and MSEADL 55.0 ± 35.5% (range 0–100%). Fourteen patients (group A) had progressive deterioration or no therapeutic response, while 15 (group B) had significant improvements in clinical status and disability scores. Their baseline demographic, clinical, laboratory features and MRI scores at initial evaluation and duration of follow up did not differ significantly (Table 2). The clinical severity scores at initial evaluation and at follow-up were: (group A) NSS 26.1 ± 8.2 vs. 28.6 ± 8.2; Chu stage 2.7 ± 0.5 vs. 2.6 ± 0.5; MSEADL 25.4 ± 20.7% vs. 23.2 ± 19.4 (no significance difference at follow-up) and (group B) NSS 26.8 ± 8.5 vs. 9.6 ± 6.1, Chu stage 2.6 ± 0.5 vs. 1.2 ± 0.4 and MSEADL 24.3 ± 14.5% vs. 84.7 ± 14.6% (significant improvement at follow-up, p < 0.0001). While the white-matter changes in MRI of brain were noted in six patients in each group, extensive signal abnormalities were observed in two patients in group A only.
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Penicillamine was discontinued on 26 occasions (19 group A, 17 group B) by 13 patients (8 group A, 5 group B). Treatment was stopped intermittently for a variable period, ranging from a few days to 6 years, after initial institution. The reasons for discontinuation varied and included financial constraints, paradoxical worsening of symptoms, haematological problems and poor knowledge regarding the need for regular life-long medication. Penicillamine was restarted in all except in two patients, who had persistent haematological side effects. Following resumption, all patients in group B showed consistent improvement while patients in group A had worsening or poor response. When the full dose of penicillamine (750 mg/day) was instituted initially, paradoxical worsening of symptoms was observed in four patients (3 group-A, 1 group-B). However, no clinical deterioration was noted on restarting penicillamine at low dose (250 mg) and slowly raising it up to full dose (750 mg/day). Two patients in Group A died after 9 and 7 years of progressive clinical course, respectively. Both deaths were attributed to septicaemia.
Repeat MRI was done in 14 patients (6 group A, 8 group B) at an interval of 2.1 ± 1.1 years (range: 0.5–3.3 years). The MRI features in this subgroup of 14 patients were similar to those of the whole group. Initial MRI scores were comparable (group B 9.6 ± 3.6; group A 12.3 ± 5.8; p = 0.21) but there was significant difference (p = 0.015) in scores on serial MRI between the two groups. At follow-up, there was a reduction in scores in group B (from 9.6 ± 3.6 to 2.4 ± 1.2, p < 0.0001) and an increase in MRI scores in group A (from 12.3 ± 5.8 to 15.5 ± 8.8, p = 0.07) (Figures 1 and 2). Two patients in group A with extensive white matter changes showed distinct progression of these MRI abnormalities.
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Discussion |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix: Chu staging2References |
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At the beginning of the last century, patients with WD had a relentless progressive course and premature death.4 Establishment of its relationship with copper by Cumings5 led to the search for de-coppering therapy. The clinical outcome of WD has improved dramatically following introduction of various drugs like dimercaprol,6 penicillamine, trientine, zinc and tetrathiomolybdate.7 These drugs reduce copper load by chelating the body copper or by inhibition of further copper absorption and deposition in the body. Early diagnosis, prompt institution of treatment and good lifelong drug compliance are essential for successful treatment. The prognosis of WD is not uniformly predictable, and a subset of patients does not respond to de-coppering agents. There is a paucity of literature focusing on prognostic aspect of WD in general and its severe form in particular.8–10 We have analysed clinical, laboratory and MRI features that might predict the clinical outcome in a large cohort of WD with predominant neuropsychiatric manifestations from a tertiary care neuroscience university centre.
Assessment of the severity of illness and long-term outcome can be done by quantifying impairment, disability, handicap and quality of life.11 We used MSEADL and Chu scores to ascertain the severity of the disease to ascertain the impact of illness on the functional status of the patient. A score of 50% on MSEADL scoring system indicates that patient requires help in half of the daily chores and has difficulty in performing all the activities, thereby reflecting severity of the illness. The scores at the time of first presentation and last evaluation were used to grade the clinical outcome. Twenty-nine patients met these criteria for the severe form of WD at initial evaluation, and 14 of them did not improve or worsened progressively. Their clinical features and biochemical parameters were not significantly different from the 15 patients who responded to treatment and acquired a score of >50% during the same period of follow-up. While the overall MRI severity scores did not differ between the two groups (Table 2), the white-matter changes were more extensive in group A.
There is a paucity of literature focusing on the prognosis and outcome in severe neurological forms of WD. However, there are a few studies dealing with the clinical outcome and the prognosis of WD. In our large cohort of 140 patients, 111 patients with a milder form of the disease and 15/29 patients with a severe neurological form of the disease showed consistent and significant improvement on de-coppering therapy during follow-up. Walshe,8 in a study of 137 intensively treated patients, noted poor therapeutic response in 35 patients, but did not observe any clinical or biochemical prognostic markers of this response. Nazer et al.9 derived a prognostic index in the hepatic form of WD using serum bilirubin, serum aspartate transferase and prothrombin time. Each parameter was graded on a 0–4 scale, and a score of 6 was considered as a good prognostic marker for chelating therapy. They also noted that jaundice and ascites were associated with higher mortality. In our study, patients in group A did not show any evidence of hepato-cellular failure to account for progressive deterioration. Further, this prognostic index cannot be applied to the other forms of WD, such as the present study, which was dominated by neuropsychiatric manifestations.
Delay in diagnosis and chelating therapy adversely affect the clinical outcome.12,13 The mean interval between the initial symptoms to diagnosis in the present study was 1.7 ± 1.7 years (range 1 month to 6 years), but did not differ between the two groups to account for differential outcome. Walshe et al.8 also observed that delayed diagnosis did not influence the outcome.
Paradoxical worsening of symptoms in patients with WD after institution of penicillamine has been noted in 10–50% of patients and some of these individuals tend to have irreversible damage.8,14,15 In our study, four patients had paradoxical worsening following the institution of full-dose penicillamine. These patients were withdrawn from penicillamine therapy and maintained on zinc sulphate. On resuming low-dose penicillamine, there was no further worsening. Drug compliance plays important role in the management and may govern the clinical outcome. It has been noted that patients who have been on medications for many years tend to deteriorate following even a brief interruption in the therapy.10,16 In the present study, patients in Group A with poor therapeutic response had more frequent breaks in treatment, and failed to respond on resumption of therapy. It is possible that discontinuation of treatment at critical phase of illness may have prognostic significance.
The clinical presentations of WD are diverse13 and attributed to genetic heterogeneity. More than 200 individual mutations have been identified in patients with WD that may contribute to the variation in the clinical outcome.17–20
Patients with severe forms of WD may have a good outcome if treated appropriately, but a subgroup of patients may not respond or worsen. The reasons for this cannot be explained exclusively on clinical grounds, but evidence of extensive white matter changes on MRI may provide a clue to the poor prognosis. Early diagnosis, prompt institution of de-coppering therapy, slowly increasing the doses of penicillamine to avoid paradoxical worsening and compliance, may favour a better outcome.
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Appendix: Chu staging2 |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix: Chu staging2References |
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Stage I: Hand tremors, slurred speech, hoarseness or tendency to fall, with minimal or no functional impairment.
Stage II: Able to walk but show moderate rigidity or involuntary movements, unsteady gait, dysphagia, dysarthria, psychiatric symptoms, or any combination of these.
Stage III: Bedridden with severe generalized rigidity or spasticity; or unable to walk because of gross ataxia or marked involuntary movements.
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References |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix: Chu staging2References |
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