First published online August 20, 2007
British Journal of Radiology (2007) 80, 744-749
© 2007 British Institute of Radiology
doi: 10.1259/bjr/48911350
Sequential MRI changes in Wilson's disease with de-coppering therapy: a study of 50 patients
S Sinha, MD, DM
1
A B Taly, MD, DM
1
L K Prashanth, MBBS
1
S Ravishankar, MD
2
G R Arunodaya, DM
1 and
M K Vasudev, MD
1
Departments of 1 Neurology and Neuroimaging and 2 Interventional Radiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Correspondence: Dr Sanjib Sinha, Associate Professor of Neurology, NIMHANS, Department of Neurology, Hosur Road, Bangalore, Karnataka 5, India. E-mail: sanjib_sinha{at}nimhans.kar.nic.in
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Abstract
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Wilson's disease (WD) is clinically and radiologically a dynamic disorder. However, there is a paucity of studies involving sequential MRI changes in this disease with or without therapy
This study looked at serial MRI changes and their clinical correlate in patients with WD
The severity of MRI changes using 1.5 T MRI in 50 patients with WD was graded based on alteration in signal intensity of focal lesions and atrophy. Details of clinical manifestations, Schwab and England Activities of daily living (MSEADL) score, Neurological Symptom Score (NSS) and Chu staging were recorded. Clinical severity and disability scores were correlated with MRI scores using SPSS v10
The mean age at onset of illness and diagnosis was 12.8±5.6 years and 14.4±6.0 years, respectively. At the time of first MRI, patients had been treated for 49.0±77.3 months. At a follow-up of 24.2±12.2 months, clinically 36 patients had improved, 9 remained the same and 5 had worsened. Serial imaging revealed an improvement in MRI parameters in 35 patients, no significant changes in 10, worsening in 4 and an admixture of resolving and evolving changes in 1. The overall MRI score improved from 8.2±5.7 to 5.9±6.6. There was an improvement in measures of disability and impairment in all: Chu stage, 11.5±0.7 to 1.3±0.6; MSEADL score (%), 79.7±27.6 to 88.0±25.4; NSS, 10.6±11.2 to 8.0±11.6, with good clinico-radiological correlation. Patients with extensive changes, white-matter involvement and severe diffuse atrophy had a poor prognosis
In conclusion, the majority of patients with WD showed variable improvement in clinical and MRI features when treated.
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Introduction
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Wilson's disease (WD) is a rare neurometabolic disorder of copper metabolism with protean clinical manifestations. Behavioural and motor symptoms are frequent at initial presentation and pathological changes in the brain are universal. Magnetic resonance imaging (MRI) helps to localize and characterize the pattern of change in the brain and facilitate monitoring of interventions in vivo.
MRI abnormalities in the brain are invariable in patients with WD, particularly with neurological manifestations, and involve almost all structures [1–5]. Improvement in the clinical state with treatment is well known but there is a paucity of literature on sequential MRI changes. Such data may provide opportunities for clinico-anatomical correlation and for predicting prognosis [6]. In this study we evaluated serial MRI and clinical changes in patients with WD.
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Design and methods
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Subjects
A large cohort of patients with WD was followed in a university teaching hospital and a major referral centre in south India. 50 patients with established Wilson's disease were recruited prospectively for this study. Their diagnosis was established on the basis of characteristic clinical manifestations, positive family history and the presence of Kayser–Fleischer (KF) rings, low serum copper and ceruloplasmin levels and increased 24 h urinary copper excretion.
A formal history, details of clinical manifestations, Schwab and England Activities of daily living (MSEADL) score (normal range: 0–100%), neurological symptom score (NSS) (normal range: 0–46) and Chu staging (normal range: 1–3) of all the patients were recorded [7–9]. Clinical and disability scores were correlated with MRI scores. All patients were clinically evaluated at the time of first and follow-up MRI study. The study had approval of the institute ethics committee.
MRI and analysis
MR images were obtained on a Siemens-magnetom MRI scanner with a super-conducting magnet of 1.5 T field strength after receiving informed consent from subjects. Spin echo (SE) T1 weighted (TR = 650 ms, TE = 14 ms) images in axial and sagittal planes were taken, with an acquisition time of 2.5 min, matrix of 256 x 256 and a 230 mm field of view (FOV). Axial and coronal images of T2 weighted images were acquired. Fluid attenuation and inversion recovery (FLAIR) sequences were obtained in the axial plane (TR = 9000 ms, TE = 119 ms). The slice thickness was 5 mm. T2 relaxometry and volumetric analyses were not carried out. MRI observations were interpreted by specialists blinded to clinical stage. The serial MRI observations were compared for individual patients as well as for the whole group.
MRI observations were recorded by both the neurologists (SS, LKP) and the neuroradiologists (SR, MKV). In case of disagreement, consensus was arrived at by discussion. The observations were made from the films that were adjusted for optimum visualization of images. The anatomic distribution of abnormalities was noted and severity was graded based on the change in signal intensity of focal lesions and associated atrophy: 0 = no abnormality, 1 = change in signal intensity with no atrophy, 2 = change in signal intensity with mild or moderate atrophy and 3 = change in signal intensity with severe atrophy [9]. The assessment of T2 weighted signal intensity changes were also performed subjectively. The degree of atrophy was quantified by measuring standardized dimensions of the brain and also subjectively based on the sulcal and ventricular enlargement. All the measurements were carried out using a measuring caliper. The minimum step between the measurements was 0.5 mm. Each diameter was measured three times, and corresponding means were used for calculations. The following structures were graded: caudate, putamen, internal capsule, thalamus, midbrain, pons, medulla, cerebellum, white matter and cortex. The grading system provided a score of 0–30, with zero being the normal scan and 30 indicating the most severe changes. In addition, imaging sets were also assessed subjectively for each patient as well as for the whole group. A specific note was made regarding the presence of a giant panda face, central pontine myelinolysis (CPM) and pallidial hypointensity.
Statistical analysis
Statistical analysis was carried out using SPSS v10. The clinical severity and disability status were scored and were correlated with MRI scores using Pearson's coefficient of correlation, and a p-value of <0.05 was considered significant. Differences between the two groups were analysed using Student's paired t-test.
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Results
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A total of 30 male and 20 female patients (n = 50) underwent serial MRI study at 9–52 month intervals. All patients were on de-coppering (penicillamine and zinc sulphate) therapy. The mean age at onset of illness was 12.8±5.6 years (range 6–32 years) and the mean age at diagnosis was 14.4±6.0 years (range 8–32 years). The mean duration of treatment of these 50 patients at first MRI was 49.0±77.3 months (range 0–360 months). Overall, a total of 92% patients (n = 46) had neurological involvement at onset (neurological, 38; hepatic and neurological, 8; hepatic, 3; osseomuscular and neurological, 1) and all of them had neurological manifestation at the time of the MRI study. The common manifestations were dysarthria and drooling (82%), gait abnormality (60%), dystonia (58%), bradykinesia and rigidity (50%), tremor (48%), ataxia (44%) and chorea (14%). Among 39 patients who were on de-coppering therapy, 23 had been treated for at least 1 year at the time of their first MRI.
Brain MRI was abnormal in all patients and was characterized by evidence of atrophy and/or signal changes of brain parenchyma at initial evaluation. Atrophy was often diffuse while signal changes were varied in distribution: focal or multifocal and symmetrical as well as asymmetrical. Atrophy was assessed visually and was best evaluated on T1 weighted multiplanar images. In six patients, cerebellar and brainstem atrophy was significant and disproportionate to cerebral atrophy. These patients had a "pseudosclerotic" presentation. The pathognomonic "giant panda face" sign and central pontine myelinosis were observed in four patients. The medulla was involved in eight patients. White-matter signal changes were diffuse and symmetrical in one patient and had a frontal preference in others. Cerebellar signal changes were evident in six cases, including the involvement of peduncles (Table 1
) (Figures 1–3).
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Figure 1. (a, b) FLAIR axial MR images performed in 1999 and 2002 showing improvement of signal changes noted in the putamen and lateral part of thalamus. (c, d) T1 weighted image axial MRI of brain in 1999 and 2002. It revealed improvement in diffuse cortical and subcortical atrophy as evident in repeat MRI after 4 years of de-coppering.
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Figure 2. (a,b) FLAIR axial sequence showing the "giant panda" pattern in 1999, which has improved after 3 years of de-coppering therapy. (c,d) FLAIR sequence MRI of brain in 1999 revealing central pontine myelinosis-like changes, which resolved substantially after 3 years of treatment.
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Figure 3. (a,b) T1 weighted image axial MRI of brain in 1998 showing brainstem and cerebellar atrophy. Further worsening of the brainstem and cerebellar atrophy was noted in the repeat MRI study in 2002. The cerebellum is replaced by cerebrospinal fluid in the figure. The patient suffered relentless progressive deterioration despite receiving the recommended treatment. (c,d) T2 weighted image axial MR image of brain showing an increase in putaminal signal changes while on regular treatment from 1999 to 2002.
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At follow-up, clinically 36 patients had improved, 9 remained the same and 5 had worsened. The changes between the two scans are shown in Table 1
. Repeat MRI was carried out after 24.2±12.2 months (median 24 months, range 8–48 months) and revealed an improvement in 35, no significant changes in 10 and worsening in 4 patients (Figures 1 and 2). One patient had an admixture of resolution of old lesions and the appearance of new lesions. There was complete resolution of MRI changes in 5 out of 35 patients, along with distinct and persistent clinical recovery (Figures 1 and 2). Among 14 patients whose MRI either did not change or worsened, 10 patients did not improve or worsened clinically, while on treatment and rest 4 improved partially (Figure 3). There was improvement in all the measures of disability and impairment: Chu stage (1.5±0.7 to 1.3±0.6; p = 0.136 paired t-test), MSEADL (79.7±27.6 to 88.0±25.4; p = 0.07 paired t-test), NSS (10.6±11.2 to 8.0±11.6; p = 0.155 paired t-test), but the changes were not statistically significant. The mean MRI score improved from 8.2±5.7 to 5.9±6.6 (p = 0.24 paired t-test). The initial and repeat Chu scores correlated significantly with those of the MRI scores using the Pearson correlation (initial, R = 0.64, p = 0.01; repeat, R = 0.83, p = <0.0001). Similarly there was significant correlation between the initial and repeat NSS and MRI scores (initial R = 0.61, p = 0.02; repeat R = 0.87, p = <0.0001). A correlation was also noted when the MSEADL scores were compared with MRI scores (initial R = –0.52, p = 0.04; repeat, R = –0.78, p = 0.001). Interestingly, there was even significant improvement in atrophy of brain at follow-up in 4 out of the 35 patients who had atrophy at initial imaging. These patients had high MRI scores (10.9±4.8) and extensive signal changes, diffuse white-matter abnormalities and severe diffuse cerebral atrophy. The initial and sequential MRI features are tabulated in Table 2.
11 patients were drug naïve at initial evaluation with MRI. Their mean age at onset of symptoms was 11.9±4.5 years (range 7–21 years); the mean duration of symptoms at evaluation was 19.1±16.9 months (range 6–60 months). Their presenting complaints included dysarthria (5), tremors (5), gait abnormalities (4), drooling (3), difficulty in writing (3), dystonia (1), behavioural disturbances (1) and musculoskeletal symptoms (1). Serial MRI was carried out at an interval of 24.6±13.3 months (range 9–48 months) while on de-coppering therapy. Their clinical status at the time of serial MRI was as follows: clinical improvement, 7; status quo, 1; and worsening, 3. Similarly, MRI scores were: improvement, 8; status quo, 1; and worsening, 2.
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Discussion
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The present study involved a large cohort of patients from a single centre with WD. The patients were heterogeneous in their demographic profile, clinical features and therapeutic status, similar to earlier published reports [1–4, 10–13]. In the present study, the interval between the first and the second MRI was 24.2±12.2 months (range 8–48 months). Improvements to a variable degree and extent were noted in the majority of patients, both in signal changes and atrophy. This is consistent with earlier reports [14–16]. Overall, an improvement in MRI observations was noted in 71%; however, the serial changes were highly varied: complete reversal to normal, variable change in signal intensities and marked worsening.
Polson et al [17] reported improvement in cerebral atrophy following hepatic transplantation. Interestingly, we also observed improvement in atrophy of the cerebral hemisphere in four patients and in the brainstem and cerebellum in one patient. There is no literature reporting such a significant improvement with chelating therapy.
Selwa et al [6] attributed the lack of emphasis of brainstem involvement in the earlier MRI studies to the lower resolution of scanners. Signal changes in the cerebellum and peduncles were evident in 6% of cases, and did not improve at follow-up. White-matter signal changes were seen in 15 patients and improved in only 3 patients. Cortical lesions were noted in six patients and improved in two. In our series, a deterioration was noted in 8% of patients, which included the appearance of new lesions, worsening and extension of signal intensities of previous lesions and associated atrophy.
Clinico-MRI correlation
In the present series MRI parameters correlated well with the clinical improvement. There was no significant improvement in Chu stage (p = 0.136), MSEADL (p = 0.078) and NSS (p = 0.155) in contrast to the overall MRI improvement (p = 0.004). In the severe neurological form of WD, in a subgroup analysis reported by us regarding the clinical and MRI pattern, 21 out of 29 patients with the severe neurological form of WD had undergone MRI and 14 had repeat MRI. The mean MRI score was 10.9±4.8. Repeat MRI was carried out in 14 patients at an interval of 2.1±1.1 years. The MRI features in this subgroup of 14 patients were similar to the whole group and there were no other clinically significant parameters. However, diffuse white-matter abnormalities were more extensive in patients who did not respond to therapy [18].
Saatci et al [2] carried out serial MRI in 12 out of 30 patients, depending upon changes in the patient's symptoms or at the patient's request. The interval between the MRIs was not specified. Among these 12 patients, 4 patients did not show any change in imaging at follow-up. 4 patients out of the 10 neurologically symptomatic individuals showed clinical as well as MRI improvement at follow-up. Two patients had the appearance of new lesions. They proposed that the "giant panda face" appearance may be related to the severity of the brainstem involvement and may appear during the course of the disease.
In another study by Roh et al [10] involving 25 neurologically symptomatic patients, serial imaging was obtained in 16 patients at an interval of 5–24 months. An improvement, both in clinical status and in MRI signal changes, was observed in 14 out of 16 patients. They also noted that thalamic or brainstem lesions disappeared/attenuated more rapidly and more extensively than those in the basal ganglia. Brain atrophy was evident in all these patients at initial MRI and did not show any improvement during serial MRI. There was good correlation between clinical course and follow-up MRI findings in 15 out of 16 patients.
Most patients with WD improve with adequate and regular de-coppering therapy. 24 h urinary excretion of copper has been used to monitor the treatment. MRI of the brain is helpful not only in the diagnosis of this treatable condition but also in the prognosis and perhaps in disease monitoring. The major limitation of this serial MRI study was the heterogeneous nature of the cohort, namely the duration and severity of the disease, and varied therapeutic status, among others. The inclusion of newer techniques such as MR spectroscopy, diffusion tensor and weighted imaging, magnetization transfer imaging in prospective serial studies involving drug naïve patients may improve our understanding.
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Conclusion
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MRI abnormalities were universal in symptomatic patients and affected almost all sites. The majority of the patients' clinical and MRI profile improved with treatment in this cohort of WD, one of the largest in the literature. Patients with extensive changes, white-matter involvement and severe diffuse atrophy did not fare well. Future well-designed studies in drug-naïve patients at defined intervals, especially with newer MRI techniques, may improve our understanding.
Received for publication June 14, 2006.
Revision received November 2, 2006.
Accepted for publication November 9, 2006.
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Abstract
Introduction
