Jpn J Radiol (2010) 28:663–671 DOI 10.1007/s11604-010-0491-4
ORIGINAL ARTICLE
Structural and neurochemical evaluation of the brain and pons in patients with Wilson’s disease Oktay Algin · Ozlem Taskapilioglu Bahattin Hakyemez · Gokhan Ocakoglu Sukran Yurtogullari · Sevda Erer · Mufit Parlak
Received: May 19, 2010 / Accepted: July 11, 2010 © Japan Radiological Society 2010
Abstract Purpose. The aim of this study was to examine the structural-neurochemical abnormalities of the frontal white matter (FWM), deep gray matter nuclei, and pons in patients with Wilson’s disease (WD) using proton magnetic resonance spectroscopy (MRS) and diffusionweighted imaging (DWI). Materials and methods. Nine patients with WD and 14 age-matched controls were examined with MRS. N-Acetylaspartate (NAA), choline (Cho), and creatine (Cr) peaks were calculated. DWI scans from six WD patients and six controls were also obtained. The relative metabolite ratios and apparent diffusion coefficient (ADC) values of the WD patients were compared to those of the control subjects by using statistical measures. Results. Measurements in the thalamus and pons showed significantly lower NAA/Cho and NAA/Cr ratios in the
O. Algin (*) Department of Radiology, Atatürk Training and Research Hospital, Ankara, Turkey Tel. +90-22429553374; Fax +90-2244428142 e-mail:
[email protected] O. Algin National Magnetic Resonance Research Center, Ankara, Turkey O. Taskapilioglu · S. Yurtogullari · S. Erer Department of Neurology, Uludag University Medical Faculty, Gorukle, Bursa, Turkey B. Hakyemez · M. Parlak Department of Radiology, Uludag University Medical Faculty, Gorukle, Bursa, Turkey G. Ocakoglu Department of Biostatistics, Uludag University Medical Faculty, Gorukle, Bursa, Turkey
WD group than in the control group (P < 0.05). Thalamic and pontine Cho/Cr ratios in the patient group were significantly higher than those of the control group (P < 0.05). No statistically significant relation was found between the patient and control groups as a result of the MRS examinations of FWM and all ADC measurements (P > 0.05). Conclusion. MRS is a noninvasive, valuable modality for detecting structural-neurochemical changes of the brain stem and deep gray matter in patients with WD. The contribution of DWI in these patients is limited. Key words Wilson’s disease · Proton MR spectroscopy · Neuroimaging · Diffusion magnetic resonance imaging · Neuronal loss
Introduction Wilson’s disease (WD) is an autosomal recessive disorder with deficient biliary copper excretion, leading to excessive copper deposition in many tissues, particularly the liver, cornea, and brain.1–3 Evidence of severe mitochondrial dysfunction in the livers of WD patients has been reported, suggesting that both free-radical formation and the ensuing oxidative damage, probably mediated by mitochondrial copper accumulation, play a role in the etiopathogenesis of WD.1,2 However, the exact etiopathogenesis of the neurological dysfunction in WD is not yet clear.4 Some authors have speculated that hepatic impairment could impact cerebral pathogenesis.1,2 Cerebral white matter, deep gray matter nuclei, and brain stem involvement are frequently described in imaging studies of WD.5–8 With the advent of magnetic resonance (MR) technology, various techniques such as magnetization transfer, diffusion-weighted imaging (DWI), MR spectroscopy
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(MRS), and T2 relaxometry have been used to characterize structural features of the brain tissue in various pathological situations.9–11 DWI and MRS have provided a quantitative, objective means of evaluating the abnormal tissue components. Proton MRS is a noninvasive technique that demonstrates some of the metabolites in brain tissue.9,10 MRS has been used with very high sensitivity to detect the structural abnormalities in the basal ganglia of WD patients with neurological involvement.1–3 MRS can aid analysis of the severity of neuronal injury and the effect of chelation before and after the treatment.12 Studies on spectroscopic metabolite changes in the basal ganglia of WD patients have been conducted, but there have been few studies assessing the neurochemicalstructural changes in the cerebral white matter and pons.13,14 There are also few DWI studies in WD patients.15,16 The purpose of our study was to examine the structural-neurochemical abnormalities of the cerebral white matter, deep gray matter nuclei, and brain stem in WD patients using MRS and DWI.
Material and methods
findings. All patients were under treatment with d-penicillamine and zinc. Three patients were additionally taking vitamins. Two patients (nos. 1 and 7) had liver cirrhosis. The mean values of the blood copper (normal 11–24 mmol/ml), blood ceruloplasmin (normal 20–60 mg/dl), and urinary copper (normal 3–35 mmol/ml) in the WD patients were 4.2 mmol/ml (1–8 mmol/ml), 0.0114 mg/dl (0.019–0.27 mg/dl), and 1236 mmol/ml (217–3848 mmol/ml), respectively. MRS examinations of the pons, frontal white matter (FWM), and basal ganglia were done in all patients. Six of the patients were also assessed by DWI. The control subjects consisted of 14 age-matched individuals (4 women, 10 men) who were admitted to the hospital with the complaint of headache and who had a normal neurological examination and normal cranial MRI. The control subjects, with a mean age of 33 years (27–44 years), had no other pathological findings or any additional illnesses. MRS examinations of the FWM and the thalami were carried out in all 14 control subjects. Pontine MRS and DWI were done in only six cases. Informed consent was obtained from all participants, and the university ethics committee approved the study protocol.
Subjects
MRI and analysis
Between April 2007 and May 2010, nine (three women, six men) WD patients with a mean age of 29 years (19–45 years) with a mean of 7.6 year disease duration (range 2–18 years) were evaluated (Table 1). They all had neurological involvement of WD based on their clinical examinations and laboratory and imaging findings.4,17 Their clinical status, neurological examinations, and physical disability were assessed by an experienced neurologist blind to the magnetic resonance imaging (MRI)
All MRI examinations were performed in a 1.5-T MRI device (Magnetom Vision Plus; Siemens, Erlangen, Germany) with a standard head coil according to the following MRI protocol: three-plane T2-weighted (T2W) fast spin-echo (FSE) (TR/TE 5400/99), axial fluid attenuated inversion recovery (FLAIR) (TR/TE/TI 8400/114/2150), and axial T1-weighted (T1W) spin echo (SE) sequences (TR/TE 550/18). Other parameters were as follows: field of view (FOV) 24 cm, 256 × 256 matrix,
Table 1. Demographic and clinical data from nine Wilson’s disease patients Patient/sex
Age (years)
Disease duration (years)
1/M 2/M
21 20
6 4
3/F
32
3
4/M 5/M 6/F
30 19 27
4 5 17
1 Brother exitus Unremarkable Unremarkable
7/F 8/M 9/M
28 45 35
9 18 2
Unremarkable Unremarkable Unremarkable
KF, Kayser-Fleischer ring
Family history
Symptoms
Neurological examination
KF
Unremarkable 1 Brother with Down syndrome 1 Brother exitus
Motor imbalance, tremor Difficulty during walking
Dysarthria, ataxia Rigidity, dysarthria, dystonia
− -
Loss of coordination, dysphagia Tremor Speech difficulty Difficulty during walking, tremor Tremor, speech difficulty Tremor Dysphagia
Dysarthria, ataxia
+
Tetraparesis, ataxia Normal Tetraparesis, spasticity
+ +
Cerebellar instability, ataxia Dysmetria, dysarthria Normal
+ +
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Fig. 1. Representative coronal (A, D, G), sagittal (B, E, H), and axial (C, F, I) T2-weighted magnetic resonance spectroscopy (MRS) images from a patient with Wilson’s disease (WD). Black rectangles indicate the volume of interest (VOI) for MRS. To achieve a reproducible position, the VOIs were placed in the same regions in all patients and controls
5 mm slices thickness, 1 mm slice gap; two excitations were obtained. Following those sequences MRS using a point-resolved spectroscopy (PRESS) sequence was performed by placing an 8 cm3 volume of interest (VOI) in the bilateral thalamus–FWM and pons [TE/TR 135/2000, number of excitations (NEX) 136] (Fig. 1). DWI scans were obtained with a single-shot, SE echo-planar imaging sequence (TR 6000, TE 139, NEX 1, matrix 96 × 200, FOV 240 mm, slice thickness 5 mm, slice gap 0 mm) in the axial plane. This sequence is labeled “b0-b500-b1000ADC” by the manufacturer. The total examination duration for the routine cranial MRI, DWI, and MRS was approximately 25 min. Following the acquisition of all images, the MRS findings and the routine MRI findings were evaluated by
an experienced neuroradiologist blinded to the clinical and laboratory data at the workstation of our MR unit. Resonances of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were calculated. Apparent diffusion coefficient (ADC) values for the bilateral putamens, thalami, and FWMs were obtained from the automatically generated ADC maps with region of interest (ROI) evaluations. All the statistical analysis was performed using Statistical Package for Social Sciences 13 program for Windows (SPSS, Chicago, IL, USA). Continuous variables were expressed as the mean ± standard error of mean; and two group comparisons were performed using the Mann–Whitney U-test. For all the results, statistically significance was set at P < 0.05.
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Fig. 2. Axial fluid-attenuated inversion recovery (FLAIR) images of a WD patient. Hyperintensities are seen in the thalami (A), cerebral peduncles (B), and pons
Fig. 3. Axial diffusionweighted (B1000 s/mm2) (A, C) and apparent diffusion coefficient (ADC) map images. ADC measurements were performed bilaterally in the frontal white matter (B) and thalamus (D). The mean thalamic ADC value was 0.79 mm2/s; and the mean frontal white matter ADC value was 0.106 mm2/s
Results There were hyperintensities in the basal ganglia (putamina, caudate nuclei, and/or thalami), the dentate nuclei, and the pons of five, one, and three patients, respectively (Fig. 2). Two of the patients also had cerebral atrophy. There were no other pathologies in the routine cranial
MRI scans of the patients. All the control subjects had normal routine cranial MRI scans. The mean ADC values from the putamina, thalami, and FWM from the WD patients/control subjects were 0.77 ± 1/0.81 ± 1.5 mm2/s, 0.81 ± 2/0.84 ± 1.6 mm2/s and 92 ± 3/0.96 ± 6 mm2/s, respectively (Fig. 3). There was no statistical significance between the ADC values of the
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Fig. 4. Thalamic MRS findings of WD patients and control subjects. WD, Wilson’s disease, NAA, N-acetylaspartate; Cho, choline; Cr, creatine; *, statistically significant
Fig. 6. Frontal white matter (FWM) MRS findings of patients with WD and controls
Table 2. Thalamic MR spectroscopic metabolite ratios of WD patients and controls Parameter
Fig. 5. Pontine MRS metabolite ratios of patients with WD and controls. *, statistically significant
patients and control subjects (P > 0.05). There were hyperintensities at the level of the basal ganglia in B1000 images and hypointensities in the ADC map images (cytotoxic edema) of two patients. There was no lactate concentration abnormality in the MRS imaging of the control subjects or the patients. The NAA/Cho and NAA/Cr ratios in the pons, thalami, and the FWM were lower in the WD patients than in the control subjects, whereas the Cho/Cr ratios of the WD patients were higher than those of the control subjects (Figs. 4–6). All the ratios obtained from the pons and thalami of the WD patients were statistically significantly different from those in the control subjects (P < 0.05) (Tables 2, 3; Fig. 7). However, there was no statistical significance between the relative spectroscopic metabolite ratios obtained from the FWM of the WD patients and the control subjects (P > 0.05) (Table 4).
Discussion An autosomal recessive disorder with an incidence of 1/30 000, WD is characterized by degenerative changes
Patients Mean Standard error Median Controls Mean Standard error Median
NAA/Cho
NAA/Cr
Cho/Cr
1.54 0.11 1.52
1.58 0.07 1.61
1.06 0.06 1.06
2.27 0.14 2.33 P = 0.001*
1.87 0.06 1.91 P = 0.01*
0.82 0.04 0.85 P = 0.004*
MR, magnetic resonance; WD, Wilson’s disease; NAA, acetylaspartate; Cho, choline, Cr, creatine * Statistically significant
Table 3. Pontine MR spectroscopic metabolite ratios of patients with WD and controls Parameter Patients Mean Standard error Median Controls Mean Standard error Median P value (α = 0.05)
NAA/Cho
NAA/Cr
Cho/Cr
1.02 0.14 1.18
1.94 0.22 2.14
1.83 0.19 1.77
2.02 0.29 2.1 0.01*
2.51 0.29 2.76 0.04*
1.3 0.14 1.1 0.04*
in the liver and brain due to a copper metabolism disorder resulting from various mutations in the long arm of chromosome 13.18–20 The presence of many mutations unfortunately makes genetic testing impractical in the diagnosis of WD.21–23 Accumulation of copper in the
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Fig. 7. Proton MRS images of two WD patients (A–C) and a control subject (D). Locations of N-acetylaspartate (NAA), choline, and creatine peaks are shown (A). NAA/Cho, NAA/Cr, and Cho/Cr ratios from the frontal white matter of a WD patient were 1.5, 1.96, and 1.31, respectively (B). The NAA/Cho and NAA/Cr ratios from the thalami of a WD patient (1.27 and 1.72, respectively) decreased compared to those of the control subject (2.26 and 1.91, respectively). Moreover, the thalamic Cho/ Cr ratio (1.35) of the WD patient was higher than that in the control subject (0.84) (C, D)
Table 4. Frontal white matter (FWM) MR spectroscopic findings of patients with WD and controls Parameter Patients Mean Standard error Median Controls Mean Standard error Median P value (α = 0.05)
NAA/Cho
NAA/Cr
Cho/Cr
1.79 0.16 1.6
1.87 0.12 1.84
1.08 0.06 1.08
2.17 0.21 2.03 0.01*
2.19 0.12 2.1 >0.05
0.95 0.07 1 >0.05
hepatocytes results in cirrhosis.15 Neurological involvement of WD cases without the presence of KayserFleischer rings or hepatic dysfunction has been reported in the literature.8,17,24,25 When hepatic binding sites are saturated, copper is released, and neurological involvement develops.15,17 The differential diagnosis of WD must be included in young
patients with extrapyramidal and cerebellar symptoms. Tremor, found in 50% of cases, is the most common neurological finding.24–27 The other common neurological disturbances are hypokinesia, dystonia, dysarthria, gait apraxia, and further cerebellar-extrapyramidal disturbances.4,27 There is no single reliable, noninvasive diagnostic test for WD.21 Diagnosis relies mostly on the clinical, laboratory, and radiological findings.6,13 The aims of treatment are to decrease intestinal absorption of copper and increase transport of copper from the tissues to the urine. D-penicillamine and zinc are used for these purposes.17 Copper accumulation in the brain, especially in the basal ganglia, leads to neuronal loss.5–8 The main pathological findings of WD in the basal nuclei are capillary endothelial swelling, gliosis, demyelination, spongy degeneration, and neuronal loss. The corresponding main MRI findings in WD are bilateral, symmetrical hyperintensities on T2W and FLAIR images of the deep gray matter and pons.15–17 In this study, hyperintensities on FLAIR and T2W images of the basal ganglia and
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pons were found in five (56%) and three (34%) patients, respectively. There are still speculations about the pathological meaning of these signal abnormalities observed at different levels of this disease on cranial MRI. Possibly, oxidative stress and other pathological damages account for the cell death and gliosis that underlie brain atrophy in WD.15,17 Proton MRS, a noninvasive technique that demonstrates some of the metabolites in brain tissue, is commonly used for differentiating a variety of brain lesions.9,10 There are a limited number of studies in the literature evaluating the role of MRS in WD patients.4,12–15 NAA, a metabolite mainly found in neurons, is accepted as the neuronal marker.4,9,10 The decrease in NAA levels indicates neuronal injury and loss because regeneration capacity of the neurons is limited.3,13 On the other hand, increased Cho/Cr ratios may be the result of gliosis and changes in membrane metabolism.10 Various MRS studies have demonstrated neuronal injury in the basal ganglia of WD patients.1,2,13 In our study, in accordance with other studies in the literature, there were decreases in the NAA/Cr and NAA/Cho ratios and the NAA concentration in the thalami of WD patients, whereas there was only a minimal increase in the Cho/Cr ratios.3,12,28–30 The reasons of these changes may be the neuronal injury secondary to the aforementioned pathologies. We placed VOIs on the thalamus to evaluate the basal ganglia with MRS. Because thalami are wider and more uniform than the other basal nuclei, we took great care to avoid overflow of the VOI from the deep gray matter to the surrounding structures. The pons has been commonly reported to be affected in WD patients.3,6,8 A solitary pontine lesion can be regarded as central pontine myelinolysis (CPM) rather than a neurological involvement in WD.14 MRS findings of CPM in case reports have been reported; but to the best of our knowledge, there has been no original investigation about the metabolite changes in the pons of WD patients with neurological involvement.14 In our study, the NAA/Cr and NAA/Cho ratios at the level of pons were lower and the Cho/Cr ratios were higher in the WD patients than in the control subjects. These findings point to neuronal injury, membrane rupture, increased cellular turnover, and neuronal loss secondary to neurodegeneration at the level of the pons in WD patients. van Wassenaer-van Hall et al. showed that abnormalities of the white matter on the cranial MR images are common findings in WD.5 Lucato et al. reported significantly lower NAA/Cr ratios in the FWM of WD patients compared to control subjects.13 We found no statistically significant difference in terms of the metabolite ratios measured from the FWM of WD patients and control subjects. The explanation of this finding may be
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the late and/or less involvement of the deep white matter compared to that of the pons and basal ganglia. The structural changes in the brain of WD patients are regarded as preventable and/or reversible with the drugs now used to treat the disease, making MRS a useful tool for assessing treatment effectiveness.4,15,17 The metabolite ratios obtained not only from the deep gray matter but also from the pons may give additional useful data in the assessment of treatment response with MRS. Because we did not have pretreatment MRS data of the WD patients involved in the study, we could not investigate the role of MRS in the treatment response. Diffusion-weighted imaging can evaluate the cerebral injury because it is a measure that increases with tissue injury, such as damage to myelin and axons.11,31 It measures the microscopic random translational motion of water molecules and so can assess the free water content of the cerebral tissue. It has been used in the differential diagnosis of various pathologies, including ischemia, infection, demyelinating plaques, and tumor.15,32 Diffusion of the water molecules is affected by the microstructures and the microdynamic process; thus, ADC can be measured quantitatively.31 DWI has identified, in several brain conditions, tissue changes that are not visible on routine cranial MRI. It has been suggested as a useful tool for evaluating the nature and extent of the structural injury in WD patients.15 ADC values from the basal ganglia in four of the six patients in our study were within normal limits. The other two patients’ ADC values decreased, a finding consistent with cytotoxic edema with restricted diffusion of water molecules, corresponding possibly to cellular damage caused by accumulation of copper and early-phase ischemia.15,16 Restricted diffusion may be seen during the early phases of neurological involvement of WD patients. In the chronic phases, necrosis and spongiform degeneration are common in these parts of the brain, and the diffusion of water molecules returns to normal.33 In our study, there were no significant differences between the patients and controls regarding the ADC measurements performed at the level of the basal ganglia of the brain. The explanation may be either an inadequate number of patients in our study or the long duration of neurological involvement in most of these patients. The ADC values at the level of the FWM level of the WD patients are normal. This may be the result of minimal white matter injury in the WD patients with neurological involvement or inadequate detection of such changes in these regions with DWI-MRS. Our study has some limitations. First, the metabolite ratios were obtained with a single voxel technique. New studies evaluating the brain globally in the light of the WD etiology are needed. Another limitation is the rela-
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tively long TE value (rather than TE 30–35), which precluded the possibility of observing such metabolic values as those for myoinositol and lipids.30 The last limitation is the absence of a comparison of pretreatment and posttreatment MRS and DWI examinations in the same WD patients. The reversibility of the biochemical-structural changes that have been found in this study should be investigated with new and more extensive studies.
Conclusion There is neuronal injury and loss in the basal ganglia and pons of WD patients due to several causes mentioned in the literature. We found the same results in our study but could not show any prominent white matter injury. MRS is a noninvasive method that can be used to assess the structural changes and neuronal injury in the brain and brain stem. DWI may be used in WD patients with acute neurological symptoms to determine the presence of cytotoxic edema. Both MRS and DWI may be useful in the follow-up of the disease progression as well as for determining the response to treatment. We need extensive new studies to find further answers to our questions. We declare that we have no conflict of interest. Acknowledgment. We thank Dr. Aylin Bican from neurology department for her work during search for the patients’ data.
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