J Neurol (2006) 253 : 10241029 DOI 10.

1007/s00415-006-0151-x

ORIGINAL CONTRIBUTION

K. Strecker J. P. Schneider H. Barthel W. Hermann F. Wegner A. Wagner J. Schwarz O. Sabri C. Zimmer

Profound midbrain atrophy in patients with Wilsons disease and neurological symptoms?

Received: 15 October 2005 Revised: 18 January 2006 Accepted: 24 January 2006 Published online: 10 April 2006

j Abstract Wilsons disease (WD)

J. P. Schneider C. Zimmer Department of Neuroradiology University of Leipzig Germany H. Barthel O. Sabri Department of Nuclear Medicine University of Leipzig Germany W. Hermann Department of Neurology Paracelsus Klinik Zwickau Germany C. Zimmer Department of Neuroradiology Technical University of Munich Germany K. Strecker (&) F. Wegner A. Wagner J. Schwarz W. Hermann Department of Neurology University of Leipzig Liebigstr.22a 04103 Liebigstr, Germany Tel.: +49-341/9724202 Fax: +49-341/9724239 E-Mail: KarlStrecker@gmx.de

is characterized by impaired hepatic copper secretion and subsequent copper accumulation in many organs predominantly liver and brain, secondary to loss of function mutations in the copper transport protein ATP7B. If the disease is recognized too late or treatment is not adequate, brain copper accumulation leads to progressive neurodegeneration with a variety of clinical symptoms. The nigrostriatal dopaminergic system seems rather vulnerable. Midbrain atrophy, however, has not been recognized as one of the prime features of patients with WD.Here we report quantication of midbrain diameter in 41 patients with WD. Data were correlated to the severity of neurological symptoms and the integrity of dopaminergic neurons measured via dopamine transporter binding. For control, we measured midbrain diameter in 18 patients with no evidence for brainstem dysfunction and 5 patients with progressive supranuclear palsy (PSP).Patients with WD had a reduced midbrain

diameter (15.5 0.4 mm) compared to controls (18.5 0.2 mm). WD patients without neurological symptoms had midbrain diameter that were not different from controls (18.0 0.3 mm), while patients with neurological symptoms showed midbrain atrophy similar to patients with PSP (14.4 0.3 mm versus 14.1 0.3). There was a strong and signicant correlation between midbrain atrophy and the severity of neurological symptoms (r= )0.68, p < 0.001) while midbrain atrophy and dopamine transporter binding correlated signicantly but was less pronounced (r=0.46, p < 0.001).In summary, we were able to show, that midbrain diameter is an easy to perform quantication of neurodegeneration induced by brain copper accumulation and that other structures than substantia nigra dopaminergic neurons seem to contribute to midbrain atrophy in WD.
j Key words Wilsons disease progressive supranuclear palsy midbrain atrophy MRI SPECT

JON 2151

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Introduction
WD is a rare autosomal recessive disease of copper metabolism. It was rst described by Samuel Alexander Kinnier Wilson in 1912 [35]. Mutations in patients with WD affect the copper transport protein ATP7B that maps to the short arm of chromosome 13 [27]. More than 200 mutations of the ATP7B gene on chromosome 13 have been identied with the His1069Gln mutation being the most predominant in North America and Europe [6]. The genetic defects result in lowered plasma levels of ceruloplasmin and elevated levels of free copper. Since effective treatment with copper chelating agents or zinc has become available, WD is a genetically dened but effectively treatable copper deposition disorder. The disorder causes damage in several organs, predominantly liver and brain [5]. Cerebral copper deposition mostly localizes to the basal ganglia, namely striatum and globus pallidus often inducing rigidity, tremor, dyskinesia, and dysarthria [5]. Several studies have highlighted the prevalence of signal changes on MRI that occur in patients with WD [9, 21, 23]. These abnormalities are most pronounced within the basal ganglia but may also extend to white matter, cerebellum or cortical areas [9, 26, 31]. Besides hyperintense and hypointense signal changes that may indicate copper accumulation and/or reactive gliosis, atrophy of white matter and cortical areas is another frequent nding [9, 19, 26]. Midbrain abnormalities have not been addressed in detail. Hyperintense signal changes in midbrain sparing the red nucleus, the face of the giant panda sign, have been described in a small group of Japanese patients [11]. Midbrain atrophy is recognized as one of the key neuroradiological features of PSP [2, 14, 20]. The sensitivity and specicity of this nding to distinguish PSP from Parkinsons disease is controversial [20, 33]. Whether midbrain atrophy is a prominent nding in other neurodegenerative disorders such as Wilsons disease has not been studied. The nigrostriatal dopaminergic system has been a focus of functional imaging in WD. The reasons for this interest are the high prevalence of Parkinsonism, dystonia and/or chorea in patients with neurological symptoms which are likely to result from basal ganglia dysfunction. Initial studies using ligands for striatal dopamine D2 receptors revealed a massive reduction of ligand binding that also correlated with the severity of clinical symptoms [18, 23]. Surprisingly, these decits in dopamine D2 receptor binding were partially reversible following adequate therapy [21]. In addition, dopamine transporter binding is also reduced in WD patients

indicating a decit of midbrain dopaminergic neurons that corresponds to the loss of dopamine D2 receptor binding [3]. The aim of our study was to evaluate midbrain atrophy in a large number of patients with WD and to compare these data with controls without evidence for brainstem disease and patients with progressive supranuclear palsy.

Patients and methods

We investigated MRI scans of 41 patients with WD. Patients have been described in detail [3, 9, 10]. The mean age of patients was 38 years and ranged from 22 to 55 years. The mean duration of disease prior to imaging was 17.5 years (ranged 0.1 to 36). At the time of imaging, 14 patients had no neurological decits (including 5 asymptomatic patients and 9 patients with hepatic manifestation of Wilsons disease) while 27 patients had neurologial decits. At the time of imaging, there was no difference with respect to age between patients with (mean 40 years, range 2255 ) and patients without (mean 36 years, range 2852) neurological symptoms (p = 0.12 in Mann Whitney Test). Also, the duration of disease did not differ signicantly between the two patient groups (p = 0.93 in Mann-Whitney Test). Patients with neurological decits had a mean disease duration of 18.0 years; patients without neurological decits had a mean disease duration of 17.4 years. The severity of neurological decits was assessed using an established semiquantitative scale: 0 (no decits), 1 (only dysarthrophonia), 2 (mild decits) , 3 (moderate decits), 4 (severe decits) and 5 (very severe decits) [8]. Diagnosis of our patients was conrmed by the following criteria (i) history (ii) physical examination (iii) serum ceruloplasmin and copper levels (iV) 24 h urinary copper excretion (v) liver biopsy (if needed) (vi) Kayser-Fleischer ring on slit lamp examination and additional (vii) genetic analysis and (viii) i.v. radio copper testing. 14 patients out of 41 had a homozygous His1069Gln mutation, while the others were compound heterozygous carrier of this mutation or had other mutations in both alleles of the gene. All patients were on treatment when imaging was undertaken (6 patients: triene , 11 patients: zinc, 24 patients: penicillamine). For controls, we recruited 18 patients who suffered from hemispheric stroke (6 patients), from transient ischemic attacks (5 patients), seizure (3 patients), psychogenic blindness (1 patient), headache (1 patient), melanoma of the head (1 patient) and Pancoast tumor (1 patient). None of these patients had any evidence for brainstem pathology. The mean age of this control group was 41.2 years, (range 2759) . Thus, it was not different from patients with WD (Mann Whitney: p = 0.16). It is well established that midbrain atrophy is a cardinal feature of PSP [2, 33]. Therefore, we also included 5 patients with this disorder in our analysis (negative controls). PSP patients were older than WD patients (mean age: 65.8 years, range 5581). The mean duration of disease was 6.8 years. All patients with WD received MRI and dopamine transporter imaging within 12 months. Routine MRI including axial T1 and T2 weighted images (sagittal images were missing in some WD patients) were performed using a 1.5 Tesla MR Scanner (Symphony Siemens, Erlangen, Germany). Midbrain diameter were measured on axial T2 turbospinecho weighted MR images (TR 4000 ms, TE 99 ms, thickness 5 mm) using the scanners internal distance measurement device following an established protocol l [33] but with slightly different angulation (parallel to a line including the nasion

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and the pontomedullary junction, comparable to the orbitomeatal line on CT), the measurement was carried out at the basal slice of the midbrain (see gure 1). The reader was aware of the patients diagnosis (WD) but had no knowledge about possible neurological decits. To determine a cut off with optimal sensitivity and specicity to distinguish WD patients with from those without neurological decits in resepect to midbrain diameter, we also performed a receiver operated characteristics (ROC) analysis using the rockit software [17]. SPECT imaging was performed using a brain-dedicated Ceraspect camera (DSI, Waltham, MA). Patients were imaged 24 hours after intravenous administration of 185200 MBq [123I]CIT. The SPECT acquisition and imaging processing has been described in detail elsewhere [3]. Specic striatal binding ratios of 123 I-CIT were calculated using the region of interest technique where the cerebellum served as reference region for non-specic tracer uptake, and by applying the equation (count densitystriatum count densitycerebellum) / (count densitycerebellum). For correlation with midbrain diameter, we calculated the arithmetical mean of specic binding in left and right striatum uptake.

Results
Midbrain diameter in our control group without evidence for brainstem pathology was measured as 18.5 0.2 (mean SEM, minimum 16.9 mm, maximum 20.6 mm). These data correspond to previously published midbrain diameter in healthy controls [33] ( tiliting slightly different). Midbrain diameter in all patients with WD was 15.5 0.4 mm (mean SEM, minimum 11.2 mm, maximum 20.3 mm). This reduction was highly signicant compared with controls (p < 0.00001, Mann Whitney Test). In WD patients with neurological decits, the midbrain diameter was (14.4 0.3 mm, mean SEM, minimum 11.2 mm, maximum 17.3 mm). In patients without decits (asymptomatic patients and patients with hepatic manifestation) midbrain diameter was (18.0 0.3 mm, mean SEM, minimum 16.7 mm, maximum 20.3 mm). Patients with neurological decits showed a highly signicant reduction in midbrain diameter

compared with patients without neurological decits (p < 0.00001, Mann Whitney Test) (Fig. 2, 3). With the rockit software 16.75 mm as the best cutoff of midbrain diameter was found to divide WD patients with and without neurologic decits. With this cut-off sensitivity was 89% and specity 90 %. However there was no difference between controls and WD patients without neurological symptoms. The mean midbrain diameter in patients with PSP, a condition with known midbrain atrophy was measured as 14.1 0.3 (mean SEM, range 12.8 to 14.9 mm). The midbrain diameter in patients with PSP was signicantly different from controls (p < 0.00001, MannWhitney) but did not differ from neurologically symptomatic WD patients (p = 0.74, MannWhitney) (Fig. 2). Thus, midbrain diameter of patients with WD and neurological decits were similar to those of PSP patients, while patients without decits did not differ from controls. Midbrain diameter of all WD patients modestly correlated (Spearman correlation coefcient r = )0.68, p < 0.001 ) with the severity of the neurological decits. Subgroup analyses did not reveal signicant results (Spearman correlation coefcient: r = )0.11, p=0.27 for WD patients with neurological

Fig. 1 Basal slice of the midbrain (B) for measurement of the anteroposterior diameter, the slice is parallel to the line between nasion and pontomedullary junction (A)

Fig. 2 axial T2 w scans (TSE) with demonstration of midbrain anteroposterior diameters A: WD with neurological deficit; B: WD without neurological deficit; C: PSP; D: controll patient

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midbrain diameter (mm, mean, SEM)

20,0 19,0
DAT-binding (str/cer)

19,0 17,0 15,0 13,0 11,0 9,0 7,0 5,0 10,0

18,0 17,0 16,0 15,0 14,0 13,0 12,0

control patients WD - neurological WD + neurological symptoms symptoms PSP

12,0

14,0

16,0

18,0

20,0

22,0

midbrain diameter (mm)

Fig. 3 Midbrain diameter in patients without brainstem pathology, patients with Wilsons disease and patients with PSP. Note that there is a significant reduction of midbrain diameter in patients with WD and neurological symptoms and PSP, both compared to control patients and WD patients without neurological symptoms

Fig. 4 Correlation of midbrain diameter (MD) with dopamine transporter binding (DAT-binding) in all patients with WD. Note the limited linear correlation (r = 0.48)

decits). In addition, midbrain diameter did not correlate with duration of disease in either sub group of WD patients (r = 0.002 for neurological WDpatients, r = )0.002 for WD patients without neurological decits). Midbrain dopaminergic neurons are also affected in patients with Wilsons disease. Therefore, we wanted to investigate whether the integrity of these neurons as estimated via dopamine transporter binding to striatal terminals of these neurons correlated with midbrain atrophy. We hypothesized that the loss of dopamine transporter binding as a function of midbrain dopaminergic neurons would parallel midbrain atrophy. Our patients showed specic striatal [123I]-CIT binding of 10.9 0.5 (mean SEM),. These data have already been included in previous reports that showed that striatal dopamine transporters are reduced in patients with neurological WD, as compared with healthy controls and/ or non neurological WD patients [3, 4]. In the latter reports, there was also a signicant correlation between the severity of neurological decits with the reduction of striatal dopamine transporter binding, which was again conrmed in this subgroup of patients (Spearman correlation coefcient r = )0.6, p < 0.001). Surprisingly, the correlation of midbrain diameter with striatal dopamine transporter binding was only loose for the total group of patients (Spearman correlation coefcient r = 0.46, p < 0.001)(Fig. 4). We were not able to detect any signicant correlations of midbrain diameter with striatal dopamine transporter binding when patients with or without neurological symptoms were examined separately (with neurological symptoms: Spearman correlation coefcient: r = 0.18, p = 0.18; without neurological symptoms: 0.04, p = 0.44). We also compared the midbrain diameter of 18 patients with homozygeous His1069Gln mutation

with midbrain diameter of patients who where only compound heterozygous for this mutation or had other mutations. No signicant differences were observed (Mann Whitney: p = 0.6 in WD-patients without neurological decits, p = 0.3 in WD-patients with decits).

Discussion
In this study, we wanted to determine whether midbrain atrophy is another characteristic feature of copper induced brain damage in WD patients. We included 41 patients with WD and stable therapy. As negative controls, we studied 18 patients without evidence for brainstem disease. As positive controls, we included 5 patients with PSP. Our data show that only patients without neurological symptoms and also normal MRI scans, had midbrain diameter that matched those of control patients and normal values reported previously [33] despite little difference in tilting angle. Patients with neurological manifestation of the disease clearly had abnormal midbrain diameter which were as dramatically reduced as in patients with PSP. In PSP, midbrain atrophy is recognized as a characteristic diagnostic radiological feature [2, 33]. The special conguration of the atrophic midbrain with relatively preserved cerebral peduncles has led to refer to these changes as Mickey mouse sign. In PSP, there are additional specic atrophic changes of the midbrain, such as the morning glory sign, which is a concavity of the lateral margin of the tegmentum of the midbrain [1] indicating that midbrain atrophy is really important for establishing this diagnosis based on MRI images. However, little is known about the specicity of such changes. Midbrain atrophy may be helpful to differentiate PSP from related disorders such as Parkinsons disease or multiple system atrophy [1, 20]. Our patients with

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WD clearly show that midbrain atrophy can occur in other degenerative diseases with more widespread pathology. The degree of midbrain atrophy in WD patients is striking since these patients were younger than PSP patients. Patients with Wilsons disease, who are neurologically symptomatic, show a wide variety of MR abnormalities. Signal changes on T2 and or T1 weighted images in the basal ganglia, pons, thalamic nuclei, cerebellum and the cortex occur [9, 19, 21, 32]. Also atrophy of cortex or white matter changes has been described [9, 19]. Biochemical changes detected by MR spectroscopy, however, are not markedly altered [15]. While signal changes may resolve following initiation of copper chelating therapy [7, 21], atrophy is more likely to represent irreversible pathology. Ligand binding studies of dopamine receptors can also parallel the improvement of neurological symptoms under therapy [21]. Although similar data have not been reported using dopamine transporter binding, it is speculated that the strong correlation of severity of neurological symptoms and reductions of dopamine transporter binding in WD patients [4] reect the potential of this procedure to monitor functional and at least partly reversible consequences of copper toxicity. Accordingly, midbrain atrophy in contrast to dopamine transporter binding did not correlate well to the severity of neurological symptoms in the present study. There are many different mutations affecting the ATP7B gene causing autosomal recessive WD [16]. Although the H1069Gln mutation is the most common in Western Europe by far, genotype-phenotype correlations have remained difcult owing to these multiple mutations [24, 28]. Accordingly, we were not able to detect differences in midbrain diameter between patients carrying homozygous H1069Gln mutations and patients with another genotype. On the other hand, individual studies were able to demon-

strate that patients with homozygous H1069Gln mutations have[24, 28] a later onset and more often a primary neurological manifestation of the disease but no difference in prognosis or severity of neurologic sequelae [6]. In agreement with that study, midbrain atrophy representing probable irreversible brain damage was not different. It was somewhat unexpected that midbrain atrophy as measured by midbrain diameter did not correlate well with dopamine transporter binding. The susceptibility of the nigrostriatal dopaminergic system is well described using several imaging modalities [4, 12, 13, 18, 21, 23, 25, 30, 34]. Thus, one would assume that midbrain dopaminergic neurons are specically affected in this disorder. However, there seem to be other structures in midbrain outside substantia nigra that are affected in this disorder and that may account for the lack of correlation reported here. It would be interesting to perform similar correlations in patients with PSP. Unfortunately, the number of PSP patients studied here is limited and not informative whether there is also a lack of correlation of dopamine transporter binding in this disorder. On the other hand, patients with Parkinsons disease usually have normal midbrain diameter [33] despite severe loss of dopaminergic neurons and dopamine transporter binding [22, 29]. Thus, the degeneration of dopaminergic neurons can occur independent of midbrain atrophy. However, this does not explain, why the degree of dopaminergic degeneration does not correspond to the severity of midbrain atrophy despite functional decits of these cells. In summary, there is marked midbrain atrophy in patients with WD and neurological symptoms irrespective of their severity. Thus, midbrain atrophy most likely represents an early and irreversible alteration due to copper induced neurodegeneration.

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