revue neurologique 169 (2013) 944–949

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Original article

Cognitive profile in Wilson’s disease:

A case series of 31 patients
Profil cognitif dans la maladie de Wilson :
une série de 31 patients

É. Wenisch a,*, A. De Tassigny b, J.-M. Trocello a, J. Beretti a,

N. Girardot-Tinant a, F. Woimant a
a
French national reference centre for Wilson’s disease, neurology department, Lariboisière hospital,
2, rue Ambroise-Paré, 75010 Paris cedex 10, France
b
CMRRF Kerpape, neurological rehabilitation department, BP 78, 56275 Ploemeur cedex, France

info article abstract

Article history: Background. – Wilson’s disease (WD) is a rare autosomal recessive disorder of copper
Received 12 March 2013 metabolism. If untreated, WD, which is initially a liver disease, can turn into a multi-
Received in revised form systemic disease with neurological involvement. Very few studies have described cognitive
29 May 2013 impairment in WD. The aim of this study is to report the cognitive profile of 31 treated WD
Accepted 4 June 2013 patients.
Available online 11 October 2013 Methods. – Patients were classed into two groups using the Unified Wilson Disease Rating
Scale (UWDRS): WD patients without neurological signs (WD-N ) (n = 13), and WD patients
Keywords: with neurological signs (WD-N+) (n = 18). The patients participated in a neuropsychological
Wilson’s disease assessment evaluating memory, executive function and visuo-spatial abilities.
Metabolic disease Results. – Both groups performed well for verbal intelligence and episodic memory skills.
Cognition However, the majority of these patients exhibited altered performance for at least one
Neuropsychology cognitive test, particularly in the executive domain. The WD-N+ group performed less well
Executive function than the WD-N group on cognitive tests involving rapid motor function, abstract thinking,
working memory and top-down inhibitory control.
Mots clés : Conclusions. – Cognitive impairment in treated WD patients essentially affects executive
Maladie de Wilson function involving fronto-striatal circuits. Verbal intelligence and episodic memory abili-
Maladie métabolique ties seem to be remarkably preserved. Neuropsychological assessment is a valuable tool to
Cognition evaluate the presence and the consequences of these cognitive impairments in WD
Examen neuropsychologique patients with or without neurological signs in the course of this chronic disease.
Fonctions exécutives # 2013 Elsevier Masson SAS. All rights reserved.

DOIs of original articles: http://dx.doi.org/10.1016/j.neurol.2013.04.006, http://dx.doi.org/10.1016/j.neurol.2013.05.002

* Corresponding author. Neurology department, Lariboisière hospital, 2, rue Ambroise-Paré, 75475 Paris cedex 10, France.
E-mail address: emilie.wenisch@lrb.aphp.fr (É. Wenisch).
0035-3787/$ – see front matter # 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.neurol.2013.06.002
 revue neurologique 169 (2013) 944–949 945

r é s u m é

Introduction. – La maladie de Wilson (MW) est une maladie rare autosomique récessive
réalisant une anomalie du métabolisme du cuivre. Si elle n’est pas traitée, initialement
hépatique, elle peut devenir systémique. Le but de cette étude est de décrire le profil cognitif
de 31 patients présentant une MW traitée.
Methode. – Un examen neuropsychologique incluant des tests mnésiques, exécutifs et
visuo-spatiaux a été réalisé auprès de 13 patients atteints de MW sans signe neurologique
(MW-N ) et 18 patients atteints de MW avec signes neurologiques (MW-N+).
Resultats. – Les deux groupes présentaient des performances moyennes normales pour les
tests d’intelligence verbale et de mémoire épisodique. Toutefois, la majorité des patients
montraient une performance altérée pour au moins un test, le plus souvent dans le domaine
exécutif. Les patients MW-N+ avaient des performances moyennes inférieures à celles des
patients MW-N pour les tests impliquant la rapidité motrice, le raisonnement abstrait, la
mémoire de travail et le contrôle inhibiteur.
Conclusion. – Les troubles cognitifs chez les patients traités pour une MW concernent
essentiellement les fonctions exécutives. L’intelligence verbale et les capacités de mémoire
épisodique semblent épargnées. L’examen neuropsychologique est un outil utile pour
évaluer la présence des troubles cognitifs et appréhender leurs conséquences chez les
patients atteints de MW.
# 2013 Elsevier Masson SAS. Tous droits réservés.

been reported in patients with neurological signs of WD:

1. Introduction
Wilson’s disease (WD), known as hepatolenticular degenera-
tion, is a rare autosomal recessive disorder of copper
metabolism which results in the accumulation of copper in
many organs. WD is one of the few inborn errors of
metabolism which can be successfully treated by specific
and effective pharmacological agents. Most often used are
chelating agents (d-penicillamine, triethylenetetramine) and
zinc salts. Intake of medicines should continue throughout the
patient’s life from the time of diagnosis. Good compliance with
treatment leads to copper excretion and a reduction of clinical
symptoms. In the majority of cases, early diagnosis and
treatment help to prevent irreversible damage.
If undiagnosed or mistreated (inadequate compliance with
treatment), WD which is initially an hepatic disease, turns into
a multisystemic disease (liver, brain, cornea, kidneys and
heart) (Lorincz, 2010). Neurological signs can then appear due
to brain lesions, classically localised in basal ganglia, and other
connected brain regions (Trocello et al., 2011). The main
neurological signs are dysarthria, dystonia, tremor, parkinso-
nism, chorea, ataxia, cognitive and psychiatric disorders
(Lorincz, 2010).
Cognitive impairments, at the neurological stage of WD,
were first considered as a subtype of subcortical dementia
because neurological deterioration is progressive without
treatment and cognitive decline is often associated to
functional impairment (Cummings and Benson, 1984). More
recent studies have described cognitive functioning in treated
patients with asymptomatic, hepatic and neurological stages
of WD and concluded that WD can be a dementing condition if
not treated adequately (Frota et al., 2009). The studies,
including patients displaying exclusively hepatic signs,
concluded that there was no significant difference between
these patients and a control group (Medalia et al., 1988; Seniów
et al., 2002). Conversely, different cognitive impairments have
slowed-down motor (Medalia et al., 1988; Littman et al., 1995),
and executive function deficits concerning short-term
memory (Seniów et al., 2002; Frota et al., 2013), retrieving
process in episodic memory (Isaacs-Glaberman et al., 1989;
Seniów et al., 2002; Frota et al., 2013) and abstract thinking
(Lang et al., 1990; Seniów et al., 2002). Nevertheless, there is no
consensus about frequency and severity of cognitive dysfunc-
tion (Rathbun, 1996; Seniów et al., 2002) and results are not
easily comparable. Because WD is a rare disease, the patients
recruited are often low in number and heterogeneous in
presentation. Some of these studies pooled all WD patients
into a single group regardless of the clinical features
(asymptomatic, hepatic or neurological). This may have
contributed to negative findings in the comparison with a
control group.
The aim of this study is to report the cognitive perfor-
mances of a French series of treated patients with or without
neurological signs of WD.
2. Methods
2.1. Patients
This study included 31 patients followed in the French
National Wilson’s disease Centre (Centre national de référence
pour la maladie de Wilson) between November 2006 and
December 2008. The diagnostic of WD was based on clinical
history, physical examination, low serum copper and cerulo-
plasmin, increased 24-hour urinary excretion of copper, liver
enzymes, slit-lamp examination to detect Kayser-Fleischer
rings, and molecular genetic studies. Brain MRI was realized
for patients with neurological symptomatology to detect the
abnormalities currently described in WD. This study did not
include a systematic MRI evaluation for WD patients without
neurological signs.
946 revue neurologique 169 (2013) 944–949

To be selected, the patients with confirmed diagnosis of
WD had to be treated with stable doses of a chelating agent or
zinc salt for at least 2 years and had to give oral consent to
undergo the neuropsychological exam. The exclusion criteria
were the presence of hepatic encephalopathy, liver trans-
plantation, severe neurological impairments (disabling dysar-
thria, tremor or dystonia) or severe psychiatric disorders
incompatible with neuropsychological examination.
The presence of neurological signs was determined by
using the Unified Wilson’s Disease Rating Scale (UWDRS)
(Członkowska et al., 2007). This scale contains 3 sections
including: consciousness, Barthel index, and neurological
examination. A total score equal to 0 indicates the absence of
neurological signs, and a total score  1 indicates the
presence of neurological impairment. According to this
criterion, the sample was divided into two groups: eighteen
WD patients (11 men, 7 women, mean age: 35.5  10.1 [23–58]),
mean years of education (13.3  2.7) with neurological signs
(WD-N+) and thirteen WD patients (4 men, 9 women, mean
age: 31.3  10.9 [17–50], mean years of education: 13.9  2.7)
without neurological signs (WD-N ). Among these 13
patients, 7 displayed hepatic signs and 6 had been diagnosed
by familial screening.
the difference (Time B – Time A) and the ratio [(Time B / Time
A)  100] were calculated as indicated by Tombaugh (2006).
Visuo-spatial abilities were assessed with the copy of
Modified Taylor Complex Figure (Hubley and Jassal, 2006).
The Beck Depression Inventory (BDI-II) was administered
to estimate the presence of depressive signs (Beck et al., 1996).
2.3. Statistical analysis
The demographic and clinical characteristics of the sample
were examined with analysis of variance for continuous
variables, and Chi2 test for categorical variables.
For each subject, standard scores of Wechsler subtests
were converted to z-scores upon a mean of 10 and a standard
deviation (SD) of 3; and raw scores of the other cognitive tests
were converted to z-scores using the normative data reported
in the literature (see Material). When appropriate the scales
were first reversed to correspond with each other (i.e., number
of errors in WCST). Neuropsychological test performances
were then studied with an analysis of variance of the z-scores.
A P value equal or less than 0.05 was regarded as statistically
significant.

2.2. Material 3. Results

Patients were examined using a neuropsychological test The two groups did not differ significantly in age, years of
battery assessing different aspects of cognitive processing. education, duration of treatment (Table 1). For the patients
Neuropsychological examination was administered by a with neurological involvement (WD-N+), the range for the
trained neuropsychologist in a 3-hour-exam session. Standard UWDRS was 1 to 11. Females were predominant in the WD-N
test instructions and scoring were applied. Current normative group whereas males were predominant in the WD-N+,
data were used, and raw scores were adjusted for age, gender however the difference between the two groups for the gender
and education. ratio was not significant (P = 0.19). There was no significant
Global cognitive function was assessed with selected correlation between gender and cognitive performances.
subtests of Wechsler Adult Intelligence Scale (WAIS) (Wechs- There was no difference between the two groups for the
ler, 2000): Information (degree of general information), BDI-II score (P = 0.22) and the WD-N+ and WD-N mean scores
Similarities (abstract verbal reasoning), Digit span (attention, reflected a minimal level of depression (12.3 and 7.8
concentration, mental control), Matrix (non-verbal abstract
problem solving), Digit symbol (visual-motor coordination,
motor and mental speed) and Symbol search (visual percep- Table 1 – Demographic and clinical features of the 31 WD
tion, scanning speed). Digit symbol and Symbol search treated patients.
scores were combined to calculate the Processing Speed WD-N WD-N+ Significance
Index (PSI). n = 13 n = 18 (P)
Memory functions were evaluated with California Verbal
Gender (M/F) 4/9 11/7 0.19
Learning Test (CVLT) (Delis et al., 1987), recall of Modified
Age (years) [16–58] 31.3  10.9 35.5  10.1 0.27
Taylor Complex Figure (Hubley and Jassal, 2006), Letter-
number sequencing (attention and working memory) and Education (years) [8–20] 13.9  2.7 13.3  2.7 0.51
Visual span selected in the Wechsler Memory Scale (Wechs- Duration of 9.1  10.8 14.6  10.3 0.17
ler, 2001). Letter-number sequencing and Visual span scores treatment (years)
were combined to calculate the Working Memory Index
Treatment
(WMI). d-penicillamine 7/13 10/18
Executive functions were appreciated with Wisconsin Card Triethylenetetramine 2/13 2/18
Sorting Test (abstract problem solving, mental flexibility, Zinc salts 4/13 6/18
response inhibition) (Nelson, 1976; Heaton et al., 2002), Stroop
BDI-II score [0-32] 7.8  8.4 12.3  11.1 0.22
test (selective attention, inhibition process) (Stroop, 1992), D2
UWDRS score [0-11] 0 4.8  3.5
test (visual cancellation, selective attention) (Brickenkamp,
1998), Baddeley’s double task test (divided attention) (Baddeley WD-N : WD patients without neurological signs; WD-N+: WD
patients with neurological signs; BDI-II: Beck Depression Inven-
et al., 1997) and the Trail Making Test parts A and B (mental
tory; UWDRS: Unified Wilson’s Disease Rating Scale (maximum
flexibility) (Reitan, 1958; Tombaugh, 2004). In order to measure
score: 185).
the mental shifting process independently from slow-down,
 revue neurologique 169 (2013) 944–949 947

Fig. 1 – Cognitive profile of 31 WD treated patients with or without neurological signs. SIM: similarities, INF: information,
MATR: matrix, SYMS: symbol search, DSYM: digit symbol, DS: digit span, VS: visual span, LNS: letter-number sequencing,
CVLT: California verbal learning test, CVLT A1: score recall 1 list A, CVLT A1-A5: total score recalls 1 to 5 list A, CVLT B: recall
list B, SDFR: short delay free recall, SDCR: short delay cued recall, LDFR: long delay free recall, LDCR: long delay cued recall,
MTCF: Modified Taylor Complex Figure, TMT: Trail Making Test, WCST: Wisconsin Card Sorting Test, WCST nb cat: number
of categories completed, WCST total err: total number of errors, WCST pers err: number of perseverative errors, Stroop W:
score Words, Stroop C: score Colours, Stroop CW: score Colour of Words, Stroop Interf: score Interference, D2: selective
attention test, D2 GZ: quantitative performance index, D2% F: qualitative performance index, D2 SB: attention variation rank,
D2 KL: concentration performance index, Double task: percentage of maintained performance.

respectively). There was no correlation between BDI-II score

and cognitive performances. There was no correlation
between the BDI-II score and the UWDRS score (r = 0.001).
For both groups, the cognitive profile (Fig. 1) was similar:
verbal intelligence performances were around the average,
episodic memory performances in visual and verbal condi-
tions were above the average, and mean executive function
scores tended to stay below the average, particularly for the
WD-N+ group.
The WD-N+ group globally performed lower than the WD-
N in all the cognitive tests and the differences were
significant for the Digit Symbol subtest (P: 0.001), Symbol
Search (P: 0.03), Processing Speed Index (P: 0.004), Matrix (P:
0.01), Digit Span (P: 0.04), CVLT recall of list B (P: 0.04), CVLT
total intrusive errors (P: 0.03), Stroop Words (P: 0.03), and
Stroop Colours (P: 0.001).
A qualitative analysis of performances showed that a
majority of patients displayed an altered performance
(z score  2) for at least one cognitive test: 72% (13/18) of
WD-N+ patients, and 54% (7/13) of WD-N patients respecti-
vely. The most frequently impaired cognitive domain was the
executive function with an altered score for at least one
executive test in 61% (11/18) of WD-N+ patients and 46% (6/13)
of WD-N patients.
4. Discussion
The results suggested that WD patients could display
cognitive impairments, even with a mild neurological symp-
tomatology (cf. UWDRS score) and without significant depres-
sive signs. In WD, the greatest damage usually occurs in the
basal ganglia, but recent brain MRI studies have found that
different parts of the brain can be involved: cerebellar
peduncles, midbrain, corpus callosum, and corticosubcortical
white matter with frontal predilection (King et al., 1996; Van
Wassenaer-van Hall et al., 1996; Mikol et al., 2005; Sinha et al.,
2006; Taly et al., 2009; Trocello et al., 2011). As the cerebral
cortex is relatively spared in WD, the cognitive and beha-
vioural abnormalities are explained by the dysfunction of the
subcortical-frontal connections (Seniów et al., 2002; Hegde
et al., 2010).
Furthermore, the results showed that 54% of neurologically
asymptomatic patients (WD-N ) displayed an altered per-
formance for at least one cognitive test which was most often
an executive test (46%). The studies, including patients
displaying exclusively hepatic signs, concluded that there
was no significant difference between these patients and a
control group (Medalia et al., 1988; Seniów et al., 2002). Brain
948 revue neurologique 169 (2013) 944–949
MRI with diffusion sequences and SPECT (single-photon
emission computed tomography) investigations have
demonstrated the presence of basal ganglia abnormalities in
WD patients without neurological signs (Favrole et al., 2006;
Piga et al., 2008; Tarnacka et al., 2008). These results give
further support to the hypothesis that cognitive abnormalities
can be detected in WD patients without neurological signs.
The patients with neurological signs performed poorly for
executive tests requiring motor speed (Digit Symbol, Symbol
Search, Processing Speed Index, Stroop Word, Stroop Colour),
working memory (Digit Span), top-down inhibitory control
(intrusive errors and interference in CVLT test) and non-verbal
abstract reasoning (Matrix). In our sample, WCST performan-
ces appeared surprisingly normal for both groups of WD
patients. Matrix subtest and WCST are both dedicated to
measure non-verbal abstract reasoning, but WCST requires
different executive components: abstract problem solving,
mental flexibility and working memory abilities. It seemed
that a normal WCST performance did not exclude impairment
of one of these executive components in another test.
Few studies have reported executive impairment in WD
patients with neurological involvement: slowness of mental
processing, impairment of non-verbal abstract reasoning,
decreased mental shifting capacities and impaired working
memory process (Medalia et al., 1992; Littman et al., 1995;
Seniów et al., 2002; Frota et al., 2013).
The impact of movement disorders (akinesia, dystonia and
tremor) on the assessment of cognitive performance has been
discussed. Previous investigations have described motor
slowness in all WD patients (Lang et al., 1990; Rathbun,
1996; Portala et al., 2001; Hegde et al., 2010). Some other studies
have reported motor slowness as a common feature at the
neurological stage of WD (Medalia et al., 1988; Littman et al.,
1995) and in other basal ganglia diseases (Cummings and
Benson, 1984; Lang, 1989). In this study, we included two types
of tasks: cognitive tests that engage motor abilities (i.e., Digit
symbol, TMT. . .) to quantify the motor slowness, and cognitive
tests that did not involve timing or fine motor responses. Then
the decreased performances of neurologically impaired
patients in the tasks assessing non-verbal abstract reasoning
(Matrix) or working memory (digit span, visual span, letter-
number sequencing) cannot be explained by the motor
component but by the executive function worsening.
Verbal learning abilities of neurologically impaired WD
patients have been previously studied. One study has
indicated lower performances in patients with neurological
signs of WD for the total recall score of RAVLT (Rey Auditory
Verbal Learning Task) (Seniów et al., 2002). Another study has
found that these patients scored worse than controls for the
delayed recall, but has shown normal performances for the
recognition task (Isaacs-Glaberman et al., 1989). In this study,
the CVLT (California Verbal Learning Task) was used to
appreciate verbal learning abilities. The CVLT procedure is
quite similar to the RAVLT procedure, except that the CVLT
includes an interference task. The WD-N+ and WD-N groups
performed within the normal range for all quantitative
measures of the CVLT implying encoding and storage process.
However, the WD-N+ group had a trend to generate more
intrusive errors in free and cued recalls than WD-N group.
These patients were also susceptible to pro-active interference
effect. These results could suggest that inhibition process was
affected in WD-N+ patients. This hypothesis is in agreement
with our clinical impression: neurologically impaired WD
patients can display an inhibitory processing deficit characte-
rized by intrusive response or behaviour, perseverative
response, interference sensitivity, impulsivity, irritability, etc.
Visuo-spatial performances did not seem impacted in our
WD-N+ group, however only one test (copy of MTCF) was
performed to investigate this cognitive domain. Studies
including WD patients, regardless to the clinical status, have
produced conflicting results. Some of them have concluded
that visuo-spatial abilities are impaired in WD (Rathbun, 1996;
Hegde et al., 2010), but others have not found any deficit in this
cognitive domain (Lang et al., 1990; Portala et al., 2001; Frota
et al., 2013). One study has reported visuo-spatial and
constructive deficits in WD patients with neurological signs
(Seniów et al., 2002).
This study had some limitations. First, to calculate z scores
we used available normative data obtained in different
samples which may have limited the interpretation of the
cognitive scores. Second, this study did not include a
systematic MRI evaluation in WD patients. Another potential
limitation of our study is the selection bias: we excluded the
patients with the most severe neurological signs that are not
compatible with neuropsychological examination. This selec-
tion may have minimized the differences between the two
groups. Further research is yet required to precise the
cognitive functioning of WD patients recently treated compa-
red with matched controls.
Despite these limitations, this study indicated that verbal
intelligence and episodic memory abilities seemed preserved in
WD patients, but executive functions involving fronto-striatal
circuits (working memory, abstract reasoning and inhibitory
process) were impaired, specifically in WD patients with
neurological manifestations. Neuropsychological examination
is useful at the diagnosis time for WD patients, even without
neurological signs. Cognitive impairments can effectively imply
reduction of autonomy, mood disturbances and lack of
compliance to treatment. Moreover, the neuropsychological
follow-up allows us to appreciate cognitive evolution of treated
WD patients throughout the course of the disease.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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