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A Case of Unilateral Neglect in Huntingtons


Disease

Aileen K. Ho , Tom Manly , Peter J. Nestor , Barbara J. Sahakian , Thomas H.


Bak , Trevor W. Robbins , Anne E. Rosser & Roger A. Barker

To cite this article: Aileen K. Ho , Tom Manly , Peter J. Nestor , Barbara J. Sahakian , Thomas H.
Bak , Trevor W. Robbins , Anne E. Rosser & Roger A. Barker (2003) A Case of Unilateral Neglect
in Huntingtons Disease, Neurocase, 9:3, 261-273

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2003, Vol. 9, No. 3, pp. 261273 # Swets & Zeitlinger

A Case of Unilateral Neglect in Huntingtons Disease

Aileen K. Ho1, Tom Manly2, Peter J. Nestor3, Barbara J. Sahakian4, Thomas H. Bak3,
Trevor W. Robbins5, Anne E. Rosser6 and Roger A. Barker1,3
1
Cambridge Centre for Brain Repair, Cambridge University, Forvie Site, Robinson Way, Cambridge, U.K., 2MRC Cognition and Brain
Sciences Unit, Elsworth House, Addenbrookes Hospital, Cambridge, U.K., 3Department of Neurology, Addenbrookes Hospital,
Cambridge, U.K., 4Department of Psychiatry, University of Cambridge, Addenbrookes Hospital, Cambridge,
5
Department of Experimental Psychology, University of Cambridge, Cambridge, U.K., and 6School of Biosciences,
Cardiff University, Cardiff, U.K.

Abstract

Unilateral neglect, an attentional deficit in detecting and acting on information coming from one side of space, is a relatively
common consequence of right hemisphere stroke. Although neglect has been observed following damage to a variety of
brain structures, to date no reports exist of neglect phenomena arising from Huntingtons Disease (HD). However, reports
in the animal and human literature suggest that neglect is possible following damage to a primary site for Huntingtons
pathology, the basal ganglia. Here we present a patient (BG) with genetically proven HD who, in the context of the mild
intellectual, executive and attentional impairments associated with the disorder, showed a remarkably severe and stable
neglect for left space. MRI and electrophysiological results make it unlikely that the spatial bias could be accounted for
by basic sensory loss. In addition, behavioural investigation indicated that, although BGs neglect operated in a very
striking manner along body-centred co-ordinates (missing almost all information presented to her left), more general
limitations in visual attention were apparent to the left-side of information presented entirely to the right of the body
midline. Further evidence is presented showing that the neglect was manifest on tactile and auditory tasks as well as
those presented in the visual domain. The presence of neglect in HD in this case is novel and somewhat puzzling,
particularly as flourodeoyglucose positron emission tomography revealed bilateral caudate hypoperfusion. Reducing
the statistical threshold on this analysis revealed a potential frontal hypometabolism that was more marked in the
right than left hemisphere. However, as this was only apparent at a threshold below that normally considered acceptable
(due to the resulting number of false positives), this possible account of the neglect must be viewed very cautiously.

Introduction
Huntingtons disease (HD) is an autosomal-dominant neuro- profound left-sided neglect in the presence of bilateral cau-
degenerative disorder which typically manifests in midlife date hypoperfusion, some indication of right rather than left
with a combination of a movement disorder as well as frontal hypometabolism, and no other abnormalities. To our
cognitive and psychiatric abnormalities. The initial neuro- knowledge, there are no other reported cases of unilateral
pathology in HD involves the loss of medium-spiny striatal neglect in HD.
projection neurons primarily in the medial caudate nucleus An association between hemispatial neglect and basal
followed by dorsal putamen and tail of the caudate. As the ganglia damage has a long experimental history. Destruction
disease progresses all basal ganglia structures are affected, of either the caudate and ventromedial internal capsule
together with the thalamus, hippocampus and cerebral cortex (Reeves and Hagamen, 1971) or the substantia nigra or lateral
(especially the frontal lobes) (Vonsattel and DiFiglia, 1998). hypothalamus (Feeney and Wier, 1979) in cats causes con-
The exact contribution of this pathological progression to tralateral sensory neglect. Similarly, reduction of dopamine
changes in symptomatology is not known. Although cognitive via infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
abnormalities occur early in HD (e.g. Mayeux et al., 1986; (MPTP) into the caudate of monkeys (resulting in unilateral
Bamford et al., 1995; Lawrence et al., 1996; Bachoud-Levi dopamine deficiency) resulted in neglect of the contralateral
et al., 2001), reflecting disruption of frontostriatal circuits and side (Miyashita et al., 1995), supporting earlier lesion studies
attentional system, patients with overt spatial inattention or that had used 6-hydroxydopamine (Marshall and Ungerstedt,
neglect have not previously been described. Here we report on 1977; Dunnett et al., 1987; Apicella et al., 1991). Restoration
a patient with genetically proven HD who presented with of dopaminergic innervation of the striatum using grafts of

Correspondence to: Aileen K. Ho, Cambridge Centre for Brain Repair, Cambridge University, Forvie Site, Robinson Way, Cambridge, CB2 2PY, U.K. Tel: 44 1223
331160; Fax: 44 1223 331174; e-mail: aileenkho@netscape.net
262 A. K. Ho et al.

embryonic ventral mesencephalic tissue (Dunnett et al., 1987) only. A structural magnetic resonance image (MRI) scan
further emphasises the importance of the dopaminergic inner- was normal. Routine haematological investigations and visual
vation of the basal ganglia in mediating contralateral atten- evoked responses, for both full and half field studies, were
tion. Unilateral damage to the rat striatum itself, using any normal.
excitotoxins, also causes neglect for contralateral space Over the next two years her left-sided neglect worsened
(Brown and Robbins, 1989; Iversen and Dunnett, 1990; and she was re-admitted for further investigation of this in
Brasted et al., 1997). November, 2000. Examination at this time continued to show
In humans, unilateral neglect is a relatively common con- left-sided visual and somatic inattention with minimal chorea
sequence of cerebrovascular disease being seen in up to 50% and dystonia, as well as eye movement abnormalities (where
of acute patients (Stone et al., 1991, 1992). Although in the she was poor at voluntary fixation, especially to the left,
early post-stroke stage it is seen with approximately equal although able to move her eyes fully to that side). Her Unified
frequency following damage to either hemisphere, an asym- Huntingtons Disease Rating Scale (UHDRS) motor
metric recovery pattern leads to the vast majority of patients score was 53, total functional capacity score was 4, and
with chronic manifestations of the disorder having right Independence scale score was 70. Medication consisted of
hemisphere damage and neglecting left space. carbamazepine, diazepam and paroxetine at initial testing
Unilateral neglect and extinction (in which patients fail to (with the latter substituted for dothiepine in February
detect a left-sided stimulus when it is in competition with a 2001). Investigation during November, 2000 again revealed
simultaneous right-sided stimulus) have been noted in the normal blood tests. Her repeat MRI (February, 2001) was
visual, auditory and tactile modalities (Robertson and North, again normal.
1993). There is also evidence that patients can fail to recall
left-sided details of familiar objects such as clocks or famous
Imaging
landmarks (Bisiach and Luzzatti, 1978; Grossi et al., 1993).
Neglect is now viewed as a highly fractionated disorder that BG underwent PET scanning to define the extent of pathology
can arise following damage to a number of cortical brain as measured by resting brain metabolism with 18flourodeoy-
structures including the parietal (Vallar and Perani, 1986) glucose. The PET data were used for a region of interest study
temporal (Karnath et al., 2001) and frontal lobes (Mesulam, of the caudate heads as well as a non-hypothesis driven
1981). It has also been observed following subcortical damage analysis using Statistical Parametric Mapping (SPM). The
including; the basal ganglia (Bradshaw and Mattingley, 1995), aim of the SPM analysis was to ensure that there was no occult
striatocapsular damage (Weiller et al., 1993; Chung et al., pathology that could have offered an alternate explanation
2000), the putamen (Hier et al., 1977; Tei et al., 1993), other than disruption of basal ganglia circuits for the neglect
caudate (Kaplan et al., 1991; Kumral et al., 1999; Lim syndrome.
and Yap, 1999), internal capsule (Vallar and Perani, 1986;
Sakashita, 1991), globus pallidus (Roeltgen et al., 1989) and
Imaging protocol
thalamus (Watson and Heilman, 1979; Perani et al., 1982;
Velasco et al., 1986). The case and 10 age-matched controls (age 56.9  3.9 years)
Although the animal and human literature suggests that underwent positron emission tomography using the tracer
18
spatial neglect can arise following subcortical basal ganglia flourodeoyglucose (FDG-PET). Each subject also under-
damage, this has, to date, not been demonstrated in the context went a volumetric MRI scan for co-registration, partial
of HD. Here we present a case where unilateral neglect is the volume correction and to define the caudate region of interest
predominant and most debilitating symptom in a patient with (ROI). Both imaging studies were performed at the Wolfson
HD. Brain Imaging Centre, Cambridge, UK. Written informed
consent was obtained and the study had the approval of the
Local Regional Ethics Committee. The MRI scans were
Case report
performed on a 3Tesla Bruker machine and comprised a
BG, a 47-year-old, right-handed lady with a known family T1 weighted 3D spoiled gradient echo sequence. The PET
history of HD, first noticed symptoms in 1993, whilst working scans were obtained using a General Electric PET Advance
as a practice nurse. At this time she noticed some difficulty system in 3D mode with a voxel size of 2.35  2.35  4.5 mm
carrying out injections, and went for a predictive test for HD, and field of view of 30.0  30.0  15.3 cm. For the PET scan,
which was positive. She subsequently decided to stop work, subjects were fasted for 8 hours and scans were performed in a
and went through a period of depression for which she dimly lit, quiet room without blind folds or ear plugs. A radial
received medication. In 1996, she first became aware of some arterial cannula was used to sample radioactivity and fasting
difficulty moving around without bumping into things on her blood glucose during the scan. A 10 minute pre-injection
left side and this was accompanied by left-sided weakness transmission scan using 68Germanium rods was used for
resulting in a tendency to drop things. In 1998, she was attenuation correction. The subjects were then injected intra-
admitted to the Addenbrookes Hospital for extensive inves- venously with 74MBq of FDG over 3060 seconds. The
tigations. Neurological examination revealed mild chorea PET images used in this study were obtained from 35 to
Neglect in Huntingtons disease 263

Fig. 1. nCMRglc rate for BG (circles) and 10 controls (crosses) for left and right caudate head. nCMRglc normalised cerebral metabolic rate for glucose.

Fig. 2. MRI (top), FDG-PET (middle) and co-registered PET to MRI (bottom) for (a) BG, and (b) an age- and gender-matched control.
264 A. K. Ho et al.

55 minutes post-injection. The cerebral metabolic rate of normalised to this (nCMRglc) to minimise intersubject var-
glucose (CMRglc) map was calculated using the Huang iability in brain metabolism.
autoradiographic method. The ROI study of the caudate head
and the SPM analysis were done on a SUN workstation.
SPM analysis
The CMRglc maps were first normalised to the CMRglc of
ROI study of the caudate head
each subjects cerebellar vermis CMRglc, the remaining
The caudate ROIs were drawn on MRI scans using Ana- steps were carried out using SPM99 (Wellcome Department
lyzeAVW version 3 software (Biomedical Imaging Resource, of Cognitive Neurology, London, UK). This nCMRglc map
Mayo Foundation, Rochester, MN, USA). The MRI scan was was co-registered to the subjects MRI and then the MRI (and
oriented to the anterior commisure-posterior commisure line therefore the PET) was spatially normalised to the T1-MR
(ac-pc line) and anatomic landmarks were compared to those template. The normalised scans were smoothed with a 16 mm
of the Duvernoy atlas (Duvernoy, 1999) which presents brain (full width at half maximum) Gaussian filter. The case
slices in this orientation. ROIs were manually traced around was compared to controls at a statistical threshold of
the caudate heads in coronal plane with the caudal limit being Puncorrected 0.001 and 0.01.
the first coronal slice on which the anterior commisure could
be seen. CMRglc maps were then co-registered to the MRI
Results
and partial volume corrected CMRglc (mg/min/100 mls tis-
sue) for the ROIs were calculated. An ROI was also traced on The ROI study confirmed a symmetrical reduction in
each subjects cerebellar vermis and the caudate ROI was then nCMRglc for the caudate heads when compared to controls

Fig. 3. SPM glass brain of areas of abnormality in BG contrasted to 10 age-matched controls at a statistical threshold of Puncorrected 0.05. Cursor indicates
basal ganglia abnormality (caudate and putamen).
Neglect in Huntingtons disease 265

(Fig. 1). The SPM analysis at Puncorrected 0.001 showed BGs difficulties in switching between two cognitive sets,
no significant regions of hypometabolsim when compared to evident on the Trails B task, was also apparent on the
the 10 controls. As the statistical threshold was reduced to a computerised CANTAB Intra/Extra Dimensional (ID/ED)
less stringent significance level (P 0.05), hypometabolism set shifting test. On this measure, which has been shown to
of the caudate and lentiform nuclei and patchy changes be sensitive to the fronto-striatal deficits of HD (Lawrence
throughout the frontal lobes (Fig. 2a, b) became evident. et al., 1996), she experienced great difficulty in the Extra-
No other abnormalities were identified, and, in particular, Dimensional shift stage and made a high number of errors.
no abnormalities within the parietal and temporal regions. Phonemic fluency performance was at borderline whilst
The FDG-PET findings of hypometabolism in the caudate semantic category fluency was impaired. In both these verbal
were consistent with the diagnosis of Huntingtons disease. fluency tasks and when asked to name pictures, BG showed
Cortical metabolic disturbance in mild Huntingtons has also some evidence of anomia and would, on occasion, need to
been reported to affect the frontal and inferior parietal lobes progressively sound out successive phonemes in order to
(Martin et al., 1992). The frontal abnormalities which arrive at the pronunciation of the intended word. Overall,
appeared more marked on the right as suggested by the however, her naming performance was within the normal
uncorrected SPM analysis (Fig. 3) are consistent with this range.
pattern and may perhaps be relevant to the neglect (which is BGs general visuo-spatial ability on material presented to
disproportionately associated with right hemisphere damage). her good (right) field was poor. She had significant difficulty
However, considerable caution is required due to the unac- in identifying objects from silhouette representations (some-
ceptably high risk of false positive findings at this uncorrected times focusing exclusively on a single salient feature without
threshold. Although the evidence for a clear difference is considering other crucial aspects of the shape), in counting the
therefore simply insufficient in this case, it remains an inter- number of dots in a random array, and in judging the location
esting possibility to explore in future work. of a dot within a box (Silhouettes, Dot Counting and Number
Location subtests of the Visual Object and Space Perception
Battery (Warrington and James, 1991)). She showed poor
Neuropsychological assessment
ability in piecing together several different features to identify
On initial neuropsychological examination, BGs perfor- the one correct object, and tended to identify two separate
mance on three measures of vocabulary, verbal reasoning objects on the basis of two different features, suggestive of a
and mental arithmetic (WAIS-R Vocabulary, Similarities and visual integration problem. Pattern recognition and spatial
Arithmetic subtests) (Wechsler, 1981) was at the 16th percen- recognition memory (conducted in right hemi-space) were
tile level for her age. Her digit span, a measure of working also impaired with performance below the 50th and 25th
memory/attention, was markedly impaired and fell at the 1st percentiles respectively.
percentile. Overall, her pro-rated Verbal IQ on the WAIS-R In summary, BG has genetically confirmed HD and demon-
was estimated at 75. This is considerably lower than her strates a profile of reduced attention and executive function
estimated pre-morbid IQ of 103 (based on the National Adult typical of the disease, with the exception of her florid uni-
Reading Test (NART) (Nelson, 1982), which was in the lateral neglect of left space. It appears that all other aetiologies
average range and consistent with her educational and occu- of neglect have been ruled out by an extensive series of
pational history. As these verbal tests, with the possible investigations on two separate occasions. Further assessment
exception of the NART, should not be influenced by the of her neglect was carried out with full consent obtained
unilateral neglect, her profile is consistent with a more gen- according to the declaration of Helsinki.
eralised decline in cognitive ability consistent with HD. This
was also evidenced in a Mini-Mental State Examination
(MMSE) (Folstein et al., 1975) score of 25. This score is Assessment of spatial neglect: Visual domain
above the threshold for dementia (23), but lower than
Cancellation task performance
expected given her average pre-morbid IQ.
Her performance on tests of executive function was gen- Cancellation tasks, in which patients are asked to find and
erally impaired, as would be expected in HD (Lawrence et al., mark particular targets randomly distributed across a sheet of
1996). Her performance on the Symbol Digit Modalities and paper, are widely used in the assessment of visual neglect.
the Stroop test (in which patients are asked to override a more Typically, neglect patients will begin their search on the right
automatic reading response in order to name the ink colour in side of the sheet and declare the task finished despite omitting
which colour words are written) was impaired primarily due some or many of the left-sided targets. BG was administered
to slowness. Slow responding, in addition to errors, was also two such standardised tests, i.e. the Balloons test (Edgworth
observed on the Trails A and B tests (where patients are asked et al., 1998) and the Star Cancellation Test (Wilson et al.,
to join randomly distributed circles based on a simple ascend- 1987). On both measures, BG indeed began her search on the
ing number rule (A) or an alternating number and letter rule right and was only able to detect 1/10 left positioned targets
(B)). Her performance on this test fell below the 10th per- and 10/10 right positioned targets on the Balloons test; 1/27
centile level. left positioned targets and 26/27 right positioned targets on the
266 A. K. Ho et al.

Star Cancellation measure both performances consistent whilst the latter analysis revealed a significant Placement
with a severe neglect of left space. Although no restrictions by Density interaction (F(1,5) 33.80, p .002). Taken
are placed on head or eye movements in either task, BG did together, this shows that letters on the right half of the page
not spontaneously turn her trunk or head to bring more of the were more successfully cancelled when placed to the right of
sheet within her right field, preferring instead to try and move midline and also when stimulus density was lower; letters on
the test sheet to her right (which is not permitted in the the left side of the page, however, were never cancelled for
instructions). midline presentations, but when right-sided presentation was
allowed, performance was improved with decreasing stimulus
density. These results suggest that the location of visual
The location of the cancellation sheet
information relative to the body midline exerts a strong influ-
relative to body midline and the effect
ence on BGs neglect. In addition, the deleterious effect of
of stimulus density
stimulus density, even when information was to the right of
Unilateral neglect can operate within different spatial frame- the body, is consistent with more pervasive attentional limita-
works. Body-centred or egocentric neglect, for example, tions regardless of spatial location.
occurs when patients miss details in left-space as defined by
their own body mid-line. Object-centred neglect is said to occur
Naming and reading
when patients miss details on the left side of objects regardless
of where these appear relative to their midline (Driver and Cancellation tests are complex measures and a lateralised bias
Halligan, 1991). Accordingly, the performance of patients on in performance can emerge for a number of reasons. Patients
cancellation tasks may be modulated to a greater or lesser may have a difficulty in compensating for a basic hemifield
extent by the position of the sheet relative to their midline. loss, in shifting attention, or in making eye-movements
Performance can also be influenced by the relative density of towards the left. They may also experience difficulty in
stimuli on the page (Kaplan et al., 1991). To investigate BGs initiating hand movements into left space (Mattingley and
neglect further we therefore performed the following experi- Driver, 1996; Husain et al., 2000). In order to clarify some of
ment (Kaplan et al., 1991). Four cancellation sheets were these issue with BG, and to further investigate the apparently
created (showing a random spatial array of letters) that varied body-centred nature of her spatial inattention, we developed a
in terms of stimulus density (14, 23, 42 and 96 letters respec- picture-naming task. In the first study, five black silhouettes of
tively). These were presented either centrally in front of the BG objects were presented in a line on a white A3 landscape
or at a position approximately 30 cm to the right. In each case orientation sheet. When the array was centred at BGs mid-
she was asked to cross out all instances of a nominated target line, she was only able to name the two right-most objects.
letter (the number of targets in each condition was constant at When, however, the sheet was displaced to lie entirely to BGs
14). Stimulus density and sheet location were randomised. right, she was able to name all of the objects (although, as
With the number of targets cancelled as the dependent might be expected given BGs performance on the VOSP (see
variable, a three-way repeated measures ANOVA was per- above) one of the objects was misidentified). In a second
formed with the factors of Sheet Placement (midline, right- examination BG was presented with outline drawings of three
sided), Target Placement on the page (left, right) and Stimulus different types of fruit, with a proportion of each picture
Density (levels 1 to 4). A total of 112 trials were performed, overlapping another. When presented at BGs midline she was
consisting of 7 trials in each of the 16 conditions. There were only able to identify the two pictures to the right of the page.
significant main effects of Sheet Placement (F(1,5) 401.29, When, however, the sheet was displaced to her right, she was
p .000), Target placement (F(1,5) 1229.09, p .000) and able to name all three drawings.
Stimulus Density (F(1,5) 20.77, p .006). Hence more Unilateral neglect can lead to profound difficulties in read-
target letters were cancelled when the stimulus was presented ing (neglect dyslexia) (Young et al., 1991). BG was asked to
to the right side of space (right-sided 5.33, midline 3.13), read from a text passage (Rainbow passage (Fairbanks, 1971))
when stimulus density was low (level 1 4.63, level 2 4.50, presented either at midline or displaced to her right. In the
level 3 4.00, level 4 3.79), and also on the right half of the midline condition she was only able to read words from the
page (right 6.40, left 2.06). There were also significant right side of the page (40.66% of text). When the page was to
Sheet Placement  Target Placement (F(1,5) 529.00, p her right her performance was improved but far from perfect
.000) and Sheet Placement  Stimulus Density (F(1,5) (82.42% of text). A trend for BGs gaze/attention to drift
22.86, p .005) interactions which were interpreted in terms progressively to the right during reading was noted (see
of a significant 3-way interaction of Sheet PlacementTarget Table 1). This apparent worsening was investigated by sub-
PlacementStimulus Density interaction (F(1,5) 13.85, sequently asking BG to read single sentences (see Table 1).
p .014). Posthoc two-way ANOVAs (PlacementStimulus When these sentences were presented at midline, BG was
Stimulus Density) were conducted separately for the right better able to maintain higher levels of accuracy in terms of
(Fig. 4b) and left (Fig. 4a) half of the page respectively. For the proportion of words read (65.71%) than during the para-
the former analysis, main effect of Placement (F(1,5) 8.45, graph condition (40.66%). In view of the contextually driven
p .003) and Density (F(1,5) 12.02, p .018) was found left-to-right scanning in English, it appeared that her attention
Neglect in Huntingtons disease 267

Fig. 4. Letter cancellation performance according to increasing levels of stimulus density for (a) left side of page, and (b) right side of page.

Table 1. Percentage of words read for a paragraph of text and a list of was directed by the left-sided start of each sentence, and this
sentences, during midline and right-sided presentation may have reduced the extent of right-ward drift in the context
of a continuous flow of sentences in a paragraph of text.
Midline presentation Right-sided presentation Interestingly, this right-ward drift (i.e. a rightward response
bias (Brown and Robbins, 1989)) was more evident for right-
Paragraph
First half 45.45 100.00 sided rather than midline placement, again implicating the co-
Second half 36.17 65.96 existence of a higher-order attentional impairment rather than
All 40.66 82.42 simply a body-centred deficit. It appeared that the successive
Sentences spatial cue for repeated re-orientation of attention to the left
First half 68.57 95.70 side of space in the line by line (rather than paragraph)
Second half 61.43 95.72
All 65.00 95.71 situation ameliorated neglect slightly by attenuating the pro-
gressive right-ward drift from midline.
268 A. K. Ho et al.

In summary, BG shows a profound neglect for tasks that do The model was then removed and BG was asked to draw it
not require movement of her arm or hand into left space and from memory with her eyes open (Fig. 5b), and then to
which, again, appear closely tied to a body-centred spatial attempt it again with her eyes closed (Fig. 5c). Finally she
framework. It is notable that while her basic reading abilities was presented with models to copy. These were a butterfly
seem relatively intact, the presence of spatial neglect is rotated through 90 degrees (to the right) such that the crucial
sufficient to render most text quite meaningless and, as symmetrical information was now in the vertical plane
might be expected, BG reports no longer reading for informa- (Fig. 5d), a right-winged butterfly (Fig. 5e), and a left-
tion or for pleasure. winged butterfly (Fig. 5f). As shown in the figures, BG
was consistently unable to produce any visual information
that lay on the left side of space in any of the copying
Neglect for remembered representations
conditions. This is in line with the results presented above
and tacit awareness of left-sided stimuli
which show a body-centred component to her neglect syn-
One of the most striking observations on the pervasiveness drome (Driver and Halligan, 1991). However, when drawing a
and cross-modal nature of unilateral neglect is that patients remembered butterfly with her eyes open or closed the
may omit left-sided information from memories of objects or representation was relatively complete. The results are con-
scenes learned prior to their injury. This may be apparent in sistent with BGs neglect exerting a greater influence on
their verbal reports, for example of famous landmarks current input than on the recall of stored representations.
(Bisiach and Luzzatti, 1978) of highly familiar objects such One of the reasons that neglect is primarily viewed as a
as clocks (Grossi et al., 1993), and in their ability to draw disorder of attention is the observation that the behaviour of
objects from memory. To examine this with BG, she was (at least some) patients can be influenced by left-sided
asked to draw a butterfly under different conditions (see information that they are unable to consciously report (e.g.
Halligan and Marshall, 1994). Initially she was asked to make Berti and Rizzolatti, 1992). Marshall and Halligan (1988)
a copy from a model kept in free view throughout (Fig. 5a). used two almost identical pictures of houses to investigate this

Fig. 5. Butterfly drawing according to different conditions, i.e., (a) to copy a full butterfly kept in free view, (b) to draw from memory with eyes open, (c) to draw
from memory with eyes closed, (d) to copy a full butterfly rotated 90 degrees clockwise, (e) to copy a right-winged butterfly and (f) to copy a left-winged butterfly.
Neglect in Huntingtons disease 269

issue. The houses, presented in the top and bottom half of a the rod until the opposite end was reached and then retrace the
single sheet, differed only in the addition of flames coming path, stopping at the perceived middle.
from one of the windows. When the flames were depicted as In the visual condition, BGs bisections were made at a
coming from a left-sided window a patient was unable to mean of 74.15 mm (SD 10.09) to the right of centre
describe any difference between the houses. When, however, consistent with a neglect of left space. Overall, her bisections
they were asked to choose which house they would prefer to in the tactile condition were a mean of 9.56 mm (SD 9.46) to
inhabit, the presence of the flames exerted a significant effect, the right that is showing considerably less bias than in the
although subsequent investigation has questioned whether visual condition, but were nonetheless statistically significant
this preference is clearly related to the semantic content of from zero (t 4.95, p < .001).
the pictures (Bisiach, 1993). When this procedure was used Previous research has shown that the hand used by a patient
with BG she indeed showed no awareness of a difference can exert a significant influence on spatial perception
between the houses when the flames were to the left. However, (Halligan and Marshall, 1989). Specifically, that when pa-
the flames also exerted no influence on her choice which, in tients use their left hands and particularly when this occurs
this condition, was at chance. in left space relative to the body significant reductions in
The results so far provide compelling evidence of a strong neglect can be observed. Carefully controlled experiments
unilateral neglect in the visual domain. The following inves- show that this is the case when the movements cannot be seen
tigations considered whether BG would also show such spatial by the patients, suggesting that the effect is not simply the
distortion in tactile and auditory modalities. result of visual cueing (Robertson and North, 1992; Robertson
et al., 1992, Robertson and North, 1993; Robertson and North,
1994). This effect was examined with regard to BGs tactile
Assessment of neglect: Tactile domain
bisection performance. There was indeed a main effect of
Line bisection tasks, in which patients are asked to estimate Hand (F(1,5) 12.273, p .017) with the right (21.08 mm
and mark the midpoint of a horizontal line, form sensitive right-biased error) showing a greater degree of neglect than
measures of neglect. Typically patients will mark the line the left (7.58 mm right-biased error). There was also a main
considerably to the right of objective centre, indicating a effect of Start Point (F(1,5) 73.00, p .000) again with
failure to take into account, or to fully perceive, the left extent greater neglect for a right start point (20.42 mm rightward
of the line. Healthy adults have, in contrast, a tendency to error) compared with the left (8.25 mm right-biased error).
bisect lines slightly to the left of centre (Bradshaw and These main effects were interpreted in the context of a
Mattingley, 1995). In order to examine any relationship significant two-way interaction between Hand and Start Point
between neglect in the visual and tactile domains, BG was (F(1,5) 18.75, p .007), such that performance was worst
first asked to bisect visually presented horizontal lines of for the right hand when starting at the right end of the rod (see
30 cm length (10 trials). In the tactile condition she was asked Fig. 6). When the right hand was given a left start, perfor-
to identify the midpoint of a 30 cm long rod. In each trial (and mance was much improved, on par with the superior left hand
before seeing the rod) she was asked to close her eyes. The use (from either start direction). The results are therefore
experimenter then guided the index finger of her left or right consistent with previously observed limb activation effects.
hand to either the left or right end of the rod (6 trials Previous studies have shown, however, that these effects,
precondition). She was encouraged to run her finger along where present, may be apparent on some, but not all tasks

Fig. 6. Tactile bisection performance for right and left hand, starting at the right and left end of the rod.
270 A. K. Ho et al.

(Brown et al., 1999). To investigate whether apparent reduc- on the left). It is certainly difficult to account for the striking
tion in neglect associated with the left-hand condition in the mis-location of monaurally presented tones in terms of mild
tactile bisection task was a more general feature of BGs hearing loss. Notably, this mislocation only affected tones
presentation, the following study was conducted. originating within left space.
Stimulus sheets showing twelve easily nameable objects in
a random spatial distribution were presented at BGs midline.
Sustained attention function
In each trial BG was asked to name the objects she could see
while simultaneously engaging in one of four hand movement Unilateral neglect in right hemisphere stroke patients has been
conditions. These were moving her left hand in left space associated with poor performance on sustained attention tasks
(relative to midline; Ll), moving her left hand in right space (Samuelsson et al., 1988; Robertson et al., 1997). Robertson
(i.e. crossing the body; Lr), moving her right hand in right et al. (1997), for example, demonstrated that performance on
space (Rr) and moving her right hand in left space (Rl). In a non-spatial and tediously slow tone-counting task (the
each case, the movements were hidden from BGs vision by Elevator Counting subtest from the Test of Everyday Atten-
the table top. Each condition appeared twice within the design tion (Robertson and North, 1994)) formed a better discrimi-
in a balanced order. In a manner consistent with the previously nator of neglect within a right hemisphere patient group than
reported naming results, BG was only able to detect a mean of some spatial tests. BG was therefore administered this task, in
0.63/12 objects on the left (SD 0.74) compared with 9.63/12 which she was asked to listen to strings of irregularly paced
on the right (SD 1.69). There was, however, no evidence of any tones and report the total number presented (between 3 and
modulation of this bias by the hand movement conditions 14) at the end of each string. BG had great difficulty in
(mean detections in each condition Ll 10.5 (SD 2.12), Lr 9.5 performing the task, which normally attracts ceiling perfor-
(SD 3.53), Rr 10.5 (SD 0.70), Rl 10.5 (SD 0.70)). This result mance in healthy adults, without recourse to using her fingers
suggests that, if left-limb activation effects underlie the or counting aloud as each tone was played. Her use of these
improvements in BGs performance in tactile bisection, the strategies persisted even when asked to attempt to keep count
effects are either insufficient to overcome the very severe bias in her head, and enabled her to achieve the maximum score
that she exhibits in the visual domain, or as argued by Brown (7/7).
et al. (1999) the effect actually varies from one task to
another, in this case being less manifest in a visual naming
Discussion
than a purely haptic task.
Animal and human studies suggest that unilateral neglect for
contralateral space can result from damage to the basal
Assessment of neglect: Auditory domain
ganglia. Although these structures are often compromised
BG had no premorbid hearing difficulties, and no obvious in Huntingtons Disease, to date there have been no reports of
neuroanatomical cause of hearing loss. As a crude measure neglect-like phenomena in HD patients. Here we have pre-
of spatial bias in the auditory domain, therefore, BG was asked sented a patient, BG with genetically proven HD and mild
to judge whether single tones had been presented to her left or manifestations, who showed bilateral caudate hypoperfusion
right ear, or to both ears simultaneously. The stimuli were and a possible although very slight suggestion of extremely
250 ms, 440 Hz simple sine tones and were presented via mild asymmetry in frontal hypometabolism. This case is
headphones. Twenty trials of each condition were administered unique and somewhat surprising, in that she also manifests
in random order during which BG was asked to sit upright with a very severe neglect for visual material presented to the left
her head central and facing forwards. She correctly identified of her midline.
all 20 right-sided trials. She made errors on 15% (5) of left- An important question is whether this neglect primarily
sided trials, reporting two as having been presented to the right results from basic sensory loss or whether, in common with
and one as having been presented to both ears. She was un- classical descriptions of the disorder, it can be seen as a higher
certain as to the location of the remaining two trials. When the level, attentional impairment. It is certainly the case that
tone was simultaneously presented to both ears, she responded funduscopy, MRI and visual evoked potentials (including
correctly on only two occasions. On all 18 errors she reported hemifields) excluded frank homonymous hemianopia as a
the sound as having been presented to the right ear only. probable cause. In addition, her failure to make compensatory
The results are clearly not compatible with complete movements of her head/trunk in order to bring stimuli into
hearing loss in the left ear and, notably, all of BGs responses her good field is consistent with an attentional neglect
followed the actual presentation of the tone (inter-trial interval with egocentric or retinotopically centred components. Her
was not fixed) suggesting that detection was adequate. performance on a tactile bisection task and in detecting
Although a mild left-sided hearing loss may account for but mislocating left-sided auditory stimuli is also consistent
the perception of bilateral trials as having been to the right with a cross-modal deficit in the allocation of attention to
(volume differences between the ears forming a spatial cue), space. It remains unclear whether her difficulty in consciously
this could also reflect a form of auditory extinction (attention mediated eye-movements is best viewed as contributing to or
to the right stimulus extinguishing the representation of that resulting from the underlying neglect.
Neglect in Huntingtons disease 271

Neglect is a highly fractionated syndrome that can arise of neglect and one of the best established cognitive hallmarks
following damage to a wide variety of brain structures. The of HD) is also consistent with this view. There is a growing
particular symptoms and difficulties experienced by one body of evidence for unilateral neglect in some hemi-parkin-
neglect patient may be very different from those experienced sonian patients (e.g. Villardita et al., 1983; Garcia-Larrea
by another. The results of our investigations to date suggest: et al., 1996) in agreement with earlier experimental work on
selective excitotoxic or dopaminergic lesions within the basal
1. BGs neglect appears to be more closely tied to body- ganglia (Brown and Robbins, 1989; Carli et al., 1989). The
centred co-ordinates with almost no visual information presence of neglect in the context of circumscribed structural
from her left-side reaching conscious awareness. and biochemical subcortical damage in HD is therefore not
2. Evidence from naming and reading tasks indicates that the entirely surprising if there appears to be a degree of hemi-
neglect is not restricted to making limb movements into left spheric imbalance to the pathology. These results, together
space. with those from Parkinsons disease (PD), previous neurop-
3. BGs reading is strongly compromised by neglect, even sychological studies and the animal literature, are consistent in
when the information is presented to her right side. Analysis emphasising the importance of intact functional basal ganglia-
of the pattern of omissions when reading a passage of text thalamo-cortical pathways for normal space-related behav-
and through comparison with single sentence reading iour. Some caution needs to be maintained, however, in
suggests that time-on-task may exert an exacerbatory conclusive attribution of neglect to basal ganglia pathology
influence over her spatial bias. There is evidence that in this case. Although requiring a threshold that leads to
maintaining compensatory strategies that correct for ne- unacceptably high levels of false positive findings, the PET
glect requires resource limited top-down control (e.g. results hinting at a lateralised pattern of frontal hypometabo-
Bartolomeo, 2000) and that patients with right hemisphere lism suggest that entirely ruling out other foci in accounting
damage may have particular difficulty in effectively re- for BGs neglect may be premature.
cruiting these resources (Samuelsson et al., 1988; Robertson In conclusion, we demonstrate a unique and convincing
et al., 1997). The worsening in BGs performance with time case of unilateral neglect in a patient with HD. Given due
may therefore reflect a similar impairment to her apparent caution occasioned by the PET investigation highlighted
difficulty in performing a simple, non-spatial sustained above, the case is consistent with findings and theoretical
attention measure. implications from the animal literature concerning subcortical
4. Although not exhaustively examined, we could find little causes of spatial bias. It furthermore emphasises that diffuse
evidence of a spatial bias in BGs recall of familiar objects. neurodegenerative processes can present with relatively selec-
It is possible, therefore, that her neglect primarily manifests tive and focal deficits at the early stage of disease.
itself in the processing of current sensory input. She also
showed no tacit awareness of stimuli in left hemispace, at Acknowledgements
least as assessed by the Marshall and Halligan burning
house paradigm (1988). Again, further investigation, for The authors thank J.R. Hodges for comments on the manu-
example using priming paradigms, would be necessary script. A. Ho is funded by an MRC grant (ICSRT No.:
before firm conclusions can be drawn on this issue. 36485475).
5. While BGs representations of familiar/remembered objects
is apparently intact, there is evidence that her current
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Neglect in Huntingtons disease 273

A case of unilateral neglect


in Huntingtons disease

Aileen K. Ho, Tom Manly, Peter J. Nestor,


Barbara J. Sahakian, Thomas H. Bak, Trevor W.
Robbins, Anne E. Rosser and Roger A. Barker
Abstract
Unilateral neglect, an attentional deficit in detecting and acting on information
coming from one side of space is a relatively common consequence of right
hemisphere stroke. Although neglect has been observed following damage to a
variety of brain structures, to date no reports exist of neglect phenomena arising
from Huntingtons Disease (HD). However, reports in the animal and human
literature suggest that neglect is possible following damage to a primary site for
Huntingtons pathology, the basal ganglia. Here we present a patient (BG) with
genetically proven HD who, in the context of the mild intellectual, executive and
attentional impairments associated with the disorder, showed a remarkably severe
and stable neglect for left space. MRI and electrophysiological results make it
unlikely that the spatial bias could be accounted for by basic sensory loss. In
addition, behavioural investigation indicated that, although BGs neglect oper-
ated in a very striking manner along body-centred co-ordinates (missing almost
all information presented to her left), more general limitations in visual attention
were apparent to the left-side of information presented entirely to the right of the
body midline. Further evidence is presented showing that the neglect was
manifest on tactile and auditory tasks as well as those presented in the visual
domain. The presence of neglect in HD in this case is novel and somewhat
puzzling, particularly as flourodeoyglucose positron emission tomography
revealed bilateral caudate hypoperfusion. Reducing the statistical threshold on
this analysis revealed a potential frontal hypometabolism that was more marked
in the right than left hemisphere. However, as this was only apparent at a threshold
below that normally considered acceptable (due to the resulting number of false
positives), this possible account of the neglect must be viewed very cautiously.

Journal
Neurocase 2003; 9: 261273

Neurocase Reference Number:


Ms #506/02

Primary diagnosis of interest


Huntingtons disease, unilateral neglect

Authors designation of case:


BG

Key theoretical issue


* Unilateral neglect in Huntingtons disease

Key words: Huntingtons disease; unilateral neglect.

Scan, EEG and related measures


MRI, FDG-PET

Standardized assessment
United Huntingtons Disease Rating Scale (UHDRS), WAIS-R subtests, Mini
Mental State Examination (MMSE), Reitan trails test, CANTAB subtests,
verbal fluency, Visual Object and Space Perception battery (VOSP) subtests,
Balloons test, Star cancellation test, Test of Everyday Attention (TEA) subtest

Other assessment
Reading, naming, spontaneous drawing, copying, letter cancellation, visual line
bisection, tactile rod bisection, limb activation effect, tone localisation

Lesion location
* Bilateral caudate hypometabolism

Lesion type
Bilateral caudate hypoperfusion

Language
English