Oculomotor deficits affect neuropsychological performance in oculomotor apraxia type 2
Post on 27-Jan-2017
Embed Size (px)
c o r t e x 4 9 ( 2 0 1 3 ) 6 9 1e7 0 1Available online atJournal homepage: www.elsevier.com/locate/cortexResearch report
Oculomotor deficits affect neuropsychological performancein oculomotor apraxia type 2Silvia Clausi a,b,1, Maria De Luca c,1, Francesca R. Chiricozzi a,b, Anna M. Tedesco a,b,Carlo Casali d, Marco Molinari b and Maria G. Leggio a,b,*aDepartment of Psychology, University of Rome Sapienza, Rome, ItalybAtaxia Laboratory, Santa Lucia Foundation, IRCCS, Rome, ItalycNeuropsychology Unit, Santa Lucia Foundation, IRCCS, Rome, ItalydDepartment of Medical and Surgical Science and Biotechnologies, University of Rome Sapienza e Polo Pontino I.C.O.T., Latina, Italya r t i c l e i n f o
Received 21 July 2011
Reviewed 26 September 2011
Revised 22 November 2011
Accepted 21 February 2012
Action editor Georg Goldenberg
Published online 6 March 2012
Saccadic intrusions* Corresponding author. Department of PsycE-mail address: email@example.com
1 S.C. and M.D. contributed equally to this0010-9452/$ e see front matter 2012 Elsevdoi:10.1016/j.cortex.2012.02.007a b s t r a c t
Introduction: Ataxia with oculomotor apraxia type 2 is a rare and early-disabling neurode-
generative disease, part of a subgroup of autosomal recessive cerebellar ataxia, in which
oculomotor symptoms (e.g., increased saccade latency and hypometria) and executive
function deficits have been described.
The aim of this study was to evaluate the impact of oculomotor symptoms on cognitive
performance and, in particular, over reading in 2 Italian siblings affected by ataxia with
oculomotor apraxia type 2.
Methods: The neuropsychological profiles and the oculomotor patterns during nonverbal
and verbal tasks were recorded and analyzed.
Results: Saccadic intrusions and/or nystagmus were observed in all eye movement tasks.
The neuropsychological profiles were substantially preserved, with only subtle deficits that
affected visuomotor integration and attention. Reading ability decreased and became
impaired. The reading scan was disturbed by saccadic intrusions and/or nystagmus.
However, an ad hoc reading task demonstrated that deficits appeared only when the items
that were displayed enhanced oculomotor requests. The preservation of lexical-semantic
processes confirmed that the reading disability was caused by oculomotor deficits, not
Conclusion: Present findings indicate that in patients who are affected by ataxia with
oculomotor apraxia type 2, performance on neuropsychological tests, especially those that
require rapid performance and eye or handeeye control, must be analyzed with respect to
2012 Elsevier Ltd. All rights reserved.hology, University of Rome La Sapienza, Via dei Marsi 78, 00185 Roma, Italy.t (M.G. Leggio).work and should be considered co-first authors.ier Ltd. All rights reserved.
c o r t e x 4 9 ( 2 0 1 3 ) 6 9 1e7 0 16921. IntroductionTable 1 e Clinical findings.Clinical findings Patient 1 Patient 2
Sex/age at onset y/age at
Sign at onset Difficulties
Visual acuity 11/10 11/10
Dystonic movements D
Choreic movements in
Dysphagia D D
Menstrual disorders D
Areflexia D D
Distal motor deficit D D
Hand and Foot deformity D
Impaired superficial senses D
Distal sock hypesthesia D D
Volitional dyskinesias D D
Gait ataxia D D
Hypotonia D D
Dysarthria D D
Cerebellar atrophy D D
Ocular motor apraxia D D
Urge incontinence D
Axonal neuropathy D D
Serum a-fetoprotein 50.71 ng/ml 39.93 ng/mlAtaxia with oculomotor apraxia type 2 (AOA2) is a rare and
early-disabling neurodegenerative disease that, with ataxia
with oculomotor apraxia type 1 (AOA1), belongs to a subgroup
of oculomotor apraxia-associated autosomal recessive cere-
bellar ataxia (ARCA) (Moreira et al., 2001, 2004).
The onset of AOA2 occurs between age 10 and 22 years
(Criscuolo et al., 2006; Le Ber et al., 2004; Tazir et al., 2009).
Elevated serum a-fetoprotein and creatine kinase (CK)
concentrations and cerebellar atrophy have been reported
(Criscuolo et al., 2006; Le Ber et al., 2004). AOA2 is character-
ized by optional oculomotor apraxia (saccade of elevated
latency due to a failure to initiate the saccade present in about
50% of subjects), peripheral neuropathy, and extrapyramidal
signs, including choreiform movements, dystonia, and
tremor. Recently, in line with the importance of cerebellum in
cognition (Leggio et al., 2011), cognitive impairments have
been also reported (Le Ber et al., 2004). However, most neu-
ropsychological tests require unimpaired visual scanning
abilities that might be affected by AOA2-induced oculomotor
In this study, we analyzed the neuropsychological profiles
of 2 Italian siblings who were affected by AOA2 and their
oculomotor patterns during nonverbal and verbal tasks to
determine the influence of impairments in visual scanning on
Fig. 1 e T1-weighted sagittal brain MRI and T2-weighted coronal MRI sequences of patient 1 (a) and patient 2 (b). Both
subjects present with diffuse cerebellar atrophy which predominates in the vermis. This pattern is more evident in patient 1
than in patient 2.
c o r t e x 4 9 ( 2 0 1 3 ) 6 9 1e7 0 1 693they had axonal sensorimotor neuropathy and high serum
a-fetoprotein concentrations. At the time of testing both
patients were free of any medication.3. Methods
3.1. Eye movement recordings
3.1.1. Apparatus and general procedureEyemovements were recorded at a sample rate of 500 Hz from
the dominant eye (Porac and Coren, 1981) in binocular vision
using an infrared eye tracker (for details, see De Luca et al.,
1999). The participant sat in front of a 1500 computer screen(60-cm eye-screen distance), with the head fixed. A calibration
was run before each experimental trial, acquiring gaze posi-
tion only during steady fixation and excluding intrusive
movements.A simple fixation task was used to evaluate the ability to
maintain gaze over a fixed target (a white dot inscribing a red
cross, subtending .4 of visual angle) that was shown ona black background at the center of the screen. The task
required the patient to look steadily at the center of the cross
for 10 sec; 6 trials were run.
A saccade task was used to assess the latency of eye
movements in response to amoving target. The target (a black
dot, subtending .2 of visual angle), displayed on a whitebackground, appeared along the horizontal meridian in 5
consecutive positions 4.0 to each other, according toa synchronous paradigm (i.e., no gap) in a left-to-right
sequence and vice versa, repeated twice (for details, see De
Luca et al., 1999). The task was to saccade to the dot as soon
as it appeared. Three trials were run.
The reading task comprised 64 high-frequencywords and 64
nonwords. For both stimuli, 2 blocks with short items (4e5
letters) and 2 with long items (8e10 letters) were presented
(for details, see De Luca et al., 2002). Each block contained 16
c o r t e x 4 9 ( 2 0 1 3 ) 6 9 1e7 0 1694items, displayed in 4 rows at the center of the screen. The task
required to read the text silently without a time limit. After
each trial, the experimenter read 4 items, and the participant
indicated the 2 that were part of the list.
3.1.2. Data analysisDuring the offline analysis, only fixations that matched the
experimental calibration points were used to transform raw
eye movements into gaze position data. Blinks and artifacts
were rejected. Quantitative analyses were performed for the
horizontal component of eye movement. Gaze position, fixa-
tions, and saccades were detected manually by visual
inspection of the traces for all eye movement tasks. The
patients data were compared with those of their healthy 35-
year-old sister, who had a normal genotype and normal clin-
ical assessment and no history of neurological disease.
188.8.131.52. FIXATION TASK. The frequency (number/minute),amplitude (degrees), velocity (degrees/second), and duration
(milliseconds) of horizontal saccadic intrusions (SI) were
measured. T-tests for independent samples were applied to
compare amplitude, velocity, and duration measures with
control data and between patients. Chi-square test was used
to analyze the frequency of SI.
184.108.40.206. SACCADE TASK. Saccade latency was measured,excluding latencies of anticipatory saccades from the anal-
ysis. Due to the presence of SI, latency data were validated
only for saccades that did not belong to trains of SI. T-tests for
independent samples were used for comparisons with control
data. For each participant, t-tests for repeated measures were
performed separately to examine latency differences between
rightward and leftward directions of the task.
220.127.116.11. READING TASK. The mean number of fixations per itemand mean fixation duration (separately for words
and nonwords, short and long) were calculated, netted of SI.
T-tests for independent samples were used for comparison
with control data.
3.2. Neuropsychological examination
3.2.1. Neuropsychological assessmentAn extensive neuropsychological battery was used to evaluate
the following cognitive domains: visuospatial abilities,
language abilities, executive functions, verbal and visuospatial
memory, visual-motor integration (VMI), and attention. Intel-
ligence was also measured. The tests (Beery, 1997; Borkowsky
et al., 1967; Carlesimo et al., 1996; Corsi, 1972; De Renzi and
Faglioni, 1978; Gainotti et al., 1977, 2001; Gauthier et al., 1989;
Miceli et al., 1994; Orsini and Laicardi, 2001; Raven, 1947; Rey,
1958; Shallice, 1982; Villa et al., 1990; Wechsler, 1997;
Weintraub and Mesulam, 1985; Zimmermann and Fimm,
1995) are detailed in Table 2.
3.2.2. Additional reading and vocal testsTo better assess reading abilities, we used a test that was based
ondifferences in text arrangement: thenew-Developedwordsand
nonwords Reading task (nDR task). In the nDR task, stimuli (words
or nonwords) were selected from the battery for evaluatingdyslexia and dysorthography (subtests 4 and 5) (Sartori et al.,
1995). The width of each stimuli ranged between .8 and 2.3.The stimuli were presented on a 1700 computer screen (blackletters in courier on a white background), arranged in columns
(vertical display) or as plain text (horizontal display). In the
vertical display, 4 lists (2 containing 23 words and 2 containing
23 nonwords) were presented separately, alternating between
8 cm left or right of the screen center. In the horizontal display,
55 words and 55 nonwords were presented at the monitor
center in2 sessions, eachcontaining7 rows, subtendinganarea
of 16 13. Reading time (sec/item) and percentage of errorswere computed for each subtest.
The simple vocal reaction time task was used to assess visual
alertness under conditions (uncued and cued) that required
only a vocal response (for details see Spinelli et al., 2002).
Median vocal reaction times (RTs) were measured.
The word length effect was evaluated by the vocal reaction
time to 4e7-letter words task (modified from Zoccolotti et al.,
2006). Forty-eight single words of various lengths (4e7
letters) were displayed (with a 6-sec time limit) in the center of
a PC screen after a fixation cross. Participants read the word
aloud as quickly as possible. Median RTs to read the words
correctly and the percentage of errors were measured.
The lexical decision task was used to evaluate the lexicality
effect. Words and nonwords were presented individually at
the center of a PC screen (for details, see Di Filippo et al., 2006).
The task required one to decide whether the stimulus was
a legal Italianword and press 1 of 2 keys as quickly as possible.
Median RTs of correct responses and percentage of errors
The articulation task (Di Filippo et al., 2005) was used to
evaluate the contribution of articulation rate to speed of
reading aloud. The mean time (sec/digit) to perform the task
3.2.3. Data analysisA group of 6 healthy adults (males/females 3/3), matched forage (mean age 38.4 years, Standard Deviation e SD 1.9) andyears of education (13), constituted the control group. The
control subjects took the reading and vocal tests, aswell as the
neuropsychological tests for the general assessment without
normative Italian data: the semantic verbal fluency task,
BeeryeBuktenica developmental test of VMI, bells test, lines
cancellation task (LC), multiple features targets cancellation
task (MFCT), and letter cancellation test. Bayesian inferential
methods (Crawford and Garthwaite, 2007) were used to
compare the results of each patient with those of the controls.
Published normative data were used for the remaining tests,
and relative cutoff values used for comparison.4. Results
4.1. Eye movements
Eyemovement traces showed oculomotor disturbancesdboth
patients had highly frequent SI, the amplitude of which was
particularly large in patient 1. Nystagmus was observed only
in patient 2. Excerpts of the traces that were recorded during
the tasks are presented in Fig. 2. As shown in the figure, both
Table 2 e Neuropsychological assessment.
Functions Tests Patient 1 Patient 2 Cutoff Controls(mean SD)
Intellectual level WAIS-R Total IQ 91 94 2
Visual 2/45 0/45 >2
Phonemic fluency test 22.8 18.5 15
Tower of London planning task 32 34
Fig. 2 e Excerpts of eye movement traces in the healthy control, patient 1, and patient 2. Black line represents gaze position
as a function of time. Gray line in insets a and b represents target position. (a) Fixation task: note the vertical displacements
in the gaze traces of patient 1 and patient 2, indicative of SI. Control data were comparable with reference data (Abadi and
c o r t e x 4 9 ( 2 0 1 3 ) 6 9 1e7 0 1696
c o r t e x 4 9 ( 2 0 1 3 ) 6 9 1e7 0 1 697patients presented clear pathological features. To provide
a direct comparison, patients results were compared to those
of the healthy sibling that was representative of the healthy
4.1.1. Fixation task (Fig. 2a)The severe condition of both patients is clearly shown: their
discontinuous fixation profile is contrasted with the normal
profile of steady fixation over time performed by the healthy
sibling. SI frequency, amplitude, and duration of the sibling
(25.5 .7 SI per minute, 1.01 .68, and 283 106 msec,...