Oculomotor deficits affect neuropsychological performance in oculomotor apraxia type 2

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    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

    Article history:

    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




    Eye movements


    Saccadic intrusions* Corresponding author. Department of PsycE-mail address: maria.leggio@uniroma1.i

    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

    cognitive problems.

    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

    oculomotor components.

    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

    examination y

    F/20/38 M/15/40

    Sign at onset Difficulties

    in writing



    Visual acuity 11/10 11/10

    Dystonic movements D

    Choreic movements in

    superior limbs


    Dysphagia D D

    Diplopia D

    Menstrual disorders D

    Areflexia D D

    Distal motor deficit D D

    Hand and Foot deformity D

    Impaired position/

    vibration sense

    D D

    Impaired superficial senses D

    Distal sock hypesthesia D D

    Volitional dyskinesias D D

    Gait ataxia D D

    Dysmetria 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

    cognitive performance.

    concentration (normal


  • 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. 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. 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. 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

    were measured.

    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

    was calculated.

    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

    populations performances.

    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,...


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