Memory guided saccades in mesial temporal lobe epilepsy with hippocampal sclerosis

Clinical Neurophysiology 117 (2006) 2392–2398 www.elsevier.com/locate/clinph

Memory guided saccades in mesial temporal lobe epilepsy with hippocampal sclerosis S. Colnaghi *, C. Arbasino, G. Beltrami, C.A. Galimberti, V. Cosi, M. Versino Laboratorio Movimenti Oculari, Fondazione Istituto Neurologico C.Mondino IRCCS, Dipartimento di Scienze Neurologiche, Universita` degli Studi di Pavia, Italy Accepted 4 July 2006 Available online 15 September 2006

Abstract Objective: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural and functional damage. The incidence and the features of this damage are still a matter of debate and vary depending on the method applied. Memory guided saccades (MGSs) with a memorization delay longer than 20 s can be used reliably to evaluate the parahippocampal cortex. Methods: MGSs with 3 and 30 s memorization delays were recorded with the search coil technique in six patients affected by right MTLE-HS, and in 13 healthy controls. Results: The patients were not able to reduce the MGSs residual amplitude error after the first saccade with a 30 s memorization delay. This finding was more evident with leftward saccades. Conclusions: MGS abnormalities suggested the functional involvement of the right parahippocampal cortex in most of the patients with MTLE-HS, and this supports the clinical and anatomopathological heterogeneity of the disease. Significance: MGSs can be used in patients with right MTLE-HS to detect a possible functional involvement of the ipsilateral parahippocampal cortex. Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Memory guided saccades; Spatial memory; Parahippocampal cortex; Mesial temporal lobe epilepsy

1. Introduction Memory guided saccades (MGSs) are volitional saccades generated towards a location in which a target was previously present. MGSs can be used as a complementary method for studying the cortical control of spatial memory in humans (Leigh and Kennard, 2004). The MGSs paradigm (Fig. 1) was studied both in normal subjects by means

Abbreviations used: E, amplitude error; ED, amplitude error difference; DLPFC, dorsolateral prefrontal cortex; MGSs, memory guided saccades; MTLE-HS, mesial temporal lobe epilepsy with hippocampal sclerosis; PHC, parahippocampal cortex; RSs, reflexive saccades; SA, saccade accuracy. * Corresponding author. Tel.: +39 0382 380340; fax: +39 0382 24714. E-mail address: [email protected] (S. Colnaghi).

of behavioural studies, functional imagery, and transcranial magnetic stimulation, and in patients by means of lesion studies. Such investigations led to a spatially and temporally accurate model of the MGSs cortical control (PierrotDeseilligny et al., 2002). In particular, several studies showed that amplitude errors in MGSs with memorization delays from 1 to 20 s reflected the function of the dorsolateral prefrontal cortex (DLPFC) (Mu¨ri et al., 1996) and that amplitude errors in MGSs with memorization delays longer than 20 s and up to a few minutes reflected the function of the parahippocampal cortex (PHC) (Ploner et al., 1999; Mu¨ri et al., 2000; Ploner et al., 2000; Nyffeler et al., 2004). Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural and functional disturbances, which can be identified both by pathological findings and by imaging. The

1388-2457/$32.00 Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.07.135

S. Colnaghi et al. / Clinical Neurophysiology 117 (2006) 2392–2398

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Fig. 1. Eye tracing during the execution of the MGS paradigm in which three phases can be distinguished: (1) the presentation of the target that involves visual and attentive cortical areas; (2) the memorization delay during which either the dorsolateral prefrontal cortex or the parahippocampal cortex stores the spatial information, respectively, for delays of up to 20 s and for delays that last longer than 20 s and up to a few minutes; (3) the movement execution, controlled by the frontal and parietal eye fields.

incidence of damage to these areas varies depending on the method applied, and additional studies are needed to define the nature and location of this extrahippocampal pathology better (Wieser, 2004). Moreover, material specific memory impairment is found in patients affected by MTLE-HS depending on their hemispheric language dominance, with verbal memory deficits lateralized to the left hemisphere if this is the language dominant hemisphere, and with a weaker association between visual memory impairment and right temporal dysfunction (Helmstaedter et al., 1995; O’Brien et al., 2003). In the present study, we used MGSs with memorization delays of 3 and 30 s to evaluate the PHC function in patients with right MTLE-HS. We decided to study only patients with right MTLE-HS because a deficit in spatial memory is more likely in the case of a right than of a left hippocampal damage. 2. Methods 2.1. Subjects Six right-handed patients with MTLE-HS were selected among the outpatients consecutively referred to the Epilepsy Centre of the Neurological Institute C. Mondino of Pavia by excluding non-collaborative patients, those older than 60 years, and those with a seizure frequency more than 2 per week. Epilepsy diagnosis was supported by clinical, EEG and MRI criteria. In all patients ictal symptoms and signs suggested a mesial temporal lobe seizure onset (Wieser, 2004). In each patient the brain MRI showed abnormalities of

volume (atrophy) and signal (T2 increase) that were limited to the right hippocampal formation, and in particular none of the patients had parahippocampal atrophy. Interictal epileptiform abnormalities detected by wake and sleep EEG studies (routine EEG and 24 h ambulatory EEG or laboratory video-EEG monitoring in each patient) were confined or more prominent on the right hemisphere in five patients and bilateral in one patient. Two patients had their typical seizures recorded by video-EEG, with ictal discharges showing onset and higher prominence on the right hemisphere. In two more patients some observed ictal phenomena (dystonic posturing of the left upper limb with extension at the elbow in one patients; retained speech in the other one) were consistent with a right-sided epileptogenic zone (Koerner and Laxer, 1988; Gabr et al., 1989; Bleasel et al., 1997; Wieser, 2004). Seizures of the remaining two patients (whose interictal epileptiform abnormalities were confined to the right hemisphere) were clinically recorded as auras followed by contact impairment with semipurposeful automatisms, right MTS being the only MRI abnormality. All patients were on treatment with antiepileptic drugs with serum levels in therapeutic range. The patients respective clinical data are reported in Table 1. The controls were 13 right-handed healthy subjects (7 women and 6 men; mean age: 39.3 years, SD: 11.3, range: 26–60 years) age-matched with the patient group (mean age: 45.5 years, SD: 14.6, range: 30–60 years, p = 0.37). All the subjects gave their informed consent before participating in the study.

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Table 1 Patients data Patient

Sex

Age (years)

Seizures per month

Epilepsy duration (years)

EEG

MRI

30 s MGSs

Drugs (mg/day)

*

1

M

30

4–5

20

R

HS

A

2*

M

53

1–2

15

B

HSc

N

3

F

39

8–9

38

Ra

HS

N

4

F

59

2–4

35

R

HSb

A

5

F

52

1–2

9

R

HSb

A

6*

F

39

2–4

7

Ra

HS

A

CBZ 800 PHT 200 CLB 30 LTG 600 CLB 20 LEV 500 CBZ 1100 LTG 500 CBZ 1000 LEV 3000 PHT 325 LEV 3000 CLB 20 CBZ 800 LTG 200

*

Patients with ictal-postictal motor and language phenomena highly suggestive for a right-sided epileptogenic zone. R: interictal epileptiform abnormalities confined or more prominent on the right hemisphere. a Typical seizures recorded by video-EEG with ictal discharges showing onset and higher prominence on the right hemisphere; B: bilateral interictal epileptiform abnormalities. HS: MRI findings limited to right hippocampal sclerosis. b Hippocampal sclerosis plus minimal cerebrovascular signs not involving the temporal lobe and the hippocampal and parahippocampal structures, and the cerebral cortex. c Hippocampal sclerosis plus arachnoid cyst in the right frontal lobe, without compressive effects. 30s MGSs: 30 seconds delay memory guided saccades (A: abnormal; N: normal). CBZ: controlled-release carbamazepine; PHT: phenitoine; LTG: lamotrigine; LEV: levetiracetam; CLB: clobazam.

2.2. Eye movements recording

2.3. Data analysis

Assessment was performed at least 36 h after the last reported seizure. The eye movements were calibrated and recorded monocularly from the right eye with the scleral search coil technique (SKALAR system S3020: spatial resolution better than 0°, 1°; sampling rate 250 Hz, bandwidth 0–70 Hz). The subjects were seated in a dark room with their head in the upright position on a chinrest. For every subject, we recorded the reflexive saccades (RSs), the MGSs with a 3 s delay, and the MGSs with a 30 s delay in three separate sessions. In each session, every subject performed 18 trials in both directions (leftward and rightward saccades) for a total of 108 trials each. In the RSs paradigm, a horizontally presented lateral target with an unpredictable direction and amplitude (10°, 15° or 20°) was lit for 2 s while the subject was staring at a central point. The subjects were instructed to look at this light immediately after its appearance and until it disappeared. The next trial began at the central fixation point. In the MGSs paradigm, the subjects tried to memorize the location of a horizontally presented lateral target lit for 200 ms while they were staring at the central point. The target had unpredictable direction and amplitude (10°, 15° or 20°). After the memorization delay of 3 or 30 s, the central fixation point was switched off, which was the signal for the subject to perform a saccade towards the memorized location. The previously flashed target was shown again after 2 s and the subject had to make a corrective saccade if necessary. The next trial began at the central fixation point.

MGSs trials with prosaccades, namely erroneous RSs directed at the flashed target, were excluded from analysis, but their frequency was acknowledged for each subject, for each task, and for each saccade direction. An interactive software analyzed the saccades off-line by identifying the beginning and the end of each saccade based on threshold velocity criteria; the difference in the eye position at these two points corresponded to the pulse amplitude. The operator positioned one additional mark that identified the final position, namely the position the eye reached after all the corrective saccades and before the reappearance of the target; the difference between the starting and final positions corresponded to the final amplitude. We computed: 1. the saccade accuracies (SAs) as: pulse SA = pulse amplitude/target amplitude, final SA = final amplitude/target amplitude 2. the amplitude errors (Es) as: pulse E = ln j1  pulse SAj, final E = ln j1  final SAj 3. the amplitude error difference (ED) as: ED = final E  pulse E. A logarithmic transformation was needed in order to approximate a normal distribution of the values, and we used the absolute value of the j1  SAj differences to express a scatter of the MGSs endpoints despite the presence of both hypo- and hyper-metric saccades.

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For each subject, paradigm, and saccade direction, we computed the mean value of latency, SAs, Es, and ED, as well as the standard deviation of SAs. The patients were compared to the controls as a group by using repeated measure analyses of variance on all the parameters listed before. The RSs and the 3 and 30 s MGSs were analyzed separately. The analyses considered one intra-individual factor (saccade direction: right or left), one inter-individual factor (group: controls or patients), and their interactions. We used v2 test to evaluate the occurrence of patients whose mean value exceeded the normal range, which was calculated on the control group as the mean ± 2.5 standard deviations. The respective percentages of the prosaccadic eye movements in the two groups were compared using a t-test. 3. Results

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influence the SA standard deviation values nor the SA, the E, and the ED mean values, with only two exceptions. The pulse SA mean value proved to be significantly larger for rightward than for leftward saccades (F(1,17) = 9.98, p = 0.006) both in patients and in controls. This abduction/adduction asymmetry was expected since saccades were recorded from the right eye in all the subjects (Collewijn et al., 1988). More interestingly, the final-pulse ED mean value for the 30 s delay MGSs was significantly different in the patients compared to the controls (F(1,17) = 8.72, p = 0.009): the patients were not able to decrease their E by means of the corrective saccades following the first saccadic eye movement. This behaviour was more evident for leftward than for rightward saccades, although this asymmetry was not statistically significant. The saccade direction did not influence the mean latency values of the RSs or the 3 and 30 s delay MGSs, and the values did not differ between the patients and the controls.

3.1. Group analyses 3.2. Individual analyses The mean values of SA, E, and ED are reported in Fig. 2. Left and right pulse, step and final amplitude errors (Es) and amplitude error differences (EDs) for each paradigm in each patient, mean of the amplitude errors and of the amplitude error differences for each saccadic direction in patients, mean and standard deviation (SD) of the amplitude errors and of the amplitude error differences for each direction in controls are reported in Table 2. Both for the RSs and for the MGSs with 3 and 30 s delays, the saccade direction and the group factor did not

The final-pulse ED of the leftward saccades was the only parameter that showed a significantly higher occurrence of abnormalities in the patients: four out of the six patients as opposed to none of the 13 controls (v2 = 10.98 p = 0.004). When there was an abnormality, the final-pulse ED mean values were positive (Fig. 3), which meant that the corrective saccades increased E in the patients rather than decreased it as they did in the controls (Fig. 4).

Fig. 2. Mean values of saccade accuracy and amplitude error difference, and natural logarithm of amplitude error mean values. More negative E values correspond to a lesser degree of E. Negative ED values mean that final E is smaller than pulse E. Arrows indicate abnormal ED values in the patients. 0 s, Reflexive saccades; 3 s, three second delay MGSs; 30 s, 30 second delay MGSs; Ctrls, controls; Pts, patients.

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Table 2 Left and right pulse, step and final amplitude errors (Es) and amplitude error differences (EDs) for each paradigm in each patient, mean of the amplitude errors and of the amplitude error differences for each saccadic direction in patients, mean and standard deviation (SD) of the amplitude errors and of the amplitude error differences for each direction in controls Parameter:

Pulse E

Paradigm:

MGS 3

MGS 30

MGS 3

MGS 30

MGS 3

MGS 30

MGS 3

Direction:

Right

Left

Right

Left

Right

Left

Right

Left

Right

Left

Right

Left

Right

Left

Right

Left

Patient Patient Patient Patient Patient Patient

1.94 2.11 1.72 1.11 1.83 1.55

2.36 1.86 1.50 1.04 2.64 1.77

1.58 2.49 1.90 0.77 1.86 2.02

2.38 2.89 1.34 0.97 3.24 2.72

1.94 2.35 1.71 1.66 2.58 1.72

2.52 2.09 1.87 1.13 2.71 1.95

1.38 2.60 1.22 1.00 1.86 1.68

2.13 2.93 1.28 1.07 3.32 2.28

2.05 3.57 2.01 1.50 2.53 2.18

2.99 3.08 1.91 2.30 3.20 2.31

1.87 2.32 1.93 1.73 2.15 1.65

1.97 2.32 2.22 1.62 2.67 2.12

0.11 1.46 0.29 0.38 0.71 0.64

0.63 1.22 0.41 1.27 0.56 0.53

0.28 0.17 0.03 0.96 0.29 0.37

0.45 0.58 0.88 0.65 0.57 0.59

1.71 2.11 0.65

1.86 1.94 0.51

1.77 1.77 0.51

2.26 1.60 0.54

1.99 2.33 0.46

2.05 2.19 0.66

1.62 1.78 0.58

2.17 1.89 0.66

2.31 2.60 0.52

2.63 2.71 0.71

1.94 2.39 0.68

2.15 2.43 0.75

0.60 0.49 0.73

0.77 0.77 0.60

0.17 0.63 0.62

0.11 0.84 0.51

1 2 3 4 5 6

Patients mean Controls mean Controls SD

Step E

Final E

3.3. Prosaccades analyses The mean percentage of the prosaccadic eye movements ranged from 4% to 17%, and it did not differ in the patients’ group compared to the controls’ group, as expected in the case of a normal function of the DLPFC. 4. Discussion The only abnormalities detectable in our patients concerned the MGSs with a 30 s delay. The amplitude and latency values of the MGSs that were detectable in the controls were similar to those previously reported by other authors (Mu¨ri et al., 1994; Ploner et al., 1998; Ploner et al., 1999; Nyffeler et al., 2002). The patients differed from the controls because of their final-pulse ED at the 30 s memorization delay, and this held true both for the mean value comparison and for the individual evaluation. The corrective saccades reduced E less effectively (rightward MGSs), or even increased it

Final-Pulse ED MGS 30

(leftward MGSs), but only for the 30 s delay MGSs. In this case, the first saccade was equally accurate in the patients and in the controls, but the patients seemed not to appreciate how close they were to the target, and, with successive saccades, they would even move their eyes away from the target (sometimes going back, sometimes going too far), wasting their initial good work. This finding is in keeping with Ploner’s research (Ploner et al., 1999), which reported an E increase after the corrective saccades in patients with a partial resection of the right mesial temporal lobe involving the PHC. The brain achieves an effective control of the eye’s position by monitoring its own motor commands (efference copy) (Leigh and Zee, 1999). The ED abnormality could be due to a defective control of the eye’s position, but this explanation is unlikely both because the 3 s delay MGSs were normal, and because none of our patients’ MRIs disclosed lesions in the thalamus (Gaymard et al., 1994) or in the cortical areas (Duhamel et al., 1992; Pierrot-Deseilligny et al., 1993; Heide et al., 1995) that may contribute to the

Fig. 3. Natural logarithm of the mean values of the pulse amplitude error (pulse E), the final amplitude error (final E), and the final-pulse amplitude error difference (final-pulse ED) of MGSs at 30 s memorization delay directed toward the left of the six patients (on the left of the figure) and of the 13 controls (on the right of the figure), respectively. More negative E values correspond to a lesser degree of E. Positive ED values mean that final E is larger than pulse E. Arrows indicate abnormal ED values in 4 out of the 6 patients.

S. Colnaghi et al. / Clinical Neurophysiology 117 (2006) 2392–2398

Fig. 4. An example of MGS tracing in a patient in which final E is larger than pulse E.

efference copy signal. Other studies demonstrated a crucial role of the PHC in the control of the MGSs with a memorization delay that lasted longer than 20 s (Ploner et al., 1999; Mu¨ri et al., 2000; Ploner et al., 2000; Nyffeler et al., 2004). These studies also suggested that the neuronal activity of the PHC related to the control of the MGSs represents an afferent extraretinal signal that updates spatial representations rather than an efferent signal that is directly involved in ocular motor control (Sobotka et al., 1997; Ploner et al., 1999). Accordingly a more plausible explanation for ED abnormality in our patients could be an impairment of the medium term spatial memory: they knew where they were, but they did not know where to go. This hypothesis suggests that patients with MTLE-HS may have functional damage in the PHC. Previous studies proved that the PHC controls contralateral MGSs (Ploner et al., 1999, 2000), thus the PHC impairment identified in our study was ipsilateral to the hippocampal atrophy. This conclusion is drawn by the comparison with healthy subjects, thus, as suggested by one of the peer reviewers, age differences, the use of antiepileptic drugs, the presence of interictal abnormalities and epilepsy itself may be regarded as possible confounding factors that could be ruled out only by evaluating an additional group of epileptic patients, possibly with MTLE and left HS or with MTLE without HS. However, the detected abnormalities are restricted to the accuracy of 30 s delay MGSs directed toward the left, while reflexive saccades and 3 s delay MGSs and 30 s delay MGSs directed toward the right did not differ from controls: the specificity of this result by itself can rule out aspecific effects of age, antiepileptic drugs, epilepsy and interictal abnormalities. Furthermore, the two groups are age-matched, and the therapeutic regimens, the disease duration and the seizure frequency are quite different among our patients; finally, the two patients without abnormal 30 s delay MGSs are not distinguishable from the other four on the basis of their age, disease duration, seizure frequency and therapeutic regimen. Thus, the ED abnormality of leftward 30 s delay MGSs is less likely

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attributable to the presence of all of these confounding factors than to the involvement of the right parahippocampal cortex in four out of six patients with right MTLE-HS. Neuropsychology enables us to evaluate the temporal lobe, but it is less efficient for the right than for the left hemisphere when trying to identify the side of impairment. In accordance with the clinical and anatomopathological heterogeneity of MTLE-HS, not all the patients in our study presented an ED abnormality, and one of the two patients with normal ED had bilateral interictal EEG abnormalities despite right HS as detected by MRI. The results of our study suggest that MGSs may contribute to the diagnosis of right MTLE-HS in the patients in which the other techniques were inconclusive regarding the side of the epileptogenic zone, in particular to detect a functional impairment of PHC in absence of MRI structural abnormalities; further studies of MGSs in patients with left MTLE-HS are needed to confirm the usefulness of the method. Pre and post-surgical studies could elucidate whether the PHC dysfunction reflects a functional involvement related to the presence of the epileptic activity or an extrahippocampal extension of the anatomopathological damage. References Bleasel A, Kotagal P, Kankirawatana P, Rybicki L. Lateralizing value and semiology of ictal limb posturing and version in temporal lobe and extratemporal epilepsy. Epilepsia 1997;38(2):168–74. Collewijn H, Erkelens CJ, Steinman RM. Binocular co-ordination of human horizontal saccadic eye movements. J Physiol 1988;404:157–82. Duhamel JR, Goldberg ME, Fitzgibbon EJ, Sirigu A, Grafman J. Saccadic dysmetria in a patient with a right frontoparietal lesion. The importance of corollary discharge for accurate spatial behaviour. Brain 1992;115:1387–92. Gabr M, Lu¨ders H, Dinner D, Morris H, Wyllie E. Speech manifestations in lateralization of temporal lobe seizures. Ann Neurol 1989;25(1):82–7. Gaymard B, Rivaud S, Pierrot-Deseilligny C. Impairment of extraretinal eye position signals after central thalamic lesions in humans. Exp Brain Res 1994;102:1–9. Heide W, Blankenburg M, Zimmermann E, Kompf D. Cortical control of double-step ssaccades: implications for spatial orientation. Ann Neurol 1995;38:739–48. Helmstaedter C, Pohl C, Elger CE. Relations between verbal and nonverbal memory performance: evidence of confounding effects particularly in patients with right temporal lobe epilepsy. Cortex 1995;31:345–55. Koerner M, Laxer K. Ictal speech, postictal language dysfunction, and seizure lateralization. Neurology 1988;38(4):634–6. Leigh RJ, Kennard C. Using saccades as a research tool in the clinical neurosciences. Brain 2004;127:460–77. Leigh RJ, Zee DS. The neurology of eye movements. third ed. New York: Oxford University Press; 1999. Mu¨ri RM, Gaymard B, Rivaud S, Vermersch A, Hess CW, PierrotDeseilligny C. Hemispheric asymmetry in cortical control of memoryguided saccades. A transcranial magnetic stimulation study. Neuropsychologia 2000;38:1105–11. Mu¨ri RM, Rivaud S, Timsit S, Cornu P, Pierrot-Deseilligny C. The role of the right medial temporal lobe in the control of memory-guided saccades. Exp Brain Res 1994;101:165–8. Mu¨ri RM, Vermersch AI, Rivaud S, Gaymard B, Pierrot-Deseilligny C. Effects of single-pulse transcranial magnetic stimulation over the prefrontal and posterior parietal cortices during memory-guided saccades in humans. J Neurophysiol 1996;76:2102–6.

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