Frontal lobe dysfunction in amyotrophic lateral sclerosis I. Evdokimidis * , T.S. Constantinidis, P. Gourtzelidis, N. Smyrnis, I. Zalonis, P.V. Zis, E. Andreadou, C. Papageorgiou ENG Lab of Neurology Clinic of Athens Medical School, Aeginitio Hospital, Vas. Sofias 72-74, Athens 11528, Greece Received 2 March 2001; received in revised form 27 September 2001; accepted 26 November 2001 Abstract The aim of the present study was to investigate the involvement of frontal lobe dysfunction in amyotrophic lateral sclerosis (ALS) using ocular motor paradigms and neuropsychological testing. Fifty-one patients with ALS participated in the following ocular motor tasks: (1) a three-choice task and (2) a remembered saccade task. The patients underwent a clinical and neuropsychological evaluation. One-third of ALS patients presented with signs of frontal dysfunction, as determined by their high distractibility factors (DF) in the three-choice task and their performances in both the Wisconsin and Stroop tests. ALS patients exhibited longer latencies to eye movement than controls in the performance of the remembered saccade task, specifically in performance of both remembered and delayed saccades, but saccade accuracy was not impaired. Finally, performance indices of the ocular motor tasks, in particular the DF, was correlated only with the degree of dysarthria. D 2002 Elsevier Science B.V. All rights reserved. Keywords: ALS; Motor neuron; Frontal lobe; Anti-saccade; Remembered saccade; Working memory 1. Introduction The clinical spectrum of ALS that was described last century by Charcot did not involve the ocular motor system. In fact, the degenerative process occurring in ALS affects mainly the corticospinal system and the anterior horn a- motorneurons while sparing the brainstem ocular motor circuitry, even in cases where the corticobulbar circuitry is also affected. Although earlier studies reported several slight oculographic abnormalities, including reduced saccadic eye movement velocity and low smooth eye pursuit gain [1–3] that were not apparent in the clinical evaluation of the patients, these findings have not been replicated in the recent literature [4,5]. Thus, it appears that the functional integrity of the saccadic system at the brainstem level is maintained. However, it is not known whether the ocular motor circuitry used in higher cognitive functions is affected by the disease. Classically, cortical degeneration in ALS was believed to be restricted to the primary motor areas. However, several clinical, pathological, imaging and neuropsychological find- ings have challenged this overly simplistic notion [5 – 9]. A small minority of patients suffering from sporadic ALS presented with memory and cognitive dysfunction, indicat- ing a dementia of frontal lobe type [9]. Furthermore, pathology studies as well as findings from PET, SPECT and MRI investigations have already revealed that the degenerative neuronal loss in ALS extends beyond the primary motor cortex and includes other areas, mainly in the prefrontal cortex [7–9]. In addition, evidence from neuropsychological studies supports frontal lobe involve- ment in sporadic ALS leading to significant impairment of executive functions. More specifically, ALS patients repeat- edly demonstrate decreased performance in the Wisconsin Card Sorting Test, poor verbal fluency and difficulties in problem solving, as well as increased latencies when per- forming the random movement joystick test. However, they perform normally in visuospatial, naming and memory tests [10 – 13]. These findings are consistent with a frontal pattern of impairment rather than, for example, the temporo-parietal pattern found in Alzheimer’s disease. The performance of a saccadic eye movement involves the activation of cortical areas and the pattern of cortical activation depends on the behavioral context in which the saccade is elicited. In the case of an anti-saccadic eye movement, the subject is instructed to perform an eye movement in the opposite direction of a visual target with 0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII:S0022-510X(01)00683-9 * Corresponding author. Tel.: +30-1-728-9115; fax: +30-1-721-6474. E-mail addresses: ievdokim@cc.uoa.gr, tscon@otenet.gr (I. Evdokimidis). www.elsevier.com/locate/jns Journal of the Neurological Sciences 195 (2002) 25 – 33