Abstract

Abstract Background. Amantadine sulfate (AS) modulates glutaminergic transmission within the central nervous system and can thus affect attention level and other cognitive processes. Objectives. The aim of this study was to evaluate attention level and parameters of auditory event−related poten− tials (ERPs) in patients with cerebrovascular disease treated with intravenous AS. Material and Methods. The study group consisted of 15 patients, aged 57-87 years, with multifocal cerebral ischemic lesions. The Trail Making Test (TMT−B) and auditory ERPs (defining parameters of the P300 component) were performed before and five days after intravenous administration of AS. The initial P300 parameters were compared with those obtained in a control group. For the patients, TMT−B and ERP results before and after admin− istration of AS were compared. Results. Initial TMT−B results were abnormal in 86.6% of the patients. Mean latency of P300 was significantly longer in the patients than in the controls. The TMT−B results improved in 66% of the patients and mean P300 latency decreased significantly after treatment with AS. Conclusions. AS given intravenously may improve attention level in patients with cerebrovascular disease (Adv Clin Exp Med 2008, 17, 5, 553-558). Key words: cerebrovascular disease, cognitive dysfunction, event−related potentials, amantadine sulfate. Streszczenie Wprowadzenie. Siarczan amantadyny (AS) moduluje przekaźnictwo glutaminergiczne w obrębie ośrodkowego układu nerwowego, wpływając w ten sposób na poziom uwagi i inne funkcje poznawcze. Cel pracy. Ocena poziomu uwagi i parametrów endogennych potencjałów wywołanych (ERP) u pacjentów z na− czyniopochodnym uszkodzeniem mózgu, leczonych dożylnie podawanym AS. Materiał i metody. Badanie objęło 15 chorych, w wieku 57-87 lat, z wieloogniskowym naczyniopochodnym uszkodzeniem mózgu. Przeprowadzono Test Kreślenia Drogi (Trail Making Test -TMT−B) oraz badanie słucho− wych ERP (z określeniem parametrów potencjału P300); badania powtórzono po 5 dniach podawania chorym do− żylnej postaci AS. Wyjściowe parametry P300 porównano z wynikami odpowiedniej wiekowo grupy kontrolnej. W grupie pacjentów porównano wyniki TMT−B i ERP przed i po podaniu AS. Wyniki. U 86,6% chorych wynik TMT−B był nieprawidłowy. Średnia latencja P300 w grupie chorych była istot− nie dłuższa niż w grupie kontrolnej. Po podaniu AS uzyskano poprawę wyników TMT−B u 66% chorych oraz zna− mienne skrócenie średniej latencji P300. Wnioski. AS podawany dożylnie może korzystnie wpływać na poziom uwagi i parametry ERP u chorych z naczy− niopochodnym uszkodzeniem mózgu (Adv Clin Exp Med 2008, 17, 5, 553-558). Słowa kluczowe: naczyniopochodne uszkodzenie mózgu, zaburzenia funkcji poznawczych, endogenne potencjały wywołane, siarczan amantadyny. Amantadine sulfate (AS) acts as a dopamine agonist (enhancing dopamine release and receptor density) and non−competitive antagonist of N−me− thyl−D−aspartate (NMDA) receptors. Because of its ability to modulate glutaminergic transmission (especially in pathological conditions caused by CNS lesions), AS may exhibit neuroprotective activity (preventing excititoxic neuronal damage) and influence processes of awareness and cognition The aim of this study was to evaluate attention level and parameters of auditory event−related potentials (ERPs) in patients with cerebrovascular disease treated with intravenous AS. Material and Methods The study group consisted of 15 patients (13 men and 2 women, age range: 50-87, mean: 69.9 years) diagnosed with cerebrovascular disease and hospitalized at the Department of Neurology, Silesian Piasts University of Medicine in Wrocław. Three patients had a history of ischemic stroke, but none of them had experienced recent stroke on admission or during the stay in the hospital. On neurological examination, 14 patients presented with signs of upper motor neuron deficit, 6 with extrapyramidal syndrome, 5 with deliberations, 7 with signs of brainstem involvement (4 with ocu− lomotor palsy, 3 with bulbar syndrome), and 3 with cerebellar ataxia. On the basis of neuropsychologi− cal assessment (including the Mini Mental State Examination, Auditory Verbal Learning Test, and Clock Drawing Test), mild cognitive impairment was recognized in 13 patients, but none of them met the criteria for a diagnosis of vascular demen− tia. In computed tomographic (CT) head scans at least two cerebral ischemic lesions (in remote regions) were found in all the patients, in 7 cases accompanied by diffuse ischemic changes in the periventricular white matter (leukoaraiosis). Risk factors for cerebrovascular disease were ascer− tained in all the patients: hypertension in 9 cases, coronary artery disease in 3, cardiac arrhythmias in 2, diabetes in 4, hyperlipidemia in 4, and smoking in 2. None of the patients had been treated with AS before and none of them were currently being treat− ed with acetylocholinesterase inhibitors or NMDA agonists. In none of the patients were contraindica− tions to the administration of AS found. All the patients gave their informed consent to participate in the study and the study design was approved by the Bioethics Committee at Silesian Piasts University of Medicine in Wrocław. The patients were given 200 mg of amantadine sulfate intravenously for five consecutive days (total dose: 1000 mg). During this period they were not given any other intravenous medications or solutions. The doses of other medications they received (antihypertensive, anti−arrhythmic, or anti− coagulative drugs, antiplatelet agents, insulin) remained unchanged. Attention level was examined using the Trail Making Test part B (TMT−B, source: Reitan Neuropsychology Laboratory, South Tuckson, USA) Auditory ERPs were also recorded in 25 con− trols (10 men, 15 women, age range: 42-74, mean: 56.6 years) with normal CT head scans and with− out features of cognitive decline. The mean and median values of the ERP para− meters of the controls and the patient group were compared using Wilcoxon's test and adjusted for the effects of age using the analysis of covariance method. Mean and median values for the ERP parameters before and after AS treatment were compared using Wilcoxon's rank test. p < 0. 05 was regarded as statistically significant. Results Initially, TMT−B results were abnormal in 8 pa− tients (prolonged time of performance according to standardized age norms) and 5 were unable to A. complete the task (they could not follow the idea of alternately joining letters and numbers and the test was stopped after five minutes). After AS administration, the results improved in 10 sub− jects, including 3 of those unable to perform the test initially. However, in all these subjects the TMT−B results still exceeded the normal range. In 3 patients the result was worse than initially and 2 were still unable to perform the test (Tab. 1). The P300 component of ERPs was recorded in 14 subjects; in one patient it could not be identi− fied. The mean latency of P300 in all the refer− ences was significantly longer in the patients than in the controls. The difference was still significant after adjusting for the effects of age (Tab. 2). No significant differences in P300 amplitude were found between these groups. After AS administra− tion, the mean latency of P300 in the patients was significantly shorter than initially Discussion Patients with multiple or diffuse cerebral ischemic lesions usually develop some cognitive impairment, ranging from mild deficit to demen− tia. The abnormal results of TMT−B in over 80% of the patients (including the five unable to per− form the test) are indicative of disturbed attention and the visuo−spatial aspects of working memory. Prolonged latency of the P300 component corre− sponds to a slowing of information processing, while a decrease in P300 amplitude is usually associated with deficits in attention. On the other hand, amplitude is regarded as the more unstable and less reliable parameter of P300 In patients with multifocal cerebral vascular lesions, the level of attention assessed by TMT−B improved after a short period of treatment with intravenous AS. In the majority of patients, treat− ment with AS also resulted in decreased latency of the P300 component of ERPs, suggesting improved speed of information processing. The potentially positive effects of AS in patients with cerebrovascular disease deserve attention and encourage further studies in this field.