Quantitative EEG and cognitive evoked potentials in anemia

Neurophysiologie Clinique/Clinical Neurophysiology (2008) 38, 137—143 Disponible en ligne sur www.sciencedirect.com

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ORIGINAL ARTICLE/ARTICLE ORIGINAL

Quantitative EEG and cognitive evoked potentials in anemia EEG quantifiée et potentiels évoqués cognitifs dans l’anémie H. Kececi ∗, Y. Degirmenci Department of neurology, Duzce University Medical Faculty, 81000 Duzce, Turkey Rec ¸u le 26 avril 2007 ; accepté le 20 janvier 2008 Disponible sur Internet le 21 f´ evrier 2008

KEYWORDS Anemia; P300; QEEG; Iron deficiency; Event-related potentials; Therapeutic monitoring

MOTS CLÉS Anémie ; P300 ; Carence en fer ;

∗

Summary Objective. — The anemic status may alter brain functions and electrogenesis, as reflected by EEG and cognitive EPs (CEPs). This study aims to evaluate CEPs and EEG power spectra in adult patients with iron-deficiency anemia and to determine the effects of appropriate iron therapy on electrodiagnostic findings. Methods. — Fifty-one patients with iron-deficiency anemia underwent CEP and EEG recording. All patients were re-assessed after three months of oral-iron therapy. Results. — All patients had recovered from their anemia through the three-month iron therapy. Central N1 amplitude and parietal P2 amplitude was increased. N2 latencies were shortened in frontal and central regions. P3 latencies were shortened in frontal, central and parietal areas and P3 amplitude was increased in the parietal region. Except in the gamma-band, all pretreatment and post-treatment mean-power values were significantly lower at the temporal, parietal and occipital regions. Conclusions. — This study indicates that in iron-deficiency anemia, appropriate iron therapy can improve brain electrogenesis, as reflected by P300 and EEG power spectra. © 2008 Publi´ e par Elsevier Masson SAS. Résumé But de l’étude. — La fonction cérébrale et l’électrogenèse cérébrale, reflétée par l’EEG et les potentiels évoqués cognitifs (PEC) peuvent être altérés dans l’anémie. Notre étude s’intéresse aux altérations des PEC et de l’analyse spectrale de l’EEG chez des patients présentant une anémie ferriprive et à l’évolution de celles-ci après administration efficace de fer.

Corresponding author. Adresse e-mail : [email protected] (H. Kececi).

0987-7053/$ — see front matter © 2008 Publi´ e par Elsevier Masson SAS. doi:10.1016/j.neucli.2008.01.004

138 EEG quantifiée ; Analyse spectrale ; Potentiels évoqués cognitifs ; Monitoring thérapeutique

H. Kececi, Y. Degirmenci Méthodes. — L’EEG et les PEC ont été enregistrés chez 51 patients présentant une anémie ferriprive. Tous les patients étaient réexaminés après trois mois d’administration orale de fer. Résultats. — Les patients avaient récupéré de leur anémie après trois mois de thérapie martiale. Parallèlement, l’amplitude de l’onde N1 augmenta en frontal et celles des ondes P2 et P3 en pariétal ; les temps de latence de l’onde N2 diminuèrent en frontal et en central, ceux de l’onde P3 en frontal, central et pariétal. Une diminution totale de puissance EEG fut notée au niveau des régions temporales, pariétales et occipitales. Conclusions. — Cette étude démontre qu’un traitement martial correct de l’anémie ferriprive peut améliorer l’électrogenèse cérébrale au niveau des PEC et de l’analyse spectrale de l’EEG. © 2008 Publi´ e par Elsevier Masson SAS.

Introduction Anemia compromises health not only because of the decreased hemoglobin (Hb) level, but also of its underlying causes. Regarding the first factor, Hb is involved in oxygen transport to the tissues so that a too low level of this protein can result in chronic tissue hypoxia; hence, oxygen is required for brain energy metabolism, intellectual function and cerebral integrity. Regarding the second factor, iron deficiency is a common cause of anemia [29] and iron may play an important role in neurotransmitter metabolism, myelin formation and brain energy metabolism [3,4]. Long-latency evoked potentials are referred to as cognitive evoked- or event-related potentials (ERPs). P300 is one of the best-known ERP and its generators are related to neuronal activity in multiple brain regions [16]. P300 reflects these neural activities that are related to perception, attention, decision-making processes and updating memory related to discrete events. The P300 is used in both clinical practice and electrophysiological research as an index of general cognitive function [6,9,11,21]. Previous studies showed that cognitive function is impaired and P300 latency is prolonged in acute isovolemic anemia and acute hypoxia [26—28]. When arterial oxyhemoglobin saturation is reduced from 80 to 85%, the auditory P300 latency is prolonged by approximately 20 ms [8]. Thus, P300 latency may indicate inadequate cerebral oxygenation. ERP studies related to adult anemia were frequently performed in hemodialysis patients [5,8,10,22], the results of which are often conflicting, perhaps due to the negative effects of both chronic anemia and uremic status on cognitive function. Some studies carried out in children with iron-deficiency anemia (IDA) demonstrated cognitive dysfunction, which significantly improved after iron treatment [1,2,12,17,20]. Parallel improvements in EEG parameters were also noted. In particular, EEGs revealed a significant decrease in slow rhythms at higher hematocrit (Htc) levels [18,22]. The aim of this study is to evaluate ERPs and EEG power spectra in adult patients with IDA and to determine the effects of iron therapy on these parameters.

Materials and methods Subjects Consecutive patients above 20 years old were recruited from the internal medicine outpatient department at our faculty hospital.

These patients were newly diagnosed and had not received any medical treatment for anemia or its complications. Before enrolling the patients, the purpose and procedures of the study were fully explained to each individual and written consent was obtained. To confirm anemic status and eliminate other possible causes of central nervous system (CNS) disorders, we performed several laboratory analyses, including a complete blood count, vitamin B12 and folic acid tests, thyroid function tests (FT3, FT4 and TSH) and routine biochemical serum tests. Based on these analyses, patients with Hb levels strictly less than 11 g/dl and Htc levels strictly less than 35% were considered anemic. To obtain a homogenous population, only patients with IDA were included. IDA was diagnosed based on the presence of microcytosis [mean corpuscular volume (MCV) strictly less than 80 fl; mean corpuscular Hb (MCH) strictly less than 27 pg; mean corpuscular-Hb concentration (MCHC) strictly less than 31 g/dl] and depleted-iron stores [serum iron level strictly less than 35 ␮g/dl; serum ferritin level strictly less than 20 ␮g/dl; total iron-binding concentration (TIBC) strictly greater than 470 ␮g/dl; red cell division width (RDW) strictly greater than 14.8%]. Patients below the age of 20, those with a history of mental, systemic, cardiac, renal, hepatic, endocrine or infectious illness and those who had ingested any drug for any reason in the previous four weeks were excluded from the study. Following baseline electrophysiological evaluation (ERP and EEG recordings), all patients were treated with 570 mg of oral ferroglycine sulfate, once daily. Control subjects were not treated. All patients were re-assessed after three months of oral-iron therapy. At this final follow-up visit, patients whose red blood cell and biochemical values had reached a normal range according to our reference laboratory values underwent a final electrophysiological evaluation. To clarify any discrepancies in electrophysiological readings, the anemic group was divided into two subgroups according to serum iron and Hb levels (above versus below the median values for each). Differences between groups were analyzed using a paired t-test.

ERP recording procedures ERPs were recorded between 14:00 and 16:00. Recordings were obtained from the Fz, Cz and Pz electrode sites of the International 10—20 System using gold electrodes affixed with electrode paste and tape; these were referred to linked-earlobe electrodes (A1A2) with a forehead (Fpz) ground. Eye movements (EOG) were monitored using infraorbital electrodes. Impedance was strictly less than 5 k. For the auditory oddball paradigm, binaural 1000 Hz (frequent) and 2000 Hz (rare) sounds were delivered through headphones. The tone bursts (85 dB) were presented with a rise/fall phase of 10 ms and a plateau phase of 100 ms. The analysis time was 1000 ms, including a 100-ms prestimulus period. The band-pass filter was 0.1 to 50 Hz and the sampling rate of averaging was 256 Hz. The frequent and rare tones were presented in a random sequence every 2 s. The rare-to-frequent tone probability rate was 20%. All subjects

Quantitative EEG and cognitive evoked potentials in anemia were asked to press a button when they heard a rare tone. During the trials, electro-oculography (EOG) and/or EEG potentials greater than ± 80 ␮V were automatically rejected. The test continued until the responses from 30 artifact-free rare tones were averaged. All signals were recorded using a Galileo NT Mizar-Sirius 33 digital EEG-EP multifunction system (EBNeuro, Florence, Italy).

CEP measurements N100 was identified as the most negative peak between 75 and 150 ms and P200 as the most positive peak between 150 and 250 ms. N200 was defined as the most negative peak between 200 and 300 ms and the P300 as the most positive peak after 275 ms. The amplitudes of all components were measured relative to the prestimulus baseline at Fz, Cz and Pz.

Quantitative EEG The EEG was recorded in a quiet room. Subjects were awake and resting with eyes closed throughout the recording period. EEG signals were recorded for 20 min from 19 scalp electrodes, according to the International 10—20 System using an average reference (MizarSirius 33 Channels; EBNeuro). Electrodes were positioned at Fp1, F3, C3, P3, O1, F7, T3, T5, Fp2, F4, C4, P4, O2, F8, T4, T6, Fz, Cz and Pz. The EEG was digitized at 256 Hz with a time constant of 0.1 s, a high-frequency filter of 70 Hz and a notch filter in each channel. Consecutive artifact-free, 2-s-long epochs were selected off-line, based on visual inspection. These 20 epochs were automatically processed using the supplied EEG software for the fast Fourier transform, and mean-power spectra (mPS) were obtained for each channel and frequency band in each subject. The frequency ranges were divided into seven bands: delta (0—4 Hz), theta (4—8 Hz), alpha (8—12 Hz), beta-1 (12—18 Hz), beta-2 (18—24 Hz), gamma (24—64 Hz) and 0—32 Hz.

Results At the end of the three-month therapy period, data from five patients with abnormal/normal red blood cell counts and biochemical values and data from two patients who did not complete the therapy were removed from the study analysis. Data were analyzed from the remaining 51 anemic patients (five men and 46 women; mean age, 30.98 ± 9.15 years; range, 20—60 years). Significant differences were observed between the pre- and post-treatment hematological parameters (Table 1), indicating that the patients recovered from anemia after three months of iron therapy. Some ERP parameters (central N1 amplitude; parietal P2 and P3 amplitudes; frontal and central N2 latencies; frontal, central and parietal P3 latencies) also differed significantly before and

Table 2

139 Table 1 Hematological parameters of patients before and after therapy. Parameters

Before

Hb (g/dl) Htc (%) MCV (fl) MCH (pg) MCHC (g/dl) Serum iron (␮g/dl) Ferritin (␮g/l) TIBC (␮g/dl) RDW (%)

9.80 28.76 74.14 24.89 28.08 24.32

After ± ± ± ± ± ±

0.42 1.56 2.54 0.91 1.74 4.93

12.93 41.96 86.14 29.02 33.95 65.82

p ± ± ± ± ± ±

0.48 2.02 2.48 0.93 0.85 10.59

0.000 0.000 0.000 0.000 0.000 0.000

12.26 ± 0.98

46.10 ± 11.98

0.000

560.09 ± 47.97 17.73 ± 1.85

321.66 ± 56.07 12.41 ± 0.55

0.000 0.000

Data are given as mean ± S.D.; Hb: hemoglobin; HT: hematocrit; MCV: mean corpuscular volume; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular-hemoglobin concentration; TIBC: total iron-binding concentration; RDW: red cell division width; p < 0.05 statistical significance (paired t-test).

after therapy (Table 2). The remaining ERP values were not significantly different. A comparison between grand-average pre- and post-treatment ERPs is shown in Fig. 1. The quantitative EEG results indicated significantly increased mean power at some electrode sites and frequency bands after treatment. The power of the delta frequency band increased at T3, T5, P3, P4, C4, and O1. The power of the theta frequency increased at T3, T5 T6, P3, P4, Cz, O1 and O2. The alpha power spectrum increased at T3, T5, T4 and T6. The beta-1 power values increased at T3, T4, T5, T6, O1, Oz and O2. The beta-2 power increased at C3, C4, T3, T4, T5, T6, P3, P4, O1 and O2. The 0—32 Hz frequency band power values increased at T3, T4, T5, T6, P4, O1 and O2. Gamma power values did not change in any area. Frontal areas did not display any change in any frequency band. The electrode locations and p values for power change after therapy are reported in Table 3. Pre- and post-treatment ERPs and mean power values were not statistically different between the subgroups with high versus low serum-iron levels. In contrast, pretreatment mean delta power values at Fz (p = 0.036), Cz (p = 0.031), T3 (p = 0.031) and P3 (p = 0.041) were significantly higher in patients with low Hb values. However, no statistically significant differences were found between post-treatment values for these subgroups. Furthermore, no statistically significant differences were observed between the preand post-treatment values for other bands or CEP values in both subgroups.

Evoked potential values of patients before and after therapy.

Parameters

Before

Central N1 amplitude Parietal P2 amplitude Parietal P3 amplitude Frontal N2 latency Central N2 latency Frontal P3 latency Central P3 latency Parietal P3 latency

7.62 6.71 18.56 225.48 222.10 319.68 312.25 312.00

After ± ± ± ± ± ± ± ±

4.41 4.04 8.16 28.13 26.99 44.04 46.18 46.88

12.16 9.84 23.17 211.94 210.62 289.92 288.66 295.28

p ± ± ± ± ± ± ± ±

9.98 6.07 10.66 20.81 20.09 48.63 35.13 23.15

Data are given as mean ± S.D.; amplitudes, ␮V; latencies, ms; p < 0.05 statistical significance (paired t-test).

0.004 0.007 0.019 0.015 0.032 0.002 0.005 0.029

140 Table 3

H. Kececi, Y. Degirmenci Electrode locations and statistical significances of power change with therapy.

Electrode positiona

Delta

Theta

Alpha

Beta1

Beta2

1—32 Hz

Gamma

Fp1

MDb 95%CIc p

11.97 − 6.72/30.67 0.207

7.54 − 3.39/18.48 0.174

2.84 − 2.06/7.75 0.254

1.69 − 0.71/4.10 0.166

0.44 − 023/1.13 0.198

24.67 − 12.83/62.17 0.195

3.13 − 6.43/12.70 0.517

Fp2

MD 95%CI p

10.13 − 13.16/33.41 0.390

6.19 − 7.21/19.61 0.362

2.37 − 3.47/8.23 0.422

1.44 − 1.44/4.32 0.324

0.39 − 0.33/1.11 0.288

20.69 − 25.41/66.80 0.375

3.08 − 6.49/12.67 0.524

F7

MD 95% CI p

6.89 − 7.00/20.80 0.327

4.87 − 3.25/13.01 0.237

2.28 − 1.63/6.19 0.251

1.24 − 0.67/3.17 0.201

0.43 − 0.14/1.01 0.140

15.93 − 12.02/43.88 0.261

3.33 − 6.30/12.98 0.494

F3

MD 95% CI p

12.71 − 3.74/29.16 0.128

8.67 − 1.77/19.12 0.103

8.68 3.84/− 21.20 0.172

5.19 − 0.52/10.90 0.075

1.28 − 0.12/2.69 0.074

80.96 − 10.48/172.41 0.082

3.76 − 5.21/13.98 0.423

Fz

MD 95% CI p

6.44 − 1.70/14.60 0.120

4.27 − 0.23/8.79 0.063

0.51 − 2.74/3.76 0.757

0.99 − 0.45/2.44 0.178

0.40 − 0.15/0.95 0.155

12.77 − 3.69/29.25 0.127

3.67 − 5.69/13.05 0.438

F4

MD 95%, CI p

4.66 − 6.01/15.33 0.388

3.51 − 2.79/9.81 0.271

9.08 − 2.15/20.31 0.112

4.59 0.78/− 9.97 0.093

1.13 − 0.16/2.42 0.084

71.84 − 16.05/159.73 0.108

3.13 − 6.40/12.68 0.516

F8

MD 95%, CI p

6.22 − 6.82/19.26 0.346

3.96 − 3.17/11.10 0.273

2.06 − 1.14/5.27 0.204

0.88 − 0.69/2.47 0.269

0.25 − 0.24/0.75 0.307

13.56 − 11.27/38.39 0.281

3.22 − 6.39/12.84 0.507

C3

MD 95%, CI p

1.25 − 0.65/25.15 0.063

19.22 − 2.77/41.22 0.086

11.09 − 3.23/25.42 0.128

4.62 − 0.45/9.69 0.074

1.32 0.04/2.59 0.042

66.59 − 8.97/142.16 0.083

3.77 − 5.67/13.23 0.430

C4

MD 95%, CI p

9.90 0.83/18.96 0.033

23.57 − 1.27/48.41 0.063

12.42 − 1.02/25.87 0.027

5.24 − 0.55/11.05 0.077

1.50 0.12/2.88 0.033

81.70 − 3.26/166.66 0.059

3.76 − 5.82/13.35 0.438

Cz

MD 95%, CI p

7.42 − 0.27/15.13 0.059

4.74 0.073/9.41 0.046

0.64 − 11.22/12.52 0.914

1.67 − 1.09/4.43 0.233

0.52 − 0.21/1.27 0.163

15.23 − 7.33/37.80 0.184

3.14 − 6.06/12.36 0.499

T3

MD 95%, CI p

16.98 0.18/33.78 0.048

11.78 1.69/21.87 0.023

12.68 1.90/23.46 0.022

4.56 0.08/9.12 0.050

1.16 0.049/2.28 0.041

72.77 0.79/144.75 0.048

3.60 5.99/13.19 0.458

T4

MD 95%, CI p

24.35 7.27/55.98 0.130

28.04 2.88/58.97 0.075

21.88 3.19/40.57 0.022

9.00 0.42/17.58 0.040

2.13 0.17/4.10 0.034

144.66 5.36/283.95 0.042

3.59 5.94/13.12 0.457

T5

MD 95%, CI p

23.79 18/47.40 0.048

28.15 0.42/55.87 0.047

27.29 4.10/50.48 0.022

6.67 0.53/12.80 0.033

1.71 0.23/3.19 0.024

108.58 11.49/205.68 0.029

3.46 6.23/13.17 0.480

T6

MD 95%, CI p

10.94 2.53/24.42 0.110

42.34 1.76/82.91 0.041

25.19 1.00/49.39 0.041

9.49 0.71/18.28 0.034

2.20 0.22/4.17 0.029

151.55 11.13/291.98 0.035

4.039 5.55/13.63 0.406

P3

MD 95%, CI p

19.38 2.54/36.21 0.024

12.57 2.03/23.11 0.020

9.06 23.28/41.40 0.580

3.05 0.82/6.93 0.121

1.01 0.05/1.97 0.038

45.40 6.16/96.96 0.084

3.52 5.90/12.59 0.460

P4

MD 95%, CI p

17.35 0.07/34.78 0.051

10.90 0.80/21.00 0.035

11.82 10.25/33.88 0.291

2.60 0.92/6.13 0.146

0.89 017/1.77 0.046

43.91 0.44/87.38 0.048

3.55 5.79/12.90 0.453

Pz

MD 95%, CI p

2.25 − 14.02/18.52 0.784

0.54 − 10.05/11.13 0.920

7.92 − 17.67/33.52 0.540

1.19 − 2.36/4.74 0.509

0.41 − 0.45/1.27 0.347

12.45 − 32.35/57.26 0.583

0.87 − 11.58/9.83 0.871

O1

MD 95%, CI p

28.36 4.59/− 52.13 0.020

18.32 − 4.30/32.34 0.011

31.34 − 3.05/− 65.75 0.074

5.63 − 91/10.380 0.020

1.27 0.17/2.36 0.024

85.29 22.10/148.47 0.009

3.45 − 6.17/13.08 0.479

23.31 − 13.73/60.35 0.215

6.54 − 0.30/12.78 0.040

1.47 − 0.053/2.88 0.042

99.56 6.45/192.67 0.036

3.52 − 5.96/13.01 0.463

O2

MD 13.90 26.27 95%, CI 0.87/28.68 2.02/50.52 p 0.065 0.034 p < 0.05 statistical significant (paired t-test). a International 10—20 system using averaged references. b MD, mean difference. c 95%CI, 95% confidence interval of the difference.

Quantitative EEG and cognitive evoked potentials in anemia

Figure 1 Grand average of ERP from rare tone stimulus trials from patients at Fz, Cz and Pz. The solid line shows before therapy; the dashed line shows after therapy.

Discussion The hematological parameters had normalized by the end of the oral-iron therapy period. Htc levels increased from 28.76 to 41.96%, which confirmed the previous diagnosis of adult IDA. In addition, some CEP and EEG power values showed changes at the end of the therapy period. The central N1 and parietal P2 amplitudes increased from 7.6 to 12.2 ␮V and from 6.7 to 9.8 ␮V, respectively. N1 and P2 are early components reflecting activity in receptors, peripheral relays and afferent pathways and are less sensitive to the subsequent cognitive processes. Therefore, our results suggest that iron therapy might improve dysfunctional peripheral perception in IDA patients. The N2 component is related to stimulus classification and discrimination. After iron therapy, N2 latencies decreased in the frontal (from 225 to 212 ms) and central (from 222 to 211 ms) electrodes. Apparently, anemia treatment decreased the time taken for classification and discrimination processes.

141 P3 latencies decreased over the frontal (from 320 to 290 ms), central (from 312 to 289 ms) and parietal (from 312 to 295 ms) areas and P3 amplitude increased over the parietal region (from 18.6 to 23.2 ␮V). P300 latency is thought to reflect the time taken for stimulus evaluation [7]. The P300 amplitude indicates the amount of information processing that is elicited by the stimulus. Longer P300 latencies and/or a decrease in P300 amplitude have been reported in some neurodegenerative diseases [6,9,11,19,21]. The improvement in latencies and amplitudes observed after iron therapy suggest that anemia decreases cognitive performance [2,5,10,14,17,18,24,26—28]. Several studies examined the effects of anemia on cognitive function. These studies were performed mainly on dialysis patients with chronic anemia, children with IDA and in experimental isovolemic acute anemia, as mentioned above. In dialysis patients with chronic anemia, P3 amplitudes increased and P3 latencies decreased after anemia treatment. Some of these studies found a significant decrease in P300 latency in parallel with an increase of Htc [10,18,22]. Other studies found that P3 amplitude significantly increased with treatment, whereas latency was unaffected [5,13]; in these studies, anemia improved, but chronic uremia and its effects on cognitive function were unaffected. Therefore, these results cannot be attributed to anemia alone, making it difficult to compare these with our findings. Previous research demonstrated that P3 latency was markedly increased in children with IDA and normalized after iron supplementation and restoration of normal hematological values [17]. Another study was conducted in 18 children with IDA and 34 healthy children as a control. Before treatment, the anemic children showed significantly lower hematological values and delayed P3 latencies as compared to controls. After therapy, P3 latency values in anemic children markedly improved as compared to pretreatment values [2]. This improvement in P3 latency after anemia treatment is in keeping with our own results. In our study, quantitative EEG results showed significant decreases in power after iron therapy, which differed according to frequency bands and electrode sites. The power of the delta frequency band decreased over left temporal areas (T3 and T5), bilateral parietal areas (P3 and P4), right central area (C4) and left occipital area. The power of the theta frequency decreased over temporal areas (T3, T5 and T6), parietal areas (P3 and P4), central area (Cz) and occipital areas (O1 and O2). The alpha power spectrum decreased over temporal areas (T3, T5, T4 and T6), beta-1 power values over temporal (T3, T4, T5 and T6) and occipital areas (O1, Oz and O2) and beta-2 power over central (C3 and C4), temporal (T3, T4, T5 and T6), parietal (P3 and P4) and occipital (O1 and O2) areas. The 0—32-Hz frequency band power values decreased over temporal (T3, T4, T5 and T6), parietal (P4) and occipital (O1 and O2) areas. Gamma power values did not change in any area. In other words, power spectrum analysis showed a consistent decrease in EEG power in all frequency bands, except gamma frequency band. Frontal areas did not undergo any change in any frequency band. Previous studies have also reported improved EEG power distribution and decreased P300 latencies after therapy [15,18,22]. Pickett et al. administered epoetin to 20 anemic patients with end-stage renal disease, which resulted in

142 the normalization of Hct levels (from 31.6 to 42.8%) and an associated decrease in EEG slowing [18]. Micheloyannis et al. performed an EEG spectral analysis in 12 young patients with thalassemia before and after regular blood transfusion and in 10 healthy volunteer students. After transfusion, the power spectral density of the alpha band increased significantly in most areas of the brain in thalassemia patients compared to the controls [15]. Sagales et al. compared EEG spectra from 43 anemic patients with chronic renal failure to a group of healthy subjects. After three, six, nine and 12 months of treatment, the total baseline power was much lower in patients with chronic renal failure than in healthy subjects. Epoetin therapy normalized total power and progressively improved power distribution [22]. However, the results of previous studies cannot be strictly compared with our results due to different etiologies of anemia. To administer oral-iron therapy to healthy individuals would be inappropriate and unethical. Because of this limitation, we were unable to compare results from our anemic patients to those from healthy individuals receiving the same treatment. Therefore, whether the initial recorded values were actually abnormal is unclear. Previous studies show that a test-retest stability of ERP parameters [23,25]. Despite this, iron therapy elicited marked changes in electrophysiological parameters. Attributing these alterations to the observed increase in either iron or Hb levels is difficult because anemic status is dependent on both parameters. A previous study reported that healthy infants who receive prophylactic iron supplementation showed early maturation of the auditory brain-stem reflex [1]. However, myelination is ongoing in the infant brain; thus, it is difficult to extrapolate results from infants to adults. In this study, no significant differences were observed in pre- and post-treatment ERPs or mean-power values between subgroups divided according to serum-iron levels. These results suggest that serum-iron levels may not have a primary effect on electrophysiological values. When the patients were divided into two groups according to Hb levels, low-Hb levels were associated with high mean deltapower values at Fz, Cz, T3 and P3. These results suggest that Hb levels may have a greater effect on electrophysiological alterations than serum-iron levels in anemic patients. Electrophysiological abnormalities detected in children with IDA were predominantly the result of myelin pathologies, in the synthesis of which iron plays a role. In IDA, patients exhibit the negative effects of both chronic hypoxia and iron deficiency on brain metabolism. Our results are consistent with other studies regarding non-IDA anemia, which revealed decreased P3 latencies and increased EEGpower values. These results indicate that the function of Hb, rather than iron, may be primarily responsible for the observed improvement in electrophysiological parameters. Chronic hypoxia due to low-Hb levels may account for prolonged P3 latencies, decreased amplitudes in the posterior region and decreased EEG power. In conclusion, IDA is relatively easy to diagnose and treat and treating anemia increases the patient’s quality of life and productivity at work. Our results indicate that iron therapy also improves electrophysiological parameters, including P300 latency and EEG power spectra in IDA patients.

H. Kececi, Y. Degirmenci

References [1] Algarin C, Peirano P, Garrido M, Pizarro F, Lozoff B. Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr Res 2003;53:217—23. [2] Bandhu R, Shankar N, Tandon OP, Madan N. Effects of iron therapy on cognition in anemic school going boys. Indian J Physiol Pharmacol 2003;47(3):301—10. [3] Beard JL, Connar JR. Iron status and neural functioning. Annu Rev Nutr 2003;23:41—58. [4] Beard JL. Iron deficiency alters brain development and functioning. J Nutr 2003;133(5 Suppl 1):1468S—72S. [5] Brown WS, Marsh JT, Wolcott D, Takushi R, Carr CR, Higa J, et al. Cognitive function, mood and P3 latency: effects of the amelioration of anemia in dialysis patients. Neuropsychologia 1991;29:35—45. [6] Bruder GE, Tenke CE, Stewart JW, Towey JP, Leite P, Voglmaier M, et al. Brain event-related potentials to complex tones in depressed patients: relations to perceptual asymmetry and clinical features. Psychophysiology 1995;32:373—81. [7] Duncan-Johnson CC, Donchin E. The relation of P300 latency to reaction time as a function of expectancy. Prog Brain Res 1980;54:717—22. [8] Fowler B, Prlic H. A comparison of visual and auditory reaction time and P300 latency thresholds to acute hypoxia. Aviat Space Environ Med 1995;66(7):645—50. [9] Goodin DS, Aminoff MJ. Electrophysiological differences between demented and nondemented patients with Parkinson’s disease. Ann Neurol 1987;21:90—4. [10] Grimm G, Stockenhuber F, Schneeweiss B, Madl C, Zeitlhofer J, Schneider B. Improvement of brain function in hemodialysis patients treated with erythropoietin. Kidney Int 1990;38(3):480—6. [11] Javitt DC, Doneshka P, Grochowski S, Ritter W. Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia. Arch Gen Psychiatry 1995;52:550—8. [12] Lozoff B, De Andraca I, Castillo M, Smith JB, Walter T, Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants. Pediatrics 2003;112:846—54. [13] Marsh J, Brown W, Wolcott D, Landsverk J, Nissenson AR. Electrophysiological indices of CNS function in hemodialysis and CAPD. Kidney Int 1986;30:957—63. [14] Massa E, Madeddu C, Lusso MR, Gramignano G, Mantovani G. Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy. Crit Rev Oncol Hematol 2006;57:175—82. [15] Micheloyannis S, Papadaki F, Jannopoulos A. The effect of blood transfusion on alpha EEG activity in thalassemic patients. Eur Neurol 1991;31(3):131—5. [16] Oken BS. Endogenous event-related potentials. In: Chiappa KH, editor. Evoked potentials in clinical medicine. Philadelphia: JB Lippincott Company; 1999. p. 529—63. [17] Otero GA, Pliego-Rivero FB, Contreras G, Ricardo J, Fernandez T. Iron supplementation brings up a lacking P300 in iron deficient children. Clin Neurophysiol 2004;115:2259—66. [18] Pickett JL, Theberge DC, Brown WS, Schweitzer SU, Nissenson AR. Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis 1999;33(6):1122—30. [19] Polich J, Romine JS, Sipe JC, Aung M, Dalessio DJ. P300 in multiple sclerosis: a preliminary report. Int J Psychophysiol 1992;12:155—63. [20] Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system development

Quantitative EEG and cognitive evoked potentials in anemia

143

in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr 1998;68(3):683—90. Rosenberg C, Nudleman K, Starr A. Cognitive evoked potentials (P300) in early Huntington’s disease. Arch Neurol 1985;42:984—7. Sagales T, Gimeno V, Planella MJ, Raguer N, Bartolome J. Effects of rHuEPO on Q-EEG and event-related potentials in chronic renal failure. Kidney Int 1993;44(5):1109—15. Sandman CA, Patterson JV. The auditory event-related potential is a stable and reliable measure in elderly subjects over a 3 year period. Clin Neurophysiol 2000;111(8):1427—37. Triantafyllou NI, Anthracopoulos M, Zalonis I, Vrettou H, Mantouvalos V, Malliara S, et al. Cognition in homozygous beta-thalassemia disease: a multichannel auditory eventrelated potential (P300) study. Electromyogr Clin Neurophysiol 1992;32:531—5.

[25] Waldhovd KB, Fjell AM. One-year test retest reliability of auditory ERPs in young and adults. Int J Psychophysiol 2002;46(1):29—40. [26] Weiskopf RB, Kramer JH, Viele M, Neumann M, Feiner JR, Watson JJ, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000;92:1646—52. [27] Weiskopf RB, Feiner J, Hopf HW, Viele M, Watson JJ, Kramer JH, et al. Oxygen reverse deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia. Anesthesiology 2002;96:871—7. [28] Weiskopf RB, Toy P, Hopf HW, Feiner J, Finlay HE, Takahashi M, et al. Acute isovolemic anemia impairs central processing as determined by P300 latency. Clin Neurophysiol 2005;116(5):1028—32. [29] Yip R. Prevention and control of iron deficiency:policy and strategy issues. J Nutr 2002;132:802s—5s.

[21]

[22]

[23]

[24]