Hematology

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Neurocognitive dysfunction in children

with β thalassemia major: psychometric,
neurophysiologic and radiologic evaluation

M. S. Elalfy, R. H. Aly, H. Azzam, K. Aboelftouh, R. H. Shatla, M. Tarif, M.

Abdatty & R. M. Elsayed

To cite this article: M. S. Elalfy, R. H. Aly, H. Azzam, K. Aboelftouh, R. H. Shatla, M. Tarif, M.

Abdatty & R. M. Elsayed (2017) Neurocognitive dysfunction in children with β thalassemia major:
psychometric, neurophysiologic and radiologic evaluation, Hematology, 22:10, 617-622, DOI:
10.1080/10245332.2017.1338212

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Published online: 16 Jun 2017.

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HEMATOLOGY, 2017
VOL. 22, NO. 10, 617–622
https://doi.org/10.1080/10245332.2017.1338212

Neurocognitive dysfunction in children with β thalassemia major:

psychometric, neurophysiologic and radiologic evaluation
M. S. Elalfya, R. H. Alya, H. Azzamb, K. Aboelftouhc, R. H. Shatlaa, M. Tarifd, M. Abdattya and R. M. Elsayed e

a
Department of Pediatric, Ain Shams University, Cairo, Egypt; bDepartment of Neuropsychiatry, Ain Shams University, Cairo, Egypt;
c
Department of Radiodiagnosis, Ain Shams University, Cairo, Egypt; dDepartment of Clinical Pathology, Ain Shams University, Cairo, Egypt;
e
Department of Pediatric, Pediatric Neurology Unit, Mansoura University, Mansoura, Egypt

ABSTRACT KEYWORDS
Objective: To evaluate the impact of iron chelating drugs and serum ferritin on the β-Thalassemia; iron chelation
neurocognitive functions of patients with β thalassemia major (β-TM), using psychometric, therapy; neurocognitive
neurophysiologic and radiologic tests. function
Methods: Eighty children with β-TM were enrolled into the study and were compared to 40
healthy controls. All participants were evaluated by measuring serum ferritin, neurocognitive
assessment by Benton Visual Retention Test, Wechsler Intelligence Scale for Children,
Wisconsin Card Sort Test, P300 and magnetic resonance spectroscopy (MRS).
Results: WISC in our study showed that 40% of cases were borderline mental function as
regards total IQ. Neurophysiologic tests were significantly impaired in patients compared to
control group, with significant impairment in those receiving desferrioxamine (DFO). P300
amplitude was significantly lower in cases compared to controls (2.24 and 4.66 uv,
respectively), recording the shortest amplitude in patients receiving DFO. Altered metabolic
markers in the brain were detected by MRS in the form of reduced N-acetylaspartate to
creatine ratio in 78.3% of our cases. There were significant correlations between
psychometric tests and both neurophysiologic (P300) and radiologic (MRS) tests.
Conclusion: β-TM is associated with neurocognitive impairment that can be assessed by
psychometric, neurophysiologic and radiologic tests. The role of hemosiderosis and iron
chelation therapy on cognitive functioning still need more research.

Abbreviations: β-TM: beta thalassemia major; DFO: Dysferal; DFP: Deferiprone; DFX:
Deferasirox; WISC: Wechsler Intelligence Scale for Children; VIQ: verbal IQ; PIQ: performance
IQ; TIQ: total IQ; BVRT: Benton Visual Retention Test; WCST: Wisconsin Card Sort Test; MRS:
Magnetic resonant spectroscopy; NAA/Cr ratio: N-acetylaspartate to creatine ratio

Introduction for implicit and explicit memory. Other risk factors for
brain damage include transient ischemic attacks,
Long-term RBC transfusion therapy is required for the asymptomatic brain infarctsand visual and auditory
treatment of several types of anemia, such as thalasse- toxicity of DFO [5].
mia. Chronic blood transfusions inevitably lead to iron Advances in measuring tissue iron noninvasively by
overload and serious clinical sequelae and patients magnetic resonance techniques have enhanced diag-
receiving such transfusions, therefore, require lifelong nostic capabilities and allowed for more precise
chelation therapy [1]. There are substantial data measurement and monitoring of iron burden [6].
demonstrating the efficacy and safety of iron chelation The major peaks of the proton magnetic resonance
therapy in the treatment of iron overload in regularly spectroscopy (MRS), corresponding to N-acetylaspar-
transfused patients with β-thalassemia [2,3]. Patients tate (NAA) and creatine (Cr), have been previously
with β-thalassemia major (β-TM) have multiple risk used to evaluate neuronal loss and breakdown of
factors for developing central nervous system (CNS) active neurons. Reduction of cerebral N-acetylaspartate
complications. CNS complications generally present to creatine (NAA/Cr) ratio can be used as a dynamic
as cognitive dysfunction, which usually results from marker of neuronal dysfunction and integrity and cog-
iron deposition and neurotoxicity of desferrioxamine nitive functions [7–9].
(DFO) which is commonly used as a chelating agent The conducted study aims to assess the magnitude
in children with β-TM [4]. Studies reported higher of neurocognitive dysfunctions in patients with β-TM
iron deposition in the putamen, caudate nucleus, and its relation to iron chelating drugs and serum ferri-
motor and temporal cortex of patients with β-TM. tin, using psychometric, neurophysiologic and radiolo-
These areas are as important for cognitive function as gic evaluation.

CONTACT R. M. Elsayed [email protected] Department of Pediatric, Pediatric Neurology Unit, Mansoura University, P. O. 35516, Mansoura,
Egypt
© 2017 Informa UK Limited, trading as Taylor & Francis Group
618 M. S. ELALFY ET AL.

Methods Benton Visual Retention Test

Benton Visual Retention Test (BVRT) is designed to
Eighty children diagnosed with β-TM were on regular
assess visual perception, visual memory and visual
blood transfusions to maintain the pre-transfusion
constructive abilities. Difference between error score
hemoglobin concentrations between 7 and 8 g/l
and correct score ≥4 signifies neurological impair-
especially in the last 3 months.
ment [12].
They were recruited from Hematology Outpatient
Clinic Ain Shams University. Compliance on treat- Wisconsin Card Sort Test
ment defined by self-reports of parent about Wisconsin Card Sort Test (WCST) is designed to assess
patient’s adherence to treatment protocol was the following frontal lobe functions strategic planning,
given [10]. We defined compliance as receiving ≥ organized searching, utilizing environmental feedback
70% of preplanned iron chelating therapy protocol to shift cognitive sets, directing behavior towards achiev-
for 6 months prior to the study. They were divided ing a goal and modulating impulsive responding [13].
into four groups according to their iron chelation
protocol; group 1 compliant to iron chelating P300 (P3) or event-related potential
therapy in the form of DFO by subcutaneous infu- By using the 10–20 system, the reference electrodes
sion (10–12 hours a day) in doses of 20–50 mg/kg were placed over the mastoid regions, while the
body weight/day as home management, group 2 active electrodes were placed over the Fz and Cz. Elec-
receiving deferiprone (DFP) oral therapy in a dose trode resistance was ≤5 kV. The frequency range was
of 75 mg/kg/day in three divided doses, group 3 between 0.1 and 50 Hz. Thirty-two responses to the
on deferasirox (DFX) and group 4 on combined target stimuli were averaged. Data were obtained
therapy. from two consecutive trials. The negative (N) or positive
They were compared to 40 age- and sex-matched (P) waves were labeled in numerical order. The latency
apparently healthy controls (free from any chronic and the amplitude of the P300 (P3) wave were taken
illness, no apparent CNS or genetic disorders that can into consideration [14,15].
affect their mental status), coming for routine visits at
outpatient clinics. Magnetic resonance spectroscopy
All children were subjected to detailed history We performed proton MRS single-voxel technique with
including: age of diagnosis of β-TM, duration of these parameters short-T1-weighted spin-echo
regular blood transfusion, duration of regular chelation sequence- (TE) 35 milliseconds. We used MRS to
therapy, chelation type, compliance and number of measure the concentrations of NAA and Cr in the brain.
blood transfusions per year. A thorough physical exam- The study was approved by our local ethics commit-
ination, including anthropometric measure, full tee, and informed consent was obtained from all parti-
abdominal examination for enlarged liver and/or cipating families.
spleen, was conducted. Other investigations were
documented from the patient’s files including: hemo-
globin level in the last 3 months and serum ferritin Statistical analysis
level in the last 3 months. Excluded from the study,
The collected data were revised, coded, tabulated and
children with associated co-morbid condition that
introduced to a PC using Statistical Package for Social
can affect their mental state (end-stage renal, hepatic
Sciences (SPSS 15.0.1 for Windows; SPSS, Inc., a division
dysfunction, endocrine dysfunction or associated CNS
of UNICOM Global, under the UNICOM Intelligence
disease and children on medications affecting their
brand., 2001). All numeric variables were expressed as
mental state).
mean – SD. The statistical significance of differences in
All the studied cases were subjected to the following
the baseline characteristics between the groups was
tests.
evaluated by Student’s test. Chi-square (χ 2) test was
used to compare frequency of qualitative variables
among the different groups. A value of p < 0.05 was con-
Neuropsychological testing
sidered significant.
Wechsler Intelligence Scale for Children third
edition
Results
Verbal IQ (VIQ) is based on information, similarities,
arithmetic, vocabulary and comprehension. In the present study, we have evaluated 80 patients of
Performance (non-verbal) IQ is based on picture (6–14 years) mean age 12.08 ± 1.93 years with β-TM
completion, coding, picture arrangement, block who were regularly attending the Pediatric Hematol-
design and object assembly. Full-scale IQ is based on ogy Outpatient Clinic at Ain Shams University; 51.3%
10 tests included in the verbal and performance were males, children were compliant on iron chelation
(non-verbal) IQ scales [11]. protocol for the last 3 months. Thirty-nine patients
 HEMATOLOGY 619

Table 1. Clinical and demographic data. performance IQ (PIQ) (94.42) and TIQ (97.11) was
Patients (80) Controls (40) observed with DFP (Table 2).
Age (years) 12.08 ± 1.93 12.23 ± 1.66 BVRT test showed that the difference between
Age at diagnosis of thalassemia 1.05 ± 0.70 –
Age of first blood transfusion 1.07 ± 0.71 –
obtained error score and expected error score of
Number of transfusion per year 16.43 ± 5.40 – BVRT was significantly higher in cases compared to
Weight (kg) 32.24 ± 9.33 34.00 ± 5.61 controls (Table 2).
Height (cm) 134.28 ± 14.16 134.82 ± 6.54
BMI 17.62 ± 2.81 18.59 ± 1.83 Percentage WCST preservative errors were higher in
Sex Male 41 (51.3%) 22 (55.0%) cases compared to controls (20.13 ± 13.54 and 14.50 ±
Serum ferritin (<1000) 17 (28.3%) <1000
(ng/ml) (1000–2000) 27 (45%) 4.72, respectively). Patients receiving DFO had a signifi-
(>2000) 16 (26.7%) cant increase in % preservative error and a decrease in
Compliance to iron Yes 50 (62.5%) –
Chelating therapy WCST% conceptual level response and WCST cat-
Iron chelating DFO 11 (13.8%) – egories when compared with other groups (Table 2).
therapy DFP 39 (48.8%) –
DFX 4 (5.0%) –
P300 amplitude was significantly lower in cases
Combination 26 (32.5%) – compared to controls (2.24 and 4.66 uv), respectively,
therapy recording the shortest amplitude in patients receiving
Splenectomy Yes 28 (35.0%) –
No 52 (65.0%) – DFO (Table 3). Also, P300 latency was significantly pro-
DFO: dysferal; DFP: deferiprone; DFX: deferasirox. longed in cases compared to controls (386.70 and
316.15 milliseconds, respectively) and recorded the
(48.8%) were receiving DFP, 32.5% were on combi- longest duration in patients receiving DFO (Table 3).
nation therapy, 13.8% were on DFO and 5.0% of In our study, significant negative correlation is
patients were on DFX; they were compared to 40 observed between P300 latency and most of neuropsy-
healthy individuals of (6–14) mean age (12.23 + 1.66) chological tests, while significant positive correlation is
years; there were 55% males and 45% females who observed between P300 amplitude and most of neu-
served as the control group. Patients were receiving ropsychological tests. Also, there was a significant posi-
average 16.43 ± 4.5 transfusion per year, and the tive correlation between NAA/Cr and WISC (r = 0.104
mean age at which transfusion started was 1.07 ± and p = 0.000), and patients with reduced NAA/Cr
0.71 years. The serum ferritin was below 1000 ng/ml ratio had a significantly higher abnormal scores on
in 17 (28.3%) of the patients, while 27 (45%) had BVRT, with a significant negative correlation between
serum ferritin 1000–2000 ng/ml and 16 (26.7%) with NAA/Cr and BVRT (r = −0.107 and p = 0.002). Also,
serum ferritin above 2000 ng/ml. Splenectomy was WCST scores were significantly lower in patients with
done in 28 (35%) of children with β-TM (Table 1). reduced NAA/Cr ratio and WCST showed a significant
Wechsler Intelligence Scale for Children (WISC) in positive correlation with NAA/Cr ratio (r = 0.448 and
our study showed that 40% of cases were borderline p = 0.003) (Table 4).
mental function as regards total IQ (TIQ), while 41%
were average TIQ, compared to 65% of controls with
Discussion
average TIQ and 22.5% were bright normal. In our
study, patient group had significantly lower full-scale Children with β-TM show impaired abstract reasoning,
(87.56), performance (85.18) and VIQs (92.03) com- constructional spatial skills and executive functions,
pared with the control group (101.40, 100.17 and which are more prominent in subjects with hemosi-
102.80), respectively. The highest VIQ was observed derosis [16]. Forty percent of our cases were borderline
with DFP and DFX (100.42 and 100.50), while highest mental function for TIQ, while 41% were average TIQ;

Table 2. Psychometric tests (BVRT, WISC and WCST) in children with β-thalassemia on different chelating therapy versus controls.
DFO DFP DFX Combination Controls
N = 11 (%) N = 39 (%) N = 4 (%) N = 26 (%) N = 40 (%) p-value
BVRT
Normal (<4) 6 (100) 22 (84.6) 4 (100) 12 (85.7) 40 (100) 0.294
Abnormal (≥4) 0 (0) 6 (15.4) 0 (0) 2 (14.3) 0 (0)
Wechsler Intelligence Scale
VIQ (mean) 91.83 100.42 100.50 90.00 102.80 0.001»
PIQ (mean) 78.83 94.42 86.75 85.57 100.17 0.000»
TIQ (mean) 83.83 97.11 93.25 86.64 101.40 0.000»
WCST%
Preservative response (mean) 45.33 15.12 12.50 23.93 16.27 0.009»
Preservative errors (mean) 36.67 14.19 23.00 20.79 14.50 0.011»
Conceptual level response (mean) 41.00 63.76 72.00 53.71 68.67 0.136
Categories completed (mean) 3.00 5.11 6.00 3.86 5.72 0.010»
Note: BVRT considered normal if the difference between obtained error score and expected error score < 4 and abnormal if ≥ 4, DFO: dysferal; DFP: defer-
iprone; DFX: deferasirox; VIQ: verbal IQ; PIQ, performance IQ; TIQ, total IQ. There is a significant increase in % preservative error with DFO, while there is a
decrease in WCST% conceptual level response and WCST categories completed with DFO compared with other groups.
p < 0.05» = significant
620 M. S. ELALFY ET AL.

Table 3. Neurophysiologic (P300) and radiologic (MRS) tests in children with β-thalassemia on different chelation therapy versus
controls.
DFO DFP DFX Combination Controls
Parameter N = 11 N = 39 N=4 N = 26 N = 40 p-value
P300 392.17* 371.23 384.25 387.86 316.15 0.000*
latency (mean value in milliseconds)
P300 1.93 2.87 2.44 2.14 4.66
amplitude (mean value in mV)
MRS
NAA/Cr ratio Normal >2% 38.5% 15.4% 30.8% 15.4% 100% 0.000*
NAA/Cr ratio Reduced <2% 31.9% 10.6% 17% 40.4% 0%
DFO: dysferal; DFP: deferiprone; DFX: deferasirox; NAA/Cr ratio: N-acetylaspartate to creatine ratio.
*p < 0.05 considered significant.

this is similar to the study of Economou et al. [17] which in children and adults, as well as in research [8].
reported abnormal TIQ scores (<85) in 36.4% of children However, limited studies have evaluated cognitive func-
with β-TM. Our work echoes similar comparative findings tion in patients with β-TM and the results have been
of significantly lower full-scale IQ, performance and VIQs conflicting. Orsini et al. [21] were the first to report intel-
compared with the control group. This is in accordance lectual impairment in such patients. Our study shows
with the study of Duman et al. [7]. They reported lower abnormal BVRT being significantly higher in cases com-
scores in the block design subtest of the PIQ and pared to controls. However, to our knowledge no other
general knowledge and comprehension subtests of studies performed BVRT in β-TM before.
VIQ, stating that there is mild cognitive impairment. Our study shows that WCST preservative errors were
However, this is in contrast to the study of Logothetis higher in cases compared to controls. WCST measures
et al. [18] which reported normal intelligence scores in the ability to learn concepts. It is considered a good
their study group. Economou et al. [17] had 9% of measure of frontal lobe functioning. In most cases,
their patients with IQ score under 70 and in another neurological involvement does not initially present
study done, in 1997, by Aydin et al. [19] 80% of their with relevant signs or symptoms (i.e. subclinical) and
patients had at least one psychiatric disorder and mild can only be detected through neurophysiologic or neu-
mental retardation, borderline intellectual functioning, roimaging evaluation [22].
generalized anxiety disorder, oppositional defiant dis- P300 denotes a noninvasive neurophysiologic
order, major depressive disorder and enuresis. method of evaluating the CNS; It is used to assess
Our study shows that highest VIQ was observed with attention, memory discrimination and target detection
DFP and DFX, while highest PIQ as well as TIQ was [23]. Previous research documented delayed P300
observed with DFP. It is worth mentioning that the latency and lower amplitude of P300 to be
lowest IQ scores were observed with DFO. Similar to accompanied by cognitive impairment [24–26]. Polich
the finding of our study, Shehata et al. [20] observed et al. [25] reported that increased P300 amplitude
a significant positive correlation between IQ and was associated with better memory performance. In
number of blood transfusion per year. They attributed our study, P300 amplitude was significantly lower in
their finding to washing of toxic agents by frequent cases compared to controls. This finding is concordant
blood transfusion and correction of the anemia which with Shehata et al. [20]. Additionally, our study shows
lead to significant positive correlation with the that P300 latency was significantly prolonged in cases
studied cognitive functions. compared to controls, which is in contrast to the
BVRT measures the perception of spatial relations study done by Duman et al. [7] which did not
and memory for newly learned material; it is used in observe difference in the P300 latency at the Fz and
the clinical diagnosis of brain damage and dysfunction Cz electrode sites in patients and in controls.

Table 4. Correlations between neurophysiologic, radiologic and psychometric tests.

WISC
Verbal Performance Total
BVRT IQ IQ IQ WCST
r p r p r p r p r p
P300
latency (milliseconds) 0.496 0.000» −0.771 0.000» −0.736 0.000» −0.818 0.000» −424 0.000
Amplitude (mV) −0.356 0.001» 0.790 0.000» 0.803 0.000» 0.873 0.000» 0.371 0.001
MRS −0.507 0.002 0.625 0.0000 0.739 0.001 0.604 0.000 0.448 0.003
(NAA/Cr)
BVRT: Benton Visual Retention Test; WISC: Wechsler Intelligence Scale for Children; WCST: Wisconsin Card Sort Test; MRS: magnetic resonance spectroscopy;
NAA/Cr: N-acetylaspartate to creatine ratio.
*p < 0.05» = significant.
p > 0.05 = non-significant.
 HEMATOLOGY 621

The relationship between DFO and neurotoxicity ORCID

needs to be elucidated. Economou et al. [17] defined
R. M. Elsayed http://orcid.org/0000-0002-3122-2656
the therapeutic index as the ratio of mean daily DFO
dosage divided by the serum ferritin level and con-
sidered it as a risk factor when exceeding 0.025. On References
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