The Islamic University of Gaza Deanship of Research and Graduate Studies Faculty of Health Sciences Master of Medical Laboratory Sciences ا ـ ـــــــــ ا ـ ــــــــ ــ ــةت ارا وا ادة ا ــــ ــــــ ـــ ا ـــــــــ ــ مــــــــ! ا"#$% ا ـــم ا& ا’ ـــ(" ــThe Association of Iron Profile Parameters and Selected Minerals (Zinc and Magnesium) with Febrile Seizures in Children (6-60 months) at Al- Nasir Hospital in Gaza City اﻝﻌﻼﻗﺔ ﺒﻴن اﻝﺤدﻴد و ﺒﻌض ﻤﻊ(اﻝزﻨك واﻝﻤﻐﻨﻴﺴﻴوم) اﻝﻤﻌﺎدن اﻝﻤﺨﺘﺎرة ارﻴﺔ ﻝدى اﻷطﻔﺎل اﻝﺘﺸﻨﺠﺎت اﻝﺤر) ٦ - ٦٠ ( ﺸﻬر ﻓﻲ ﻤﺴﺘﺸﻔﻰ اﻝﻨﺼر ﻓﻲ ﻤدﻴﻨﺔ ﻏزةBy Ohood Mohammed Shamallakh Supervised by A thesis submitted in partial fulfillment of the requirements for the degree of Master of Medical Laboratory Science May/2019 Dr. Mazen Medhat Alzaharna Assistant Prof. of Biomedical Sciences
119
Embed
The Association of Iron Profile Parameters and Selected ...
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
�ھ�ه ا�� ��� ?<5 أو أي �=ء �+�� �> �47م �6 �:5 ا67�89 �+�5 در�� أو �34 ��1 أو �2%1 ��ى أي �/ .
� أو ��%2� أ�8ى.���A)
Declaration I understand the nature of plagiarism, and I am aware of the University’s policy on
this.
The work provided in this thesis, unless otherwise referenced, is the researcher's own
work, and has not been submitted by others elsewhere for any other degree or
qualification.
:3��C�ا > ا �� ���& ��د �2��D Student's name:
:E����D ا��� ���& ��د �2�� Signature:
:D7ر���14/05/2019 ا Date:
III
Abstract Background: Febrile seizures (FSs) are the commonest form of seizures in children aged between 6-60 months with 38oC or higher body temperature. 2-5% of neurologically healthy children encounter at least one, usually simple FS. Iron is a nutritional element that plays a significant role in brain energy metabolism, myelin formation, and neurotransmitter metabolism. So, it is likely that iron deficiency anemia (IDA) may predispose to other neurological disturbances like FS. Zinc (Zn) and Magnesium (Mg) play a crucial role in the function of the brain and neurological disorders development and prevention, these elements could also be involved in the etiology of FS. Objective: To investigate the association between iron profile parameters, Zn, and Mg levels among children in Gaza City. Materials and methods: The study is a case-control one, performed on eighty patients, 40 patients with FS and 40 without seizures. Informed consent was obtained, a detailed history and clinical examination has been carried out for both groups, serum ferritin, iron, total iron binding capacity, and soluble transferrin receptor were measured by ELISA, Zn and Mg were determined chemically, transferrin saturation was calculated, complete blood count indices measurements and anthropometric measurements were performed for all participants. An approval was obtained from Helsinki committee to perform this study. SPSS program version 22 was used for all data analysis.
Results: The mean age of the cases (24.7 ± 13.8 months) and controls (23.2 ± 15.7 months), (p = 0.634). Moreover, the percentage of male and female participants was 52.5% & 47.5% for cases while 60.0% & 40.0% for controls respectively with (p = 0.499). The mean levels of serum iron, and transferrin saturation among cases were higher significantly compared to controls (50.9 ± 23 Fg/dL & 19.8 ± 13.3% versus 24.3 ± 16.3 Fg/dL & 7.5 ± 8.0% respectively with p < 0.001). The mean level of TIBC among cases was lower significantly compared to controls (296.6 ± 64.6 Fg/dL versus 372.1 ± 56.5 Fg/dL respectively with p < 0.001). In addition, the percentage of cases with anemia was 85% compared to 80% for controls (p = 0.556). In contrast, 12.5% of cases had ID and IDA compared to 30% and 27.5% in controls respectively, (p > 0.05). The mean level of serum Zn in cases was lower compared to control group (77.3 ± 11.4 µg/dL versus 78.8 ± 9.5 µg/dL respectively), (p > 0.05). The mean levels of Mg [Fg/dL] and hs-CRP [mg/L] were lower among cases (2.0 ± 0.2 & 3.0 ± 2.7) compared to controls (2.1 ± 0.2 & 8.5 ± 5.8) with (p < 0.05). Conclusions: There was no association between IDA or decreased serum level of Zn and the presence of FS. While, our results showed that Mg may play a role in FS pathogenesis.
Complete Blood Count; WBCs: White Blood Cells; RBCs: Red Blood Cells; Hb: Hemoglobin; Hct: Hematocrit; MCV: Mean Corpuscular Volume; MCH: Mean Corpuscular Hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; RDW: Red Blood Cell Distribution Width; MPV: Mean Platelet Volume; PDW: Platelet distribution width; r: Pearson correlation.
69
70
Chapter 5
Discussion
Convulsions or seizures are one of the important problems in the health of
pediatrics in developing and developed countries. FSs are the most common childhood
seizure disorder that affects 2 to 5 percent of children aged 6 to 60 months. In general,
FS is thought to be an age-dependent response of the immature brain to fever. This is
based on the fact that most FSs (80 - 85 percent), occur between the ages of 6 months
and 3 years, with a peak incidence at 18 months (Joshi, 2014).
In febrile children, some may develop FSs and some may not develop FSs. The
underlying mechanism is still not clear. Various mechanisms like genetic factors,
family history of FS, disturbance in the levels of serum minerals, and IDA were
proposed (Kliegman et al., 2016). Various studies showed that IDA, deficiency of Zn
and Mg as risk factors for development of seizures. In the present study, we
investigated the relationship between Fe, Mg and Zn levels with FS on children from
Gaza City.
5.1 General characteristics of the study population
The age of the children who participated in the present study was between (6 -
60 months). The mean age of occurrence of FS was 24.7 ± 13.8 months which was
comparable to the other studies such as Namakin et al., (2016) study who reported
similar observation with mean age of 24 months. Mahyar et al., (2008) also reported a
mean age of 27.1 ± 15.1 months in cases. Furthermore, Ganesh & Janakiraman (2008)
and Jehangir et al., (2018) reported the mean age of FS occurrence at 23.8 & 22.1
months respectively.
In the present study, there was a male predominance with a male to female ratio
of 1.3:1. 21 (52.5%) in the FS group and 24 (60%) in the control group were males.
This finding is in agreement with other studies which showed that males have
consistently emerged with a higher frequency of FS (Daoud et al., 2004; Hartfield et
al., 2009; Jehangir et al., 2018; Nemichandra et al., 2017; Singh & Yadav, 2018; Sultan
et al., 2017; Talebian et al., 2009).
71
On the other hand, the results of the present study showed that there were no
significant differences in the means of weight and height in cases compared to controls.
This is similar to the results of different studies who also didn’t find any significant
difference of weight and height between cases and controls (E. D. Kumar &
Annamalai, 2017; Kunwar Bharat et al., 2015; Vaswani et al., 2010). Moreover, basic
demographic characteristics (monthly income, type of home, and no. of households)
were comparable in the two studied groups with no significant difference. Moreover,
none of the neonatal history data (Length of pregnancy, type of delivery and birth
weight) had a significant incidence in the FS group compared to the control group (P
> 0.05).
Regarding the length of pregnancy, it was found that the majority of cases and
controls were delivered after full-term pregnancy (97.5% & 92.5% respectively) (P >
0.05), which is similar to Aly et al., (2014) who indicated that preterm labor is not a
risk factor for FS.
Consanguineous marriages are common practice among the Palestinians in the
Gaza Strip, with a significant difference between different governorates and age
groups. Consanguineous marriages were associated with a higher risk for autosomal
recessive diseases as well as increased susceptibility to polygenic and multifactorial
disorders, infertility, infant mortality, congenital malformations and miscarriage
(Sirdah, 2014). In the present study, there was no significant difference between cases
and controls in parental consanguinity status, which is similar to Aly et al., (2014) who
reported parental consanguinity in 5 children with FS. However, the genetic part of FS
is complicated, and the risk changes significantly between families with the history for
similar conditions (Fetveit, 2008).
5.2 Clinical characteristics and medical history of the study
population
In the present study, the difference in the heart rate between cases and controls
was statistically significant, but the difference in the temperature rate was not
observed, which was similar to Aly et al., (2014) results who reported that "there was
72
a significant difference in the heart rate but no significant difference in temperature
and respiratory rate between case and control groups".
In patients with FSs, a threshold for FSs has been established based on body
temperature increase. The threshold varies depending on the age and maturity of the
individuals. Increased temperature degree after admission has been reported to
progressively increase the risk of first FS (Bidabadi & Mashouf, 2009). The most
significant risk factor for the development of a first FS as was reported by Berg et al.,
(1995) and Weng et al., (2010) is the degree temperature rising. The higher the
temperature, the higher the probability of simple FS occurrence. On the other hand,
other studies could not show a relationship between the mean high temperature and FS
(Aly et al., 2014; Daoud et al., 2002). In our study, the mean peak temperature upon
admission was higher in FS group (39.1°C) when compared to the control group
(38.9°C) but the difference was statistically non-significant (P > 0.05).
Fever is "a clinical signal that is characterized by rising body temperature more
than normal level". Hypothalamus controls the central body temperature in normal
conditions and sets it within the normal range (36.5-37.5 °C). An exogenous pyrogen
or endogenous ones cause fever by acting directly on the hypothalamic
thermoregulatory center and then rise the body temperature by releasing epinephrine,
vessels contraction (particularly peripheral vessels), finally reach a new regulation
point and fever occurs (Dinarello, 2004; Shokrzadeh, Abbaskhaniyan, Rafati,
Mashhadiakabr, & Arab, 2016).
In our study, the main cause of fever was URTI (85.0%) in children with FSs.
Rutter et al. reported that URTI was the most common trigger followed by tonsillitis
(Rutter & Smales, 1976). Different studies have reported that acute respiratory
infection is the main cause of FS (Gündüz, Kumandaş, Yavuz, Koparal, & Saraymen,
1994; Margaretha & Masloman, 2010; Nemichandra et al., 2017). In Shah & Parmar,
study, (2017) the common causes of fever were undifferentiated viral fever that was
present in 52.9% of children, and acute URTI was present in 32.4% of children.
Also, it was found that (85%) of the case group and (82.5%) of the control
group had no history of a nursery stay in ICU but the difference was not statistically
significant (p > 0.05). This finding was in agreement with (Aly et al., 2014) study.
While Millar, (2006) and Sadleir & Scheffer, (2007), indicated that the neonatal
73
nursery increases the possibility of simple FSs occurrence by staying for more than 30
days.
The etiology of FSs is still not understood clearly. It is believed that simple FS
occurs as a combination between genetic and environmental factors. Today, there is a
consensus that the most important factor for FS risk is genetic predisposition (Waruiru
& Appleton, 2004). In the present study, 30% of children have family history of FS
and 5% has a history of epilepsy in their family. We found that family history of FS is
associated with FS condition which is similar to the results of different researchers
who reported a positive family history of seizures (Daoud et al., 2002; Kafadar, Akinci,
Pekun, & Adal, 2012; Kumari et al., 2012; Margaretha & Masloman, 2010; Van Esch
et al., 1994).
5.3 Biochemical parameters among the study population
It may be challenging to diagnose IDA in the presence of fever/ infection.
Hematological parameters (like Hb, Hct, MCV, RDW), microscopic examination of
peripheral blood film, SF, SI, TIBC, Tsat, sTfR, and FEP may aid in the diagnosis.
The gold standard test for the diagnosis of IDA is bone marrow examination, but
unfortunately it is painful and traumatic method and, therefore, it is not used in the
current study.
Most of the authors have compared mean levels of SI, TIBC, Tfsat, SF, and
hematological parameters with FS case and control groups, while others have also
studied the number of cases having ID & IDA in a given subject population. In the
present study, data were analyzed by using both methods. According to WHO
guidelines, anemia is defined as Hb <11.0 g/dl, ID is defined as SF < 12 and < 30 Fg/l
in the presence of infection and inflammation respectively and Tfsat < 16%, and IDA
is defined as having both anemia and ID (World Health Organization, 2001). These
guidelines were used in our study.
5.3.1 Iron profile parameters, CBC, and CRP
In the present study, SI was significantly higher (p < 0.001) and TIBC was
significantly lower (p < 0.001) in cases with FS compared to controls which disagree
74
with the studies that related FSs with IDA. The incidence of ID & IDA was higher in
controls compared to cases.
The results of SI and TIBC in the present study agreed with the study of Bidabadi
& Mashouf, (2009) who reported: "higher levels of SI and lower levels of TIBC in
children with FS compared to the control febrile group". Also, Derakhshanfar et al.,
(2012) found a statistically significant difference between the case and control groups
in the mean of SI level and TIBC. Moreover, the mean TIBC level was lower in FS
group compared to the control group but failed to reach a statistically significant level
(p = 0.85) in Salma et al., (2015) study.
Contrary to our observations, Nawar et al., (2017) and Modaresi et al., (2012)
indicated that the mean SI levels were lower significantly among the FS group than
those in the control febrile group without a seizure. However, the mean level of TIBC
in Nawar et al., (2017) study was higher significantly in cases compared to controls.
Moreover, other studies did not show a significant difference in the mean level
of TIBC between cases and controls (Modaresi et al., 2012). While others showed that
there was no significant difference in SI & TIBC levels between case and control
groups (P > 0.05) (Shaikh, Inamdar, & K., 2018; Yousefichaijan et al., 2014).
On the other hand, the mean Tfsat percent in our study was higher in the seizure
group compared to controls with statistically significant difference (p < 0.001). The
findings coincide with Shaikh et al. study which showed that the mean value of Tfsat
in children with FS was higher compared to the control group, but the difference was
not statistically significant (p > 0.05) (Shaikh et al., 2018).
Our findings are inconsistent with the results of different studies who showed
that the mean value of Tfsat in children with FS was lower compared to the control
group, but the difference was statistically non-significant (Miri-Aliabad, Khajeh, &
Arefi, 2013; Potdar et al., 2017; Salma et al., 2015; Sharif, Kheirkhah, Madani, &
Kashani, 2016). Also, Nawar et al., (2017) study showed that "the mean Tfsat level
was lower significantly in cases compared to control (p < 0.001)".
Serum ferritin concentration is a reliable way of examining the body's iron status.
SF is ≤ 12 ng/ml in ID cases. Diagnostic levels raised up to ≤ 30 ng/ml in the presence
of infection/inflammation (World Health Organization, 2001). The disadvantage of SF
75
is that it rises non-specifically with inflammation because it belongs to acute phase
proteins.
The current study showed a fever/infection in both case and control groups;
therefore, any difference in the levels of ferritin between cases and controls could not
be attributed solely to fever. Our study's main limitation is the use of hospital control
that may have introduced a selection bias, as this group of patients shows higher ID
levels than the cases group. It would be better to use community control (Neupane,
Walter, Krueger, & Loeb, 2010), but there are ethical difficulties in taking blood in
well children unless there is an ID screening program with adequate treatment in
children.
In the present study and concerning SF and Hb, the mean levels in the case
group were lower compared to the control group but the differences were statistically
non-significant (p > 0.05). This agrees with a study carried out by Shaikh et al., (2018)
who showed that the mean values of SF and Hb in patients with FS were lower than
the control group, but the difference was statistically not significant (p > 0.05). Also,
similar observations were seen in the studies carried out by Kamalammal & Balaji,
(2016); Kunwar Bharat et al., (2015); Miri-Aliabad et al., (2013).
Differently, different studies showed that the mean levels of SF and Hb in the
case group were lower significantly when compared to the control group (p < 0.001)
(E. D. Kumar & Annamalai, 2017; Naseer & Patra, 2015; Nawar et al., 2017).
On the other hand, different researchers' results disagree with our findings. They
reported that SF levels are significantly higher among cases compared to controls
(Bidabadi & Mashouf, 2009; Potdar et al., 2017). Derakhshanfar, et al. (2012) results
showed that the mean Hb level in cases was significantly higher compared to controls.
The mean levels of sTfR in the present study were lower in cases in comparison
to controls but the difference failed to reach a statistically significant value (p > 0.05).
Similar observation was seen in Papageorgiou et al., (2015) study. Another study did
not agree with our results, where the sTfR level in cases was higher than controls (p =
0.007) and suggesting that sTfR was a risk factor in children with FS (Salma et al.,
2015).
76
Our data clearly reveals that there were no significant differences between the
two groups (p > 0.05) in the mean levels of Hct, MCH, MCHC, and RDW. The mean
levels of MCV were significantly higher (p = 0.045) and RBCs count was significantly
lower (p = 0.002) in cases compared with controls. In a study carried out by Azizet
al., (2017) they reported that "the mean level of Hct, RBCs, MCV, MCH, MCHC, and
RDW were significantly lower in cases compared to controls", which was in agreement
with our finding in the mean level of RBCs count only. Moreover, Yousefichaijan et
al., (2014) and Derakhshanfar, et al., (2012) showed that "the mean level of Hct, MCV,
MCH, and MCHC were higher significantly in the FS group in comparison to the
control group", which agrees with our finding in the mean level of MCV.
According to our results, 34 (85.0%) of children in the case group and 32
(80.0%) in the control group were anemic, revealing no significant relationship (p =
0.556). The results also show that 32.5% of cases had an ID and 32.5% had IDA while
the controls 40.0% had ID & 30.0% had IDA with no statistically significant difference
between the results. The findings of the previous studies are controversial; some of
them concluded that ID &/or IDA caused intensification of FS, others mentioned
protective effects of ID &/or IDA against FS and the remaining confirmed our results.
Moreover, the study by Kamalammal & Balaji, (2016) showed no strong
association between IDA and FS. Similarly, Amirsalari et al., (2010) indicated that
there was no relationship between IDA and FS. In addition, in the research by Miri-
Aliabad et al., (2013), 44% of the cases and 36% of the controls were diagnosed with
anemia.
On the other hand, Derakhshanfar et al., (2012) reported the lower risk of FS in
anemic children. Similarly, Bidabadi & Mashouf, (2009) indicated that "IDA was
less frequent among FS than controls". The incidence of IDA was higher significantly
in controls compared to the cases as the results of another study by Yousefichaijan et
al., (2014) which revealed that "22.5% of children in the group of FS were anemic
compared to 34.0% in the control group (p < 0.001)".
While Momen et al., (2010) claimed that ID was more common among the
children with the first episode of FS. Kumar & Sasikumar, (2015) reported also the
higher susceptibility to FS in the cases with ID, which is consistent with the results
77
obtained by Kankane & Kankane, (2015) and Sreenivasa et al., (2015). In other
researches, Fallah et al., (2013) and Ghasemi & Valizadeh (2014) considered IDA to
be a risk factor that might be involved in FS. The findings showed a higher rate of ID
in FS cases compared to healthy controls in the study by Hartfield et al., (2009)
suggested that screening for ID should be considered in FS - presented children.
Febrile seizure is a multi-factorial disease. Independent risk factors for FSs
include the rise of temperature, family history of FS, fever episodes each year, history
of smoking or alcoholism during pregnancy. It was also found that children with IDA
mostly have low socioeconomic status and may have a deficiency of other
micronutrients like Zn, Mg, selenium, and Cu which may act as important confounding
factors (Huang et al., 1999).
Possible factors that may cause contradictory of the results of various studies
include different diagnostic criteria for the diagnosis ID &/or IDA, sample size, age of
patients in each study, nutritional status, geographical area, retrospective nature of
many studies and the background prevalence of ID &/or IDA. However, even with
greater frequency of anemia in patients, a causal relationship cannot be assumed
between ID and FS. More prospective studies with a larger sample size should be
conducted. Furthermore, another possible explanation is that the rate of anemia is high
(59.7%) in our population (El Kishawi et al., 2015), the difference between the ratio
of anemia in FS patients and controls is not high enough to show a significant
difference.
The current study showed that the mean count of neutrophils (103/Fl) in
children with FS was lower significantly compared to the control group (40.0 versus
50.6; p < 0.002). Our results agree with Goksugur et al., (2014) and Yigit et al., (2017).
Higher counts of neutrophils may correlate with the more advanced inflammatory
process in the control group. Children with fever without seizure were entered to the
hospital at the peak of the febrile illness (with the highest value of the body
temperature). The count of neutrophils may also be predicted to be higher than those
in the children with FS.
Contrary to our observations, Gontko–Romanowska et al., (2017) reported that
the mean count of neutrophils among FS children was higher than among febrile
78
children without seizures (62.55 vs. 48.48; p < 0.001). During the intense activity of
skeletal muscle (e.g., seizures and chills), may result from an inflammatory reaction
(after 4-5 hours) or may be associated with the presence
of circulating toxins in the blood, the number of neutrophils can increase temporarily
and rapidly.
In comparison with febrile children without a seizure, FS children had high
mean counts of lymphocytes and the difference was statistically significant. This result
is inconsistent with Gontko–Romanowska et al., (2017) who showed that lymphocytes
count in FS-children were lower significantly compared to febrile children without
seizures. In our study, the main cause of fever was URTI (85%) in children with FSs
which may results of viral infection this lead to a higher count of lymphocyte, as
expected, higher lymphocytes seen in viral than in bacterial infections (Inoue &
Willert, 2018; Korppi, Kröger, & Laitinen, 1993).
In children with FS, the levels of CRP were lower significantly compared to
children in the control group (3.0 vs 8.5 mg/L; p < 0.001). This may depend on the
infection which leads to a significant increase in children's body temperature, usually
viruses. The half-life of CRP is about 19 hours long, begins to rise after 12-24 hours
of an inflammatory response, and peaks within 2-3 days. The presence of infection
causes an increase in CRP values. Children with FS may be suspected of developing
inflammatory processes and increasing body temperature to very high values fast
enough that CRP levels do not reach their highest values. In febrile children without
seizures, the inflammatory process grew slowly enough to achieve higher levels of
CRP (Gontko–Romanowska et al., 2017; Markanday, 2015).
Several studies evaluated CBC in febrile and FS children but they did not
analyze the inflammatory mediators. However, Gontko–Romanowska et al., (2017)
showed that the mean CRP levels in FS children were lower significantly in
comparison to children without seizures (15.73 versus 58.50 mg/L; p < 0.001) which
is similar to our observation.
79
5.3.2 Zinc and Magnesium
The functions of TEs in CNS were emphasized in recent years and are
considered to play a role in the production of certain brain neurotransmitters. Zn is
one of these most important TEs. It enters in many metalloenzyme structures and acts
in the CNS as a neurotransmitter or neuroregulator (Burhanoğlu, Tütüncüoğlu, Tekgül,
& Özgür, 1996). It is a fundamental component of body enzymes that modulates CNS
activities. CSF hypozincemia activates NMDA receptors or disinhibits GABAergic
action, thus resulting in FS (Joshi, 2014). Several studies in this field were performed,
some of which showed that hypozincemia was associated with FS, while few
concluded that no association exists.
Most of the authors have compared the mean levels of serum Zn in children
with FS cases and controls, while others have also studied the number of cases having
hypozincemia in a given subject population. In the present study, data were analyzed
by both these methods. As recommended by WHO, the cut-off value for hypozincemia
that was used is 65 Fg/dl (Simon-Hettich et al., 2001; World Health Organization,
2004).
In our study, the mean level of serum Zn in the case group was lower (77.3
Fg/dl) compared to the control group (78.8 Fg/dl). The percentage of hypozincemia in
cases was 15.0% compared to 7.5% in controls but the differences were not statistically
significant. Similar to our observations, different studies found that the difference in
the concentration of serum Zn in children with FS and control groups were not
statistically significant (ÇELİK et al., 2012; Kafadar et al., 2012; Salah et al., 2014;
On the other hand, different studies disagree with our results. They found that
Zn levels are significantly lower in the case group compared to those in the control
group (Bonu S, 2016; Burhanoğlu et al., 1996; Choudhury & Sidharth, 2016;
Ehsanipour et al., 2009; Ganesh & Janakiraman, 2008; L. Kumar, Chaurasiya, &
Gupta, 2011; Palliana, Singh, & Ashwin, 2010). While in another study, Gatoo et al.,
(2015) reported that "hypozincemia in the presence of other risk factors of FS may
enhance the occurrence of FS".
80
The relationship between low levels of Zn and convulsion is not understood
whether it is a cause or a result. The lower levels of serum Zn in the FS group were
elucidated by the fact that Zn levels decrease in cases of acute infection and stress, and
that Zn is found in concentrated levels in recovering tissue (Kafadar et al., 2012).
Magnesium is involved in neuronal function and inhibits the calcium
facilitating effects on synaptic transmission and also exerts a voltage-dependent
blockage of NMDA receptor channel. Mg's effect on the nervous system is that it
reduces acetylcholine releasing at the neuromuscular junction by antagonizing calcium
ions at the presynaptic junction, reduces nerve excitability and acts as an
anticonvulsant, reverses cerebral vasospasm (Sreekrishna et al., 2016).
Hypomagnesemia has been suggested to have significant effects on the CNS,
particularly in causing seizures. An alteration of Mg levels in the plasma and
intracellular matrix has suggested that the cell membranes will be impaired
functionally, which could cause a seizure. Recent evidence indicates that in FS, Mg
deficiency can play an important role (Sreekrishna et al., 2016). The deficiency of this
element is therefore assumed to have a contributing effect on the incidence of FS.
In our study, we observed that mean serum levels of Mg were lower
significantly in the FS group when compared with controls. Percentage of cases with
hypomagnesemia (25.0%) was higher compared to controls (10.0%) but the difference
was not statistically significant (p = 0.288).
Chhaparwal et al., (1971) found out that levels of serum Mg were low
significantly among children with FS than that of normal children in the same region,
boosting the hypothesis that "Hypomagnesemia may be related to the occurrence of
FS". Later on, different studies indicated that the levels of serum Mg in children with
FS were lower significantly when compared to normal children which strengthened
this association (Bharathi & Chiranjeevi, 2016; Mishra, Singhal, Upadhyay, Prasad, &
Atri, 2007; Namakin et al., 2016; Nemichandra et al., 2017; Salah et al., 2014; Sherlin
& Balu, 2012; Talebian et al., 2009).
In contrast to our results and in separate studies, it was reported that the level
of serum Mg in children with FS is in the normal range. The results indicate that there
81
was no role for serum Mg in the case of FSs (Donaldson, Trotman, Barton, &
Melbourne-Chambers, 2008; Rutter & Smales, 1976; Sreekrishna et al., 2016).
Overall, two major reasons for diversity in results were the difference in the
target population of studies and sample sizes. Given present discrepancies among
findings, it seems that there is a need for further researches with larger sample sizes or
different methodologies to show the role of Mg in inducing convulsion in febrile
children.
The mean levels of SI had a negative correlation which is statistically
significant with hs-CRP. A Similar finding was observed in Richardson et al. study
(Richardson, Ang, Visintainer, & Wittcopp, 2009). In addition, our results also showed
a significant negative correlation of SI with RDW. In contrast, SI showed a significant
positive correlation with MCV and MCH. In this aspect, a similar finding was
observed (Hadler, Juliano, & Sigulem, 2002).
Our results also showed that the mean levels of sTfR have a moderate negative
correlation which is statistically significant with age, our results are in line with a
physiological perspective of Kratovil et al., (2007) study who found that sTfR levels
appear to be high during the toddler period, a period in which ID is common, is
potentially novel finding because it suggests that there may be increased physiological
need for iron during this time. Increased sTfR levels reflect increased RBC surface
expression of transferrin receptor on RBCs which in turn reflects increased iron need.
In addition, our results also showed a significant negative correlation of sTfR with Hb,
and MCV, and it showed a significant positive correlation of sTfR with RDW, this is
in agreement with Çulha & Uysal, (2002) and Yoon et al., (2015) studies which
indicated that the serum sTfR levels are significantly correlated with other diagnostic
iron parameters of IDA.
On the other hand, the mean levels of serum Mg showed a significant negative
correlation in our study with the age of onset.
82
83
Chapter 6
Conclusions and Recommendations
6.1 Conclusions
The conclusions of the present study are:
1. The main cause of fever was URTI which accounts for (85%) of children with
FSs.
2. The mean MCV was significantly higher and RBCs count was significantly lower
in cases compared with controls.
3. The mean levels of SI and Tfsat were significantly higher and TIBC was
significantly lower among the cases with FS compared to controls.
4. The incidence of ID & IDA was higher among the control group compared with
the case group.
5. In children with FS, the mean level of hs-CRP was lower significantly than in
children without seizures.
6. The mean count of neutrophils in FS children was significantly lower than in the
control group. While, the mean count of lymphocytes was higher significantly
among children with FS in comparison to febrile children without seizures.
7. The mean level of serum Zn and the percentage of Zn deficiency in the case group
was lower than in the control group, but the differences were not statistically
significant.
8. The mean levels of serum Mg were low significantly in FS group when compared
with control group. Despite, hypomagnesemia between cases and controls was
statistically insignificant.
6.2 Recommendations
1. Using Mg loading test to evaluate the Mg stores of the body properly or measure
the physiologically active free, and ionized form of Mg.
2. In FSs, the levels of other micronutrients such as selenium, Cu, and iodine
can be evaluated to uncover the probable etiology.
84
3. Conduction of another study with a larger sample size and different control groups
(e.g. healthy children) to investigate the existing hypothesis that IDA, low serum
and CSF Zn and Mg have significant roles in FSs.
6.3 Limitations
1. The use of only hospital controls in this study may have introduced a selection
bias since these patients are more likely to have higher levels of ID than does the
reference population. A better design would have included two sets of controls:
hospital and community controls.
2. Different definitions and different parameters used for ID diagnosis.
3. Lumbar puncture (LP) is strongly advised in children under one year old with first
FS to rule out meningitis because of the probability of absence of other signs of
infection. For similar reasons, LP is suggested until 18 months (Kliegman et al.,
2016), but after that, performing LP has considerable limitations.
4. The study performed at Al Nassir Pediatric Hospital and the sample size wasn't
large enough. Sample collection was relatively difficult due to the objection of
many parents to participate and the rare of the cases in our country.
85
86
References
Abe, A., & Yiamashita, S. (1989). Colorimetric method for the estimation of zinc. Clin
Chem, 35(4), 552-554. Åkesson, A., Bjellerup, P., & Vahter, M. (1999). Evaluation of kits for measurement
of the soluble transferrin receptor. Scandinavian Journal of Clinical and
Laboratory Investigation, 59(2), 77-81. Allen, J., Backstrom, K. R., Cooper, J. A., Cooper, M. C., Detwiler, T. C., Essex, D.
W., . . . Pearlman, S. R. (1998). Measurement of soluble transferrin receptor in serum of healthy adults. Clinical chemistry, 44(1), 35-39.
Aly, I., Kmal, H. M., Soliman, D. R., & Mohamed, M. H. (2014). Iron profile parameters and serum zinc and copper levels in children with febrile convulsions in Banha. J Am Sci, 10(7), 320-327.
American Academy of Pediatrics. (1980). Febrile seizures: long-term management of children with fever-associated seizures. Pediatrics, 66(6), 1009-1012.
Amiri, M., Farzin, L., Moassesi, M. E., & Sajadi, F. (2010). Serum trace element levels in febrile convulsion. Biological trace element research, 135(1-3), 38-44.
Amirsalari, S., Doust, Z. T. K., Ahmadi, M., Sabouri, A., Kavemanesh, Z., Afsharpeyman, S., . . . Ghazavi, Y. (2010). Relationship between iron deficiency anemia and febrile seizures. Iranian journal of child neurology,
4(1), 27-30. Andrews, N. C. (1999). Disorders of iron metabolism. New England Journal of
Medicine, 341(26), 1986-1995. Artiss, J. D., Vinogradov, S., & Zak, B. (1981). Spectrophotometric study of several
sensitive reagents for serum iron. Clinical biochemistry, 14(6), 311-315. Aziz, K. T., Ahmed, N., & Nagi, A. G. (2017). Iron deficiency anaemia as risk factor
for simple febrile seizures: a case control study. Journal of Ayub Medical
College Abbottabad, 29(2), 316-319. Baek, S.-J., Byeon, J. H., Eun, S.-H., Eun, B.-L., & Kim, G.-H. (2018). Risk of low
serum levels of ionized magnesium in children with febrile seizure. BMC
pediatrics, 18(1), 297. Benoist, B. d., McLean, E., Egll, I., & Cogswell, M. (2008). Worldwide prevalence of
anaemia 1993-2005: WHO global database on anaemia. Worldwide prevalence
of anaemia 1993-2005: WHO global database on anaemia. Berg, A. T., Shinnar, S., Shapiro, E. D., Salomon, M. E., Crain, E. F., & Hauser, W.
A. (1995). Risk factors for a first febrile seizure: a matched case control study. Epilepsia, 36(4), 334-341.
Bharathi, S., & Chiranjeevi, K. (2016). Study of serum magnesium levels and its correlation with febrile convulsions in children aged 6 months to 5 years of age. IAIM, 3(11), 61-68.
Bidabadi, E., & Mashouf, M. (2009). Association between iron deficiency anemia and first febrile convulsion: a case–control study. Seizure, 18(5), 347-351.
87
Bohuon, C. (1962). Microdosage du magnesium dans divers milieux biologiques. Clinica Chimica Acta, 7(6), 811-817.
Bonu S, M. A., Mishra R. . (2016). SERUM ZINC LEVEL IN CHILDREN WITH FEBRILE CONVULSIONS AND ITS COMPARISION WITH THAT OF CONTROL GROUP. Yuva Journal of Medical Science, 2(4), 133-135.
British Nutrition Foundation. (2009). Minerals and trace elements. Retrieved from https://www.nutrition.org.uk/nutritionscience/nutrients-food-and-ingredients/minerals-and-trace-elements.html?start=1
Brittenham, G. M., Sheth, S., Allen, C. J., & Farrell, D. E. (2001). Noninvasive
methods for quantitative assessment of transfusional iron overload in sickle
cell disease. Paper presented at the Seminars in hematology. Burhanoğlu, M., Tütüncüoğlu, S., Tekgül, H., & Özgür, T. (1996). Hypozincaemia in
febrile convulsion. European journal of pediatrics, 155(6), 498-501. Burke, R. M., Leon, J. S., & Suchdev, P. S. (2014). Identification, prevention and
treatment of iron deficiency during the first 1000 days. Nutrients, 6(10), 4093-4114.
Burtis, C. A., Ashwood, E. R., & Bruns, D. E. (2012). Tietz textbook of clinical
chemistry and molecular diagnostics-e-book: Elsevier Health Sciences. Byeon, J. H., Kim, G.-H., & Eun, B.-L. (2018). Prevalence, Incidence, and Recurrence
of Febrile Seizures in Korean Children Based on National Registry Data. J Clin
Neurol, 14(1), 43-47. Campbell, A. K., & Campbell, A. K. (1988). Chemiluminescence: principles and
applications in biology and medicine. 68-126. ÇELİK, K., GÜZEL, E. Ç., NALBANTOĞLU, B., GÜZEL, S., ÖZKUL, A. A.,
ELEVLİ, M., & NALBANTOĞLU, A. (2012). Febril Konvülsiyonda Serum Çinko Düzeyleri: Eksiklik Gerçekten Bir Risk Faktörü müdür? Turkiye
Klinikleri Journal of Pediatrics, 21(1), 1-6. Cendes, F., & Sankar, R. (2011). Vaccinations and febrile seizures. Epilepsia, 52(s3),
23-25. Centers for Disease Control and Prevention. (1998). Recommendations to Prevent and
Control Iron Deficiency in the United States. Retrieved from https://www.cdc.gov/mmwr/preview/mmwrhtml/00051880.htm#top
Čepelak, I., Dodig, S., & Čulić, O. (2013). MAGNESIUM--MORE THAN A COMMON CATION. Rad Hrvatske Akademije Znanosti i Umjetnosti.
Medicinske Znanosti, 517(39). Chhaparwal, B., Kohli, G., Pohowalla, J., & Singh, S. (1971). Magnesium levels in
serum and in CSF in febrile convulsions in infants and children. The Indian
Journal of Pediatrics, 38(5), 241-245. Choudhury, J., & Sidharth, S. (2016). A Study on Role of Zinc In Febrile Seizures in
Children. European Journal of Biomedical and Pharmaceutical Sciences, 3(1), 408-410.
Chung, S. (2014). Febrile seizures. Korean journal of pediatrics, 57(9), 384-395.
88
Conrad, M. E., & Umbreit, J. N. (2000). Iron absorption and transport—an update. American journal of hematology, 64(4), 287-298.
Costello, R. B., Elin, R. J., Rosanoff, A., Wallace, T. C., Guerrero-Romero, F., Hruby, A., . . . Song, Y. (2016). Perspective: the case for an evidence-based reference interval for serum magnesium: the time has come. Advances in Nutrition, 7(6), 977-993.
Çulha, V. K., & Uysal, Z. (2002). The importance of serum transferrin receptor and TfR-F index in the diagnosis of iron deficiency accompanied by acute and chronic infections. Turkish Journal of Hematology, 19(4), 453-459.
Daoud, A., Ajloni, S., El-Salem, K., Horani, K., Otoom, S., & Daradkeh, T. (2004). Risk of seizure recurrence after a first unprovoked seizure: a prospective study among Jordanian children. Seizure, 13(2), 99-103.
Daoud, A., Batieha, A., Abu Ekteish, F., Gharaibeh, N., Ajlouni, S., & Hijazi, S. (2002). Iron status: a possible risk factor for the first febrile seizure. Epilepsia,
Petersen, P. (1996). Consensus of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins in serum based on the standardization against the IFCC/BCR/CAP reference material (CRM 470). European Journal of Clinical Chemistry and Clinical
Biochemistry, 34(6), 517-520. Derakhshanfar, H., Abaskhanian, A., Alimohammadi, H., & ModanlooKordi, M.
(2012). Association between iron deficiency anemia and febrile seizure in children. Med Glas (Zenica), 9(2), 239-242.
Dinarello, C. A. (2004). Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res, 10(4), 201-222. doi:10.1179/096805104225006129
Donaldson, D., Trotman, H., Barton, M., & Melbourne-Chambers, R. (2008). Routine laboratory investigations in infants and children presenting with fever and seizures at the University Hospital of the West Indies. West Indian Medical
Journal, 57(4), 369-372. Dougherty, D., Duffner, P. K., Baumann, R. J., Berman, P., Green, J. L., Schneider,
S., . . . McInerny, T. K. (2008). Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics,
121(6), 1281-1286. Dupuy, A. M., Badiou, S., Descomps, B., & Cristol, J. P. (2003). Immunoturbidimetric
determination of C-reactive protein (CRP) and high-sensitivity CRP on heparin plasma. Comparison with serum determination. Clinical chemistry and
laboratory medicine, 41(7), 948-949. Ehsanipour, F., Talebi-Taher, M., Harandi, N., & Kani, K. (2009). Serum zinc level in
children with febrile convulsion and its comparison with that of control group. Iranian Journal of Pediatrics, 19(1), 65-68.
89
El Kishawi, R. R., Soo, K. L., Abed, Y. A., & Muda, W. A. M. W. (2015). Anemia among children aged 2–5 years in the Gaza Strip-Palestinian: a cross sectional study. BMC Public Health, 15(1), 319.
El-Radhi, A., Withana, K., & Banajeh, S. (1986). Recurrence rate of febrile convulsion related to the degree of pyrexia during the first attack. Clinical pediatrics,
25(6), 311-313. Ems, T., & Huecker, M. R. (2019). Biochemistry, Iron Absorption StatPearls.
Treasure Island (FL). Epilepsy, I. L. A. (1993). Guidelines for epidemiologic studies on epilepsy.
Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia, 34(4), 592-596.
Fallah, R., Tirandazi, B., Karbasi, S. A., & Golestan, M. (2013). Iron deficiency and iron deficiency anemia in children with febrile seizure. Iranian journal of
pediatric hematology and oncology, 3(1), 200. Fetveit, A. (2008). Assessment of febrile seizures in children. European journal of
pediatrics, 167(1), 17-27. Fisher, R. S., van Emde Boas, W., Blume, W., Elger, C., Genton, P., Lee, P., & Engel,
J., Jr. (2005). Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia, 46(4), 470-472. doi:10.1111/j.0013-9580.2005.66104.x
Gambino, R., Desvarieux, E., Orth, M., Matan, H., Ackattupathil, T., Lijoi, E., . . . Gunter, E. (1997). The relation between chemically measured total iron-binding capacity concentrations and immunologically measured transferrin concentrations in human serum. Clinical chemistry, 43(12), 2408-2412.
Ganesh, R., & Janakiraman, L. (2008). Serum zinc levels in children with simple febrile seizure. Clin Pediatr (Phila), 47(2), 164-166. doi:10.1177/0009922807306165
Gattoo, I., Harish, R., & Quyoom Hussain, S. (2015). correlation of serum zinc level with simple febrile seizures: A Hospital based Prospective Case Control Study. International Journal of Pediatrics, 3(2.2), 509-515.
Ghasemi, F., & Valizadeh, F. (2014). Iron-deficiency anemia in children with febrile seizure: a case-control study. Iranian journal of child neurology, 8(2), 38.
Goksugur, S., Kabakus, N., Bekdas, M., & Demircioglu, F. (2014). Neutrophil-to-lymphocyte ratio and red blood cell distribution width is a practical predictor for differentiation of febrile seizure types. Eur Rev Med Pharmacol Sci, 18(22), 3380-3385.
Gontko–Romanowska, K., Żaba, Z., Panieński, P., Steinborn, B., Szemień, M., Łukasik–Głębocka, M., . . . Górny, J. (2017). The assessment of laboratory parameters in children with fever and febrile seizures. Brain and behavior,
7(7), e00720.
90
Greer, J. P. e. o. c., & Wintrobe, M. M. C. h. Wintrobe's clinical hematology (13th edition. ed.).
Greer, J. P. e. o. c., & Wintrobe, M. M. C. h. (2014). Wintrobe's clinical hematology (13th edition. ed.).
Gündüz, Z., Kumandaş, S., Yavuz, I., Koparal, M., & Saraymen, R. (1994). Serum and cerebrospinal fluid zinc levels in febrile convulsions. Turkiye Klinikleri
Journal of Case Reports, 12(6), 239-242. Hadler, M. C., Juliano, Y., & Sigulem, D. M. (2002). Anemia in infancy: etiology and
prevalence. Jornal de pediatria, 78(4), 321-326. Hartfield, D. S., Tan, J., Yager, J. Y., Rosychuk, R. J., Spady, D., Haines, C., & Craig,
W. R. (2009). The association between iron deficiency and febrile seizures in childhood. Clinical pediatrics, 48(4), 420-426.
Higgins, T. (1981). Novel chromogen for serum iron determinations. Clinical
chemistry, 27(9), 1619-1620. Hoffman, R. (2008). Hematology : basic principles and practice (5th ed. ed.).
Edinburgh: Churchill Livingstone. Huang, C. C., Wang, S. T., Chang, Y. C., Huang, M. C., Chi, Y. C., & Tsai, J. J. (1999).
Risk factors for a first febrile convulsion in children: a population study in southern Taiwan. Epilepsia, 40(6), 719-725.
IBM/SPSS. (2018). Statistical Package for the Social Sciences (Version 22): International Business Machines Corporation (IBM). Retrieved from https://www.ibm.com/analytics/spss-statistics-software
Inoue, S., & Willert, J. R. (2018). Leukocytosis Clinical Presentation. Retrieved from https://emedicine.medscape.com/article/956278-clinical#b4
Iyshwarya, U., Kalyan, P. P., Suma, H., & Aruna, K. R. (2013). Serum trace elements and oxidative stress marker in children with febrile seizure. Journal of
Biomedical Sciences, 2(1). Jehangir, A., Rajesh, K., Roshan, A., & Santosh, K. (2018). Level of Micronutrient
[Zinc] and its Association with Seizures in Children: A Case Control Study. Academic Journal of Pediatrics & Neonatology (AJPN), 7(2).
Jockers, D. (2019). Is Your Brain Making Enough GABA? . Retrieved from https://drjockers.com/gaba/
Johnston, M. V. (2012). Iron deficiency, febrile seizures and brain development. Indian Pediatr, 49(1), 13-14.
Joshi, S. S. (2014). Assessment of Serum Iron and Zinc Status in Febrile Seizures–A Prospective Case Control Study. IOSR Journal of Dental and Medical Sciences
(IOSR-JDMS), 13(10). Kafadar, İ., Akinci, A. B., Pekun, F., & Adal, E. (2012). The role of serum zinc level
in febrile convulsion etiology/Febril konvulsiyon etyolojisinde serum cinko duzeyinin rolu. Journal of Pediatric Infection, 6(3), 90-94.
Kamalammal, R., & Balaji, M. (2016). Association between iron deficiency anemia and various red cell parameters with febrile convulsions in children of age
91
group 3 to 60 months. . International Journal of Contemporary Pediatrics,
3(2), 559-562. Kankane, A., & Kankane, A. (2015). Status of serum iron in children with febrile
transferrin receptor assay when screening for iron deficiency in an unselected population of elderly anaemic patients. Journal of internal medicine, 267(3), 331-334.
Khair, A. M., & Elmagrabi, D. (2015). Febrile seizures and febrile seizure syndromes: an updated overview of old and current knowledge. Neurology research
international, 2015. Khosroshahi, N., Ghadirian, L., & Kamrani, K. (2015). Evaluation of Magnesium
Levels in Serum and Cerebrospinal Fluid of Patients with Febrile Convulsion Hospitalized in Bahrami Hospital in Tehran in 2010-2011. Acta Medica
Iranica, 53(12), 778-781. Kirtichandra, K. (2015). Serum Zinc and Iron Levels in Children With Febrile
Seizures. (M.D. PEDIATRICS), The Tamil Nadu Dr.M.G.R Medical University Chennai, Tamil Nadu. Retrieved from http://repository-tnmgrmu.ac.in/id/eprint/6426
Klein, N. P., Lewis, E., Baxter, R., Weintraub, E., Glanz, J., Naleway, A., . . . Belongia, E. A. (2012). Measles-containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics, 129(5), 809-814.
Kliegman, R. e., Stanton, B. e., St. Geme, J. W. I. I. I. e., Schor, N. F. e., Behrman, R. E. e., & Nelson, W. E. T. o. p. (2016). Nelson textbook of pediatrics (20th edition. ed.).
Kobrinsky, N. L., Yager, J. Y., Cheang, M. S., Yatscoff, R. W., & Tenenbein, M. (1995). Does iron deficiency raise the seizure threshold? Journal of child
neurology, 10(2), 105-109. Korppi, M., Kröger, L., & Laitinen, M. (1993). White blood cell and differential counts
in acute respiratory viral and bacterial infections in children. Scandinavian
journal of infectious diseases, 25(4), 435-440. Koulaouzidis, A., Said, E., Cottier, R., & Saeed, A. A. (2009). Soluble transferrin
receptors and iron deficiency, a step beyond ferritin. A systematic review. J
Gastrointestin Liver Dis, 18(3), 345-352. Kratovil, T., DeBerardinis, J., Gallagher, N., Luban, N. L., Soldin, S. J., & Wong, E.
C. (2007). Age specific reference intervals for soluble transferrin receptor (sTfR). Clinica chimica acta; international journal of clinical chemistry,
380(1-2), 222-224. Kroger, A., Atkinson, W., Marcuse, E., & Pickering, L. (2006). Advisory Committee
on Immunization Practices Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the
92
Advisory Committee on Immunization Practices. MMWR Recomm Rep, 55, 1-48.
Kumar, E. D., & Annamalai, T. (2017). Correlation of iron deficiency anemia and events of febrile seizures among children aged 6 months to 5 years. Int Arch
Integrat Med, 4, 196-201. Kumar, L., Chaurasiya, O. S., & Gupta, A. H. (2011). Prospective study of level of
serum zinc in patients of febrile seizures, idiopathic epilepsy and CNS infections. People’s Journal of Scientific Research, 4(2), 1-4.
Kumar, S. M., & Sasikumar, B. R. (2015). Low iron status: a possible risk factor for febrile seizures. JOURNAL OF EVOLUTION OF MEDICAL AND DENTAL
SCIENCES-JEMDS, 4(90), 15546-15548. Kumar, V., Kumar, A., Singh, S., Tripathi, S., Kumar, D., Singh, R., & Dwivedi, S.
(2016). Zinc deficiency and its effect on the brain: An Update. Int J Mol Genet
and Gene Ther, 1(1). Kumari, P. L., Nair, M., Nair, S., Kailas, L., & Geetha, S. (2012). Iron deficiency as a
risk factor for simple febrile seizures-a case control study. Indian pediatrics,
49(1), 17-19. Kunwar Bharat, Yadav R.K., Durgesh Kumar, Yadav A, Sharan R, & V., C. (2015).
Association between iron deficiency anemia and febrile seizures. Pediatric
Review: International Journal of Pediatric Research, 2(4). Kutscher, M. L. (2006). Children with seizures : a guide for parents, teachers, and
other professionals (1st ed.). London: Jessica Kingsley. Lin, C.-N., Wilson, A., Church, B. B., Ehman, S., Roberts, W. L., & McMillin, G. A.
(2012). Pediatric reference intervals for serum copper and zinc. Clinica
Chimica Acta, 413(5-6), 612-615. Mahyar, A., Pahlavan, A., & Varasteh-Nejad, A. (2008). Serum zinc level in children
with febrile seizure. Acta Medica Iranica, 46(6), 477-480. Makino, T. (1991). A sensitive, direct colorimetric assay of serum zinc using nitro-
PAPS and microwell plates. Clinica Chimica Acta, 197(3), 209-220. Mann, C. K., & Yoe, J. H. (1957). Spectrophotometric determination of magnesium
with 1-azo-2-hydroxy-3-(2.4-dimethylcarboxanilido)-naphthalene-1-(2-hydroxybenzene). Analytica chimica acta, 16, 155-160.
Margaretha, L., & Masloman, N. (2010). Correlation between serum zinc level and simple febrile seizure in children. Paediatrica Indonesiana, 50(6), 326-330.
Markanday, A. (2015). Acute phase reactants in infections: evidence-based review and
a guide for clinicians. Paper presented at the Open forum infectious diseases. MayoClinic. (2019). Mayo Clinic: Mayo Medical Laboratories Web Site. Soluble
Transferrin Receptor (sTfR), Serum. Retrieved from https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/84283
93
McDonagh, M. S., Blazina, I., Dana, T., Cantor, A., & Bougatsos, C. (2015). Screening and routine supplementation for iron deficiency anemia: a systematic review. Pediatrics, 135(4), 723-733. doi:10.1542/peds.2014-3979
Millar, J. S. (2006). Evaluation and treatment of the child with febrile seizure. Am Fam
Physician, 73(10), 1761-1764. Millichap, J. J., & Gordon Millichap, J. (2015). Clinical features and evaluation of
febrile seizures: UpToDate. Miri-Aliabad, G., Khajeh, A., & Arefi, M. (2013). Iron status and iron deficiency
anemia in patients with febrile seizure. . Zahedan Journal of Research in
Medical Sciences, 15(9), 14-17. Mishra, O. P., Singhal, D., Upadhyay, R. S., Prasad, R., & Atri, D. (2007).
Cerebrospinal fluid zinc, magnesium, copper and gamma-aminobutyric acid levels in febrile seizures. Journal of Pediatric Neurology, 5(1), 39-44.
Modaresi, M., Mahmoudian, T., Yaghini, O., Kelishadi, R., Golestani, H., Tavasoli, A., & Mosayebi, D. (2012). Is Iron Insufficiency Associated With Febrile Seizure? Experience in an Iranian Hospital. J Compr Ped, 3(1), 21-24.
Momen, A. A., Nikfar, R., & Karimi, B. (2010). Evaluation of Iron Status in 9-month to 5-year-old Children with Febrile Seizures: A Case-control Study in the South West of Iran. Iranian journal of child neurology, 4(2), 45-50.
Namakin, K., Zardast, M., Sharifzadeh, G., Bidar, T., & Zargarian, S. (2016). SerumTrace Elements in Febrile Seizure: A Case-Control Study. Iranian
journal of child neurology, 10(3), 57. Naseer, M. R., & Patra, K. C. (2015). Correlation of serum iron and serum calcium
levels in children with febrile seizures. International Journal of Contemporary
Pediatrics, 2(4), 406-410. Nawar , E. A., Abd El Moneim, E. R., Eissa, H. A., & Massoud, M. G. (2017).
Studying The Relation Between Iron Deficiency Anemia & Febrile Seizures. International Journal of Advanced Research (IJAR), 5(8), 2084-2091.
Nemichandra, S., Prajwala, H., Harsha, S., & Narayanappa, D. (2017). Implications of Alteration of Serum Trace Elements In Febrile Seizures. International Journal
of Current Research, 9(7). Neupane, B., Walter, S. D., Krueger, P., & Loeb, M. (2010). Community controls were
preferred to hospital controls in a case-control study where the cases are derived from the hospital. J Clin Epidemiol, 63(8), 926-931. doi:10.1016/j.jclinepi.2009.11.006
Nriagu, J. (2007). Zinc deficiency in human health. School of Public Health. Orkin, S. H., & Nathan, D. G. (2009). Nathan and Oski's hematology of infancy and
childhood. Philadelphia: Saunders/Elsevier. Palliana, R. R., Singh, D., & Ashwin, B. (2010). Zinc deficiency as a risk factor for
febrile seizure. Pediatric OnCall, 7(4), 104-105. Papageorgiou, V., Vargiami, E., Kontopoulos, E., Kardaras, P., Economou, M.,
Athanassiou-Mataxa, M., . . . Zafeiriou, D. I. (2015). Association between iron
94
deficiency and febrile seizures. european journal of paediatric neurology,
19(5), 591-596. Pediatrics, A. A. o. (2002). Iron insufficiency as a risk factor for febrile seizures. AAP
Grand Rounds, 8(6), 62-63. Petry, N. (2014). Polyphenols and low iron bioavailability Polyphenols in human
health and disease (pp. 311-322): Elsevier. Potdar, S., Junagade, S., Panot, J., Kumavat, V., Rojekar, M. V., Malgaonkar, A., &
Bhusare, M. (2017). Case-control study of iron deficiency anaemia in febrile seizures. Journal of Evolution of Medical and Dental Sciences, 6(65), 4717-4720.
Provan, D. e. (2018). ABC of clinical haematology (Fourth edition. ed.). Radi, S., El Sayed, N., Nofal, L., & Abdeen, Z. (2013). Ongoing deterioration of the
nutritional status of Palestinian preschool children in Gaza under the Israeli siege.
Ramos, P. (2012). Trace elements in human brain: age-related changes in diferent anatomical regions and changes related with neurodegenerative processes.
Richardson, M., Ang, L., Visintainer, P., & Wittcopp, C. (2009). The abnormal measures of iron homeostasis in pediatric obesity are associated with the inflammation of obesity. International journal of pediatric endocrinology,
2009(1), 713269. Roganović, J., & Starinac, K. (2018). Iron Deficiency Anemia in Children Current
Topics in Anemia: InTech. Rothkrantz-Kos, S., Schmitz, M. P., Bekers, O., Menheere, P. P., & van Dieijen-
Visser, M. P. (2002). High-sensitivity C-reactive protein methods examined. Clinical chemistry, 48(2), 359-362.
Rutter, N., & Smales, O. (1976). Calcium, magnesium, and glucose levels in blood and CSF of children with febrile convulsions. Archives of Disease in
childhood, 51(2), 141-143. Sadleir, L. G., & Scheffer, I. E. (2007). Febrile seizures. Bmj, 334(7588), 307-311. Salah, O. N., Abdelraouf, E. R., Abdelhameed, M. H., Dawood, A. A., Hashish, A. F.,
Kilany, A., & Helal, S. I. (2014). Assessment of the Level of GABA and some trace elements in blood in children who suffer from familial febrile convulsions. Macedonian Journal of Medical Sciences, 7(1), 68-73.
Salma, S., Arifin, R., Bahar, E., & Purnamasari, R. (2015). Soluble transferrin receptor as an indicator of iron deficiency and febrile seizures. Paediatrica
Indonesiana, 55(2), 95-100. Sangani, S., Shah, N., Murlikrishna, M., Parikh, S., & Patel, V. (2014).
Epidemiological study of Paediatric Seizures and Its Management in Paediatric Emergency Department.
Schlebusch, H., Liappis, N., Kalina, E., & Klein, C. (2002). High Sensitive CRP and Creatinine: Reference Intervals from Infancy to Childhood/Hochsensitives
95
CRP und Kreatinin: Referenzbereich für Neugeborene und Kinder. LaboratoriumsMedizin, 26(5/6), 341-346.
Schuchmann, S., Hauck, S., Henning, S., Grüters Kieslich, A., Vanhatalo, S., Schmitz, D., & Kaila, K. (2011). Respiratory alkalosis in children with febrile seizures. Epilepsia, 52(11), 1949-1955.
Seinfeld, D. S., & Pellock, J. M. (2013). Recent research on febrile seizures: a review. Journal of neurology & neurophysiology, 4(165).
Selvaraju, K. (2018). Role of Serum Magnesium Levels in Febrile Seizures- A Case
Control Study From a Paediatric Referral Centre in South India. . INSTITUTE OF CHILD HEALTH. Retrieved from http://repository-tnmgrmu.ac.in/9225/2/200700118selvaraju.pdf (M.D., Degree in Paediatrics Madras Medical College. )
Shah, G., & Parmar, R. (2017). A study of febrile seizures in children in relation to iron deficiency anemia. International Journal of Contemporary Pediatrics,
4(5), 1599-1605. Shaikh, A. M., Inamdar, N. R., & K., S. D. (2018). Association of iron deficiency states
and febrile seizures in children-a case control study. International Journal of
Research in Medical Sciences, 6(3), 869. Shalini Paruthi, E. B. S. (2015). Transferrin Saturation Retrieved from
https://emedicine.medscape.com/article/2087960-overview Sharif, M. R., Kheirkhah, D., Madani, M., & Kashani, H. H. (2016). The relationship
between iron deficiency and febrile convulsion: a case-control study. Global
journal of health science, 8(2), 185. Sherlin, & Balu, R. (2012). Serum Magnesium Level in Febrile Convulsions.
International Journal of Science and Research (IJSR), 3(10). Shinnar, S., & Glauser, T. A. (2002). Febrile seizures. Journal of child neurology,
17(1_suppl), S44-S52. Shokrzadeh, M., Abbaskhaniyan, A., Rafati, M., Mashhadiakabr, M., & Arab, A.
(2016). Serum zinc and copper levels in children with febrile convulsion. Pharmaceutical and Biomedical Research, 2(3), 19-24. doi:10.18869/acadpub.pbr.2.3.19
Simon-Hettich, B., Wibbertmann, A., Wagner, D., Tomaska, L., & Malcolm, H. (2001). Environmental Health Criteria 221: Zinc.
Singh, V., & Yadav, D. (2018). Serum zinc levels in children with simple febrile seizure. Indian Journal of Child Health, 584-587.
Sirdah, M. M. (2014). Consanguinity profile in the Gaza Strip of Palestine: large-scale community-based study. Eur J Med Genet, 57(2-3), 90-94. doi:10.1016/j.ejmg.2014.01.003
Sreekrishna, Y., Adarsh, E., Jesw, C., & Malavika, J. (2016). Serum Magnesium Levels In Children With Febrile Convulsions. Journal of Evolution of Research
In Paediatrics And Neonatology, 2(1), 4-6.
96
Sreenivasa, B. N., Kumar, G. V., & Manjunatha, B. N. (2015). Study of Role of Iron Deficiency Anaemia in Febrile Seizures in Children in a Tertiary Care Centre. Journal of Nepal Paediatric Society, 35(2), 148-151.
Stevens, G. A., Finucane, M. M., De-Regil, L. M., Paciorek, C. J., Flaxman, S. R., Branca, F., . . . Group, N. I. M. S. (2013). Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995–2011: a systematic analysis of population-representative data. The Lancet Global Health, 1(1), e16-e25.
Sultan, T., Hanif, A. I. H., & Ali, S. (2017). Iron deficiency anemia as a risk factor for simple febrile seizures. Pakistan Journal of Neurological Sciences (PJNS),
12(3), 36-40. Suominen, P., Punnonen, K., Rajamäki, A., & Irjala, K. (1997). Evaluation of new
immunoenzymometric assay for measuring soluble transferrin receptor to detect iron deficiency in anemic patients. Clinical chemistry, 43(9), 1641-1646.
Swaminathan, R. (2003). Magnesium metabolism and its disorders. The Clinical
Biochemist Reviews, 24(2), 47. Talebian, A., Vakili, Z., Talar, S. A., Kazemi, S. M., & Mousavi, G. A. (2009).
Assessment of the relation between serum zinc & magnesium levels in children with febrile convulsion. Iranian journal of pathology, 4(4), 157-160.
Thurnham, D. I., McCabe, L. D., Haldar, S., Wieringa, F. T., Northrop-Clewes, C. A., & McCabe, G. P. (2010). Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis. The American journal of clinical nutrition, 92(3), 546-555.
Uluhan, C., Yucemen, N., Unaldi, O., & Güvener, A. (1990). Febril Konvülsiyonlu Çocuklarda Serum Çinko ve Bakır Düzeyleri. Turkiye Klinikleri Journal of
Case Reports, 8(4), 367-369. Van Esch, A., Steyerberg, E., Berger, M., Offringa, M., Derksen-Lubsen, G., &
Habbema, J. (1994). Family history and recurrence of febrile seizures. Archives
of Disease in childhood, 70(5), 395-399. Vaswani, R. K., Dharaskar, P. G., Kulkarni, S., & Ghosh, K. (2010). Iron deficiency
as a risk factor for first febrile seizure. Indian pediatrics, 47(5), 437-439. Waruiru, C., & Appleton, R. (2004). Febrile seizures: an update. Archives of Disease
in childhood, 89(8), 751-756. Weng, W.-C., Hirose, S., & Lee, W.-T. (2010). Benign convulsions with mild
gastroenteritis: is it associated with sodium channel gene SCN1A mutation? Journal of child neurology, 25(12), 1521-1524.
White, D., Kramer, D., Johnson, G., Dick, F., & Hamilton, H. (1986). AmJ Clin. Path,
72, 346. Wick, M., Pinggera, W., Pinggera, W., & Lehmann, P. (2003). Clinical Aspects and
Laboratory. Iron Metabolism, Anemias: Iron Metabolism, Anemias: Novel
97
Concepts in the Anemias of Malignancies and Renal and Rheumatoid
Diseases: Springer Science & Business Media. World Health Organization. (2001). UNU. Iron deficiency anaemia: assessment,
prevention, and control. Geneva, WHO. World Health Organization. (2004). WHO/Unicef Joint Statement Clinical
Management of Acute Diarrhoea. United Nations Child Fund. World Heal
Organ [Internet], 1-8. World Health Organization. (2006). WHO Child Growth Standards based on
length/height, weight and age. Acta paediatrica, 95, 76-85. World Health Organization. (2007). Assessing the iron status of populations: report of
a joint World Health Organization/Centers for Disease Control and Prevention technical consultation on the assessment of iron status at the population level. World Health Organization, Geneva, Switzerland.
World Health Organization. (2008a). Training course on child growth assessment. Geneva: WHO, p17-25.
World Health Organization. (2008b). Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia.
World Health Organization. (2011). Software for assessing growth and development of the world's children (Version 3.2.2). Retrieved from https://www.who.int/childgrowth/software/en/
World Health Organization. (2014a). Global Nutrition Targets 2025: Low birth weight policy brief.
World Health Organization. (2014b). Serum transferrin receptor levels for the
assessment of iron status and iron deficiency in populations. Retrieved from World Health Organization. (2017). Nutritional anaemias: tools for effective
prevention and control. Geneva: World Health Organization, p83. Wu, A. C., Lesperance, L., & Bernstein, H. (2016). Screening for iron deficiency.
Policy Statement. Wyllie, E., Cascino, G. D., Gidal, B. E., & Goodkin, H. P. (2006). Wyllie's treatment
of epilepsy: principles and practice (4th ed.): Lippincott Williams & Wilkins. Yigit, Y., Yilmaz, S., Akdogan, A., Halhalli, H., Ozbek, A., & Gencer, E. (2017). The
role of neutrophil–lymphocyte ratio and red blood cell distribution width in the classification of febrile seizures. Eur Rev Med Pharmacol Sci, 21(3), 554-559.
Yoon, S. H., Kim, D. S., Yu, S. T., Shin, S. R., & Choi, D. Y. (2015). The usefulness of soluble transferrin receptor in the diagnosis and treatment of iron deficiency anemia in children. Korean journal of pediatrics, 58(1), 15.
Yousefichaijan, P., Eghbali, A., Rafeie, M., Sharafkhah, M., Zolfi, M., & Firouzifar, M. (2014). The relationship between iron deficiency anemia and simple febrile convulsion in children. Journal of pediatric neurosciences, 9(2), 110.
Zheng, W., Aschner, M., & Ghersi-Egea, J. F. (2003). Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol, 192(1), 1-11.
98
99
Annex (1): Helsinki approval
100
Annex (2): Ministry of Health facilitation letter
101
Annex (3): Questionnaire
I am a researcher: Ohood Mohammed Shamallakh - I am studying at the Faculty of
Health Sciences, Islamic University of Gaza " The Role of Iron Profile Parameters and
Selected Minerals (Zinc and Magnesium) with Febrile Seizures in Children from Gaza
City", As a requirement to graduate and obtain a master's degree in Medical Laboratory
Sciences. I will be very thankful for your help.
Basic Information:
1. Date of interview: / /
2. Research Category
□ Case □ Control
General and Social Information:
1. Name: ....................................................... 1. File Number ....................................
2. Birth Date: ............................................ 3. Age in years ....................................
4.
Gender: □ Male □ Female
5. Address: ........................................................ 6. Telephone/Mobile ........................... 7. Number of household: ( ................. )
1. Length of Pregnancy: ( ......................... ) weeks
□ Premature (<37 wks) □ Full term (37-42 wks)
□ Post mature (>42 wks)
2. Type of delivery: □ Normal vaginal, □ CS, □Assisted vaginal 3. Birth weight (………....…) Kg
4. Admission to ICU □ Yes □ No
Medical History:
1. Fever □ Yes □ No
Cause of fever ..........................................................................................
102
2. Febrile seizures □ Yes □ No 3. Type of febrile seizures □ Generalized □ Focal 4. Duration of seizure □ < 15 minutes □ > 15 minutes 5. Number of episodes □ Once/24hr □ More than once/24hr
6. Past history of febrile
seizures □ Yes □ No
If yes;
- Mention age of onset of seizure ..........................................................................................
-How many times it occurred/ year?...........................................................................................
7.
Family history of
febrile seizures
□ Yes □ No 8. Family history of epilepsy □ Yes □ No The clinical examination