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ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 3  |  Page : 1261-1266

Neuroglobin as a novel biomarker in childhood seizures


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Pediatrics, Shebin El-Kom Tropical Hospital, Menoufia, Egypt

Date of Submission09-Jan-2022
Date of Decision15-Feb-2022
Date of Acceptance20-Feb-2022
Date of Web Publication29-Oct-2022

Correspondence Address:
Yasmeen K E. El-Fiky
Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_17_22

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  Abstract 


Objectives
The aim of this study is to investigate the possible role of neuroglobin as a novel biomarker in children with febrile seizures and epileptic children.
Background
Neuroglobin is a new globin member that is highly expressed in the central and peripheral nervous system.
Patients and methods
This case–control study has been conducted on 75 children, divided into three groups: group I included children with simple febrile convulsions, group II included children with newly diagnosed idiopathic epilepsy, and group III included healthy children selected as controls. Serum neuroglobin assay, complete blood count, C-reactive protein level, random blood sugar, serum electrolytes, liver-function and kidney-function tests, and electroencephalogram were performed for all children.
Results
The overall results showed that serum neuroglobin levels were significantly increased in patients' groups than in controls and more in epileptic children than children with febrile seizures (P<0.05 for all). Neuroglobin levels were negatively correlated with the hemoglobin levels and positively correlated with the total leukocytic count in the patients' groups.
Conclusion
Higher serum neuroglobin levels among children with seizures, especially epileptic ones, reflecting its involvement in seizure process. This study may give the initial clue to newer anticonvulsant or antiepileptic therapy through acting on neuroglobin levels.

Keywords: children, epilepsy, especially epileptic ones, febrile seizures, neuroglobin, seizures


How to cite this article:
Abd Elnaby SA, Eldeeb SM, El-Fiky YK, Abd Elsalam HB. Neuroglobin as a novel biomarker in childhood seizures. Menoufia Med J 2022;35:1261-6

How to cite this URL:
Abd Elnaby SA, Eldeeb SM, El-Fiky YK, Abd Elsalam HB. Neuroglobin as a novel biomarker in childhood seizures. Menoufia Med J [serial online] 2022 [cited 2024 Mar 28];35:1261-6. Available from: http://www.mmj.eg.net/text.asp?2022/35/3/1261/359467




  Introduction Top


Seizures are a common neurological disorder in children, especially the febrile one[1].

Febrile seizures can be defined as a seizure that occurred in children with group-age range from 6 to 60 months that associated with any febrile disorder not caused by central nervous system infection or metabolic disturbance with vague pathophysiology[2].

Childhood epilepsy is also a common central nervous system disease, with significant effect on the development of the child, and occurrence of two or more unprovoked seizures is mandatory for its diagnosis[3].

The crude lifetime prevalence rate of childhood epilepsy in Egypt was 12.67/1000[4].

Neuroglobin, a new globin-family member that is specifically expressed in neurons of the brain, has been reported by several experimental animal studies to have an endogenous neuroprotective effect against seizures, oxidative-stress-related insults, and may play a role in valproic acid-induced neuroprotection, with poorly defined underlying mechanisms[5].

Studies have also proved the induction of neuroglobin by ischemia/hypoxia in vivo, but the situation is more complex. An early study reported that immunostaining sections from cerebral cortex of mice subjected to focal cerebral ischemia by middle cerebral-artery occlusion for 90 min, followed by reperfusion for 4–24 h, showed increased neuroglobin immunoreactivity in the cytoplasm of cortical neurons from the ischemic hemisphere compared with the nonischemic hemisphere[6].

The aim of this study is to investigate the possible role of neuroglobin as a novel biomarker in children with febrile seizures and epileptic children.


  Patients and methods Top


After acceptance of the Local Institutional Ethical Committee of Menoufia University Hospital, the present study was done in Pediatric Department and Emergency Room, Menoufia University Hospital. It was carried out on 75 children, after taking written informative consents from their parents between November 2020 and May 2021. The studied children were classified into three groups: group I included children with simple febrile convulsions. Group II included children with newly diagnosed idiopathic epilepsy. Group III included healthy children selected as controls. With inclusion criteria: patients were enrolled in the study after fulfilling the following inclusion criteria: patients aged (since birth up to 18 years) diagnosed with epileptic disorder or febrile convulsion. Exclusion criteria: exclusion criteria for group I: children who had previous nonfebrile seizure and children with abnormal electroencephalogram changes. Exclusion criteria for group II: children with a history of any neurosurgical intervention, children with metabolic and/or electrolyte disturbances, presence of an active neurological disorder, major neurological disabilities, associated mental retardation or psychiatric disorders such as autism or attention-deficit hyperactivity disorder, and children who are on chronic medications. All patients and control children were subjected to the following: detailed history: personal history, including name, age, sex, history of perinatal insult, history of any old brain insult that may underlie the current condition, developmental history for evidence of psychomotor retardation or regression, history of consanguinity, family history of a similar condition or other neurological illness, and present history with special emphasis on age of onset of the seizure(s) disorder, type(s) and description, evidence of external environmental or internal stimuli that are associated with seizure provocation, and manifestations of central nervous system infections. Intellectual deterioration: neurodegenerative diseases and treatment received by patients. Thorough clinical examination: vital signs: temperature: for febrile seizures, blood pressure: for exclusion of hypertensive encephalopathy and respiratory rate and heart rate, anthropometric measurements: weight and height, skin: for exclusion of neurocutaneous diseases such as neurofibromatosis, tuberous sclerosis, Sturge–Weber, etc., abdominal examination, for example, organomegaly in neurometabolic causes, and neurological examination: motor, sensory, cranial nerves, and meningeal irritation. Laboratory and radiological investigations: routine laboratory investigations: complete blood count, alanine aminotransferase, aspartate aminotransferase, serum creatinine, serum urea, and serum electrolytes Na, K, Mg, total and ionized-calcium C-reactive protein, and random blood sugar, and quantitative estimation of serum level of neuroglobin by ELISA technique. Data were collected, tabulated, and statistically analyzed using an IBM-compatible personal computer with Statistical Package for the Social Sciences (SPSS Inc., Chicago, Illinois, USA) software version 23. χ2 test: it was used to study the association between two qualitative variables. Whenever any of the expected cells were less than five, Fisher's exact test was used.


  Results Top


The mean age in simple febrile convulsions, idiopathic epilepsy, and control groups was 2.6 ± 1.2, 3.0 ± 1.5, and 3.4 ± 1.7, respectively, with no significant differences between the three studied groups (P = 0.21). There was male predominance in the three groups (56, 60, and 56%, respectively) with no significant differences between the three studied groups regarding sex (P = 0.95). The mean BMI in simple febrile convulsions, idiopathic epilepsy, and control groups was 15.3 ± 0.64, 15.01 ± 0.88, and 15.5 ± 1.2, respectively, with no significant differences between the three studied groups (P = 0.14). Likewise, there was no statistically significant difference between the three studied groups regarding consanguinity (P = 0.42), perinatal history (P = 0.16), and developmental history (P = 0.36). Family history of similar condition was significantly found in simple febrile-convulsion group (24%), followed by idiopathic epilepsy (12%) compared with control group (P = 0.3) [Table 1].
Table 1: Sociodemographic characteristics among studied groups

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Clinical characteristics of seizure cases in simple febrile convulsions and idiopathic epilepsy groups: fever was significantly found in simple febrile-convulsion group compared with idiopathic epilepsy group (P < 0.001). Also, the frequency of seizures was significantly higher in idiopathic epilepsy group compared with simple febrile-convulsion group (P < 0.001), while it was noticed that onset and tonic–clonic type were significantly higher in simple febrile-convulsion group compared with idiopathic epilepsy group (P < 0.001 and P = 0.02, respectively). Regarding the duration of episodes, it was observed that simple febrile-convulsion group had significantly longer duration compared with idiopathic epilepsy group (P = 0.006). There was no statistically significant difference between the two studied groups regarding the presence of aura (P = 1.0) and post-ictal phase (P = 1.0) [Table 2].
Table 2: Clinical characteristics of seizure cases

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There was a statistically significant difference between simple febrile-convulsion group and control group and a significant difference between idiopathic epilepsy group and control group regarding hemoglobin level (P < 0.001). There was a statistically significant difference between idiopathic epilepsy group and control group regarding platelet-count level (P = 0.006).

There was a statistically significant difference between simple febrile-convulsion group and idiopathic epilepsy group and a significant difference between simple febrile-convulsion group and control group regarding total leukocyte (P < 0.001) [Table 3].
Table 3: Complete blood picture among studied groups

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There was a significant negative correlation between neuroglobin level and duration of seizures (r = −0.356, P = 0.01), as well as total leukocyte (r = −0.654, P < 0.001). While there was significant positive correlation between neuroglobin level and Na level (r = 0.312, P = 0.03) [Table 4].
Table 4: Correlation between neuroglobin level and other parameters among simple febrile-convulsion group and idiopathic epilepsy group (n=50)

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The mean neuroglobin level in simple febrile convulsions, idiopathic epilepsy, and control groups was 103.7 ± 12.3, 153.6 ± 32.8, and 7.04 ± 1.4, respectively, with significant differences between the three studied groups (P = 0.21). Neuroglobin level was significantly higher in idiopathic epilepsy group compared with simple febrile-convulsion group (P < 0.001), in simple febrile-convulsion group compared with control group (P < 0.001), and idiopathic epilepsy compared with control group (P < 0.001) [Table 5].
Table 5: Neuroglobin level among studied groups

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  Discussion Top


A seizure is an attack of abnormal, rhythmic brain electrical activity in part or all of the brain. Many underlying pathologies can cause seizures and the types of seizures and their clinical presentation vary, depending on the cause and the locations in the brain, which are affected by each seizure. While some of the causes of seizures may be acute and do not lead to further seizures, some cause a chronic infant-epilepsy condition[7].

Epilepsy is a clinical diagnosis, and to diagnose epilepsy, epileptic seizures must be differentiated from provoked seizures and other paroxysmal[8].

Childhood epilepsy has a large spectrum of clinical manifestations, and many other conditions may resemble epilepsy. This often makes the diagnostic process challenging, with a considerable risk of misdiagnosis[9].

Neuroglobin is a hemoprotein that presents intracellularly in the neural tissues that bind to oxygen in a reversible manner with higher affinity than that of hemoglobin. In addition, neuroglobin increases the availability of oxygen to the neurons and potentially limiting the brain damage[10].

Epilepsy is more common in young children and older people. Slightly more males than females have epilepsy[11].

In our study, male children with epilepsy outnumbered females as males were 56.0%, females were 44% in simple febrile-convulsion group, and males were 60%, females were 40% in idiopathic epilepsy group, this is in line with Adhikari et al.[12] who found that male children were 45.3%, female children were 54.7% in simple febrile-convulsion group, and males were 61.3%, females were 38.7% in idiopathic epilepsy group.

Consanguinity is a common marital habit practiced in many developing countries. It is defined as unions contracted between persons biologically related as second cousins or closer[13].

The health complications, including mental retardation, neural-tube defects, epilepsy, and other hereditary neurological diseases that are associated with consanguinity, are caused by the expression of recessive genes inherited from a common ancestor. Further population studies revealed an increased familial clustering of epilepsy among first-degree, and to a lesser extent, second-degree relatives[14].

In this study, the mean serum-Na level in febrile-convulsion group 136.8 ± 1.9 and 137.9 ± 2.0 in idiopathic-convulsion group, the mean serum-K level in febrile-convulsion group 4.1 ± 0.59 and 4.2 ± 0.39 in idiopathic-convulsion group, the mean serum-Ca level in febrile-convulsion group 10.0 ± 0.88 and 10.2 ± 0.73 in idiopathic-convulsion group, and the mean serum-Mg levels in febrile-convulsion group 1.8 ± 0.25 and 1.9 ± 0.24, this is in line with Wahid[15], who found that the mean serum-Na level in epileptic children 137.0 ± 4.0, the mean serum-K level 4.7 ± 0.56, the mean serum-Ca level 9.7 ± 0.6, and the mean serum-Mg level 1.7 ± 0.2.

As regards to serum-neuroglobin level in our study, there were significant differences between the mean serum-neuroglobin level in idiopathic epilepsy group and control group and between febrile-convulsion group and control group, and also between febrile-convulsion group and idiopathic epilepsy group, serum neuroglobin in our study showed 100% sensitivity and 100% specificity in the diagnosis of seizures, this is in line with Mahgoob and Moussa[3], who found a significant increase of serum-neuroglobin levels in epileptic group compared with nonepileptic and control groups, serum neuroglobin showed 95% sensitivity and 95.7% specificity in the diagnosis of generalized seizures.

In this study, the mean serum-neuroglobin level in febrile-convulsion group 103.7 ± 12.3, 153.6 ± 32.8 in idiopathic-convulsion group, and 7.04 ± 1.4 in control group. These results were lower than Mounir et al.[16], who found that the mean serum-neuroglobin level in febrile-convulsion group 273.80 ± 83.33, 483.56 ± 131.91 in idiopathic-convulsion group, and 98.25 ± 12.64 in control group, this may be due to the use of different type of kits.

Receiver operating characteristic (ROC)-curve analysis was conducted to explore the validity of neuroglobin level among simple febrile-convulsion group versus controls [area under the curve (AUC), sensitivity, and specificity] for diagnosis of febrile convulsions. AUC was 1.00, which indicates high validation of neuroglobin level for diagnosis of epilepsy. The cutoff point 44.75, the sensitivity 100.0% confidence interval (CI), and specificity 100.0% CI.

ROC-curve analysis was conducted to explore the validity of neuroglobin level among idiopathic-convulsion group versus controls (AUC, sensitivity, and specificity) for diagnosis of idiopathic convulsions among the studied cases. AUC was 1.00, which indicates high validation of neuroglobin level for diagnosis of epilepsy. The cutoff point 62.25, the sensitivity 100.0% CI, and specificity 100.0% CI.

Also, ROC-curve analysis was conducted to explore the validity of neuroglobin level among idiopathic-convulsion group and febrile-convulsion group versus controls (AUC, sensitivity, and specificity) for diagnosis of convulsions among the studied cases. AUC was 1.00, which suggests good performance of neuroglobin level for diagnosis of epilepsy. The cutoff point 44.75, the sensitivity 100.0% CI, and specificity 100.0% CI.


  Conclusion Top


Finally, this study revealed that the serum-neuroglobin level was elevated in both idiopathic-convulsion and febrile-convulsion groups compared with control group. So, serum neuroglobin may be a promising biomarker to differentiate epileptic versus nonepileptic disorders in children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Mahgoob MH, Moussa MM. Neuroglobin and prolactin as potential biomarkers for differentiating epileptic versus nonepileptic paroxysmal disorders in children. J Pediatr Epilepsy 2021; 10:104–109.  Back to cited text no. 3
    
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Baez E, Echeverria V, Cabezas R, Ávila-Rodriguez M, Garcia-Segura LM, Barreto GE. Protection by neuroglobin expression in brain pathologies. Front Neurol 2016; 7:146.  Back to cited text no. 5
    
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Wen H, Liu L, Zhan L, Liang D, Li L, Liu D, et al. Neuroglobin mediates neuroprotection of hypoxic postconditioning against transient global cerebral ischemia in rats through preserving the activity of Na+/K+ATPases. Cell Death Dis 2018; 9:1–8.  Back to cited text no. 6
    
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Stafstrom C, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med 2015; 5:a022426.  Back to cited text no. 7
    
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Kee VR, Gilchrist B, Granner M. A systematic review of validated methods for identifying seizures, convulsions, or epilepsy using administrative and claims data. Pharmacoepidemiol Drug Saf 2012; 21:183–193.  Back to cited text no. 9
    
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Giordano D, Boron I, Abbruzzetti S, Van Leuven W, Nicoletti FP, Forti F, Gilchrist B. Biophysical characterisation of neuroglobin of the icefish, a natural knockout for hemoglobin and myoglobin. Comparison with human neuroglobin. PLoS ONE 2012; 7:e44508.  Back to cited text no. 10
    
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Beghi E. The epidemiology of epilepsy. Neuroepidemiology 2020; 54:185–191.  Back to cited text no. 11
    
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Adhikari S, Sathian B, Koirala DP, Rao KS. Profile of children admitted with seizures in a tertiary care hospital of Western Nepal. BMC Pediatr 2013; 13:1–7.  Back to cited text no. 12
    
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Hamamy H. Consanguineous marriages: preconception consultation in primary health care settings. J Community Genet 2012; 3:185–188.  Back to cited text no. 13
    
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Sindi S, Alanazi Y, El-fetoh N. Consanguinity between parents and risk of epilepsy among children in Northern Saudi Arabia. Egypt J Hosp Med 2018; 70:1925–1928.  Back to cited text no. 14
    
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Wahid H. Evaluation of serum electrolytes and uric acid in Iraqi epileptic patients. Iraq Postgrad Med J 2010; 9:84–87.  Back to cited text no. 15
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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