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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 587-595

Evaluation of serum matrix metalloproteinase-9 as a potential biomarker for diagnosis of epilepsy in children


1 Department of Pediatric, Faculty of Medicine, Al Azhar University, Cairo, Egypt
2 Department of Pediatric, National Research Centre; Department of Theodor Bilharzi Research Institute, National Research Centre, Cairo, Egypt
3 Department of Medical Biochemistry, National Research Centre, Cairo, Egypt
4 Department of Pediatric, New Cairo Hospital, Ministry of Health, Cairo, Egypt

Date of Submission18-Jun-2019
Date of Decision18-Jun-2019
Date of Acceptance01-Jul-2019
Date of Web Publication10-Feb-2020

Correspondence Address:
Maha S Zein Elabdeen
Mina House Tower Nasr City Cair Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_57_19

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  Abstract 


Introduction Epilepsy is a common serious neurological disorder. Medical histories and electroencephalogram are not always sufficient for epilepsy diagnosis; therefore, exploring the novel methods for the accurate diagnosis of epilepsy is of great importance. Matrix metalloproteinase (MMP) are vital drivers of synaptic remodeling in health and disease. It plays a well described role in neuroinflammation; it is suggested that at early stages of epileptogenesis, inhibition of MMP may help ameliorate cell death, aberrant network rewiring, and neuroinflammation and prevent development of epilepsy.
Aim MMPs especially MMP-9 and MMP-2 are sensitive to seizures; thus, MMP-9 may be a potential biomarker for epilepsy diagnosis, we assessed MMP-9 levels in the context of its possible use as a biomarker of the activity and diagnosis of epilepsy and evaluation of the nutritional state by anthropometric measurement.
Patients and methods Thirty epileptic patients aged from 4 to 17 years, selected randomly from the inpatient and outpatient neurological unit of pediatric department in Alzhraa University Hospital between 2018 and 2019 were subjected to: etailed medical history, general and neurological examination, routine laboratory studies, electroencephalogram, anthropometric measurement, and serum MMP-9 level measurement. Thirty age-matched and sex-matched healthy controls were selected and their serum MMP-9 and anthropometric measurements were obtained.
Results Serum MMP-9 levels were statistically significantly high in patients with idiopathic epilepsy compared with the control group. Sensitivity of MMP-9 as biomarkers was 62.07% with 96.67% specificity. The cutoff point of MMP-9 more than 4.
Conclusion MMP-9 levels increased in patients with epilepsy. This tool may be a helpful diagnostic biomarker for epilepsy with good sensitivity and specificity.

Keywords: biomarkers, epilepsy, matrix metalloproteinase-9


How to cite this article:
El Moneam Abdallah NA, Kandeel WA, Elmalt HA, Zein Elabdeen MS. Evaluation of serum matrix metalloproteinase-9 as a potential biomarker for diagnosis of epilepsy in children. Sci J Al-Azhar Med Fac Girls 2019;3:587-95

How to cite this URL:
El Moneam Abdallah NA, Kandeel WA, Elmalt HA, Zein Elabdeen MS. Evaluation of serum matrix metalloproteinase-9 as a potential biomarker for diagnosis of epilepsy in children. Sci J Al-Azhar Med Fac Girls [serial online] 2019 [cited 2020 Aug 10];3:587-95. Available from: http://www.sjamf.eg.net/text.asp?2019/3/3/587/278035




  Introduction Top


Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate seizures and by the neurobiologic, cognitive, psychologic, and social consequences of this condition [1].

Epilepsy is a common disease affecting about 50 million people worldwide each year, Approximately 4–10% of children experience at least one seizure in the first 16 years of life, with a prevalence of 5–10 cases per 1000 [2].

The diagnosis of epilepsy is largely based on a patient’s detailed, reliable medical history, and electroencephalogram (EEG) may help in the diagnosis. However, medical histories are not always sufficient, making diagnosis difficult in some cases. Therefore, exploring novel methods for the accurate diagnosis of epilepsy is of great importance (Wang et al., 2016) [3].

Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent proteases with a wide range of substrates. They are major executors of extracellular matrix (ECM) remodeling throughout the body and have complex functions under normal and pathological conditions [4].

The activities of MMPs are regulated by tissue inhibitors of metalloproteinases (TIMP-1–4), a family of multifunctional secreted proteins that promote growth and regulate the cell cycle in various cell types [5].

One of the proteases that is implicated in ECM remodeling and consequently synaptic plasticity is MMP-9 [6]

MMP-9 and MMP-2 are the most commonly expressed MMPs in the brain [7].

MMP-9 is an extracellularly/pericellularly operating protease that regulates numerous cell activities, such as cell differentiation, cell migration, cytokine release, survival, apoptosis and inflammation [8].

MMP-9 is able to bind with various substrates, for example, TIMPs, laminin, gelatin, collagen types I and IV, procollagen type II, β-amyloid (1–40), precursors of growth factors, chemokine’s, surface receptors, and adhesion molecules [9].

MMP-9 plays a vital role in blood–brain barrier damage. The increase in blood–brain barrier permeability is one of the first abnormalities which occur in status epilepticus [10].

MMP-9 is suggested to play a role in epileptic focus formation and in the stimulation of seizures. Its proteolytic action on the elements of blood–brain barrier and activation of chemotactic processes facilitates accumulation of inflammatory cells and induces seizures; also modification of glutamatergic transmission by MMP-9 is associated with seizures [11].

MMP-9-related synaptic plasticity has been shown to play an important role in the development of epilepsy in both humans and rodents. MMP-9 deficiency inhibits epileptogenesis, and excess MMP-9 facilitates it; prolonged seizures are related to high serum MMP-9 levels in humans [12].

Although epilepsy is a prevalent disorder during childhood; there is still little knowledge regarding its effects on the growth and nutrition of affected patients. Epilepsy might accompany with malnutrition and noted as the two key health problems [13].

Malnutrition might be indicated due to chronic use of anticonvulsant drugs because they may influence food intake and energy metabolism. In addition, they can induce vomiting, anorexia, and feeding difficulties in chewing or swallowing. Moreover, their energy requirement may be changed according to the impedance of disabilities with their common activities [14].

Malnutrition is not considered to be a direct cause of epilepsy although it seems to favor the occurrence of epilepsy or seizures due to many nutritional deficiencies which have a profound and often permanent effect on central nervous system development in early life [15].


  Aim of this study Top


The aim was to assess serum MMP-9 levels in patients with idiopathic epilepsy and to evaluate its role as a biomarker for the diagnosis of idiopathic epilepsy and evaluation of the nutritional state by anthropometric measurement.


  Patients and methods Top


The present study is a cross-sectional case–control study. It was carried out on 30 epileptic children and 30 age-matched and sex-matched healthy nonepileptic children as control. The age of the participants ranged between 4 and 17 years old. They were selected randomly from the inpatient and outpatient neurological unit of Pediatric Department in Alzhraa University Hospital. Data were collected between 2018 and 2019.

The diagnosis of epilepsy was based on history from reliable eyewitness account. The patients were classified according to the Commission on Classification and Terminology of the International League against Epilepsy.

Ethical consideration

Ethical approval was obtained through the ethics committee before start of the study. An informed consent was obtained from each participant before doing tests.

Inclusion criteria

In our study we include only children aged from 4 to 17 years and diagnosed with idiopathic epilepsy according to International League against Epilepsy classification, 1981 [16].

Exclusion criteria

Children with any concomitant neurological, developmental disabilities, chronic, or current illness. Preexisting mental retardation, history of psychiatric disorders, history of nonepileptic and neurologic disorders or those who received chronic medications other than antiepileptic drugs (AEDs) were excluded from the study. As we intend to investigate the effect of epilepsy alone in the absence of any confounders that can impair the level of serum MMP-9 among those children.

Control group

Thirty healthy individuals (age and sex matched) with no history of epilepsy or other medical, neurological, or psychiatric disorders.

All patients and controls were subjected to the following:
  1. Written informed consent signed by the patient.
  2. Full history taking according to the epilepsy sheet which is consistent with the current guidelines of the International League Against Epilepsy and Seizure Description by thorough history taking of epilepsy: age at onset, seizure frequency, seizure type (focal or generalized), presence of aura, and duration of epilepsy. Type and duration of AEDs utilized according to whether the child is controlled or not.
  3. Thorough general and neurological examination.
  4. Routine laboratory investigations: complete blood picture, liver, and kidney function tests.
    1. EEG: Interictal EEG was done for 20–30 min using 18-channel digital EEG Nicolet Biomed alliance works. Electrodes were arranged according to the international 10–20 system of surface electrodes placement using monopolar and bipolar montages. It was carried out under standard conditions, that is the patients were lying supine, completely relaxed in a quiet dark room. The EEG tracings were analyzed and categorized into: normal EEG, generalized, focal, focal with secondary generalization carefully as regards the background activity, presence of any generalized or focal abnormalities, revised and reported by the neurology department staff members.
  5. Anthropometric assessment.
    • According to the recommendations of the International Biological Program [17], measures were taken on the left side of the body under supervision of well-trained anthropologists.
    • The body weight (WT), height (HT), head circumference (HC), mid-upper arm circumference (MUAC), hip circumference, waist circumference, BMI, and waist /hip ratio were calculated. Measurements were transformed into Z scores for weight/age (W/A), height/age (H/A), and BMI/age (BMI/A), using the WHO AnthroPlus software.
  6. Quantitative determination of serum MMP-9.


Quantitative determination of serum, metalloproteinase-9 concentration was done using the ELISA technique, 5 ml of venous blood was collected from both epilepsy and control children and was delivered into a tube were allowed to clot and after centrifugation sera were separated and stored frozen at −20°C after careful labeling till the time of assay.

Normal range of plasma MMP-9 concentration was determined to be 0.3–18 ng/ml.

Statistical analysis

Data were collected, coded, tabulated, revised, and statistically analyzed and were entered to using the Statistical Package for the Social Sciences (IBM SPSS, USA), version 20. The data were presented as number and percentages for qualitative data, mean, SDs, and ranges (minimum and maximum) for the quantitative data with parametric distribution and median with interquartile range for the quantitative data with nonparametric distribution.

χ2 test for categorical variables for comparison between two groups and Monte Carlo correction: correction for χ2.

Independent t test was used in comparison between two groups with quantitative data and parametric distribution and Mann–Whitney test was used in the comparison between two groups with quantitative data and nonparametric distribution.

Receiver operating characteristic curve was used to assess the best cutoff point between two groups with its sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve.

The confidence interval was set to 95% and the margin of error accepted was set to 5%. So, the P value was considered significant as the following.

P value more than 0.05: nonsignificant.

P value less than 0.05: significant.

P value less than 0.01: highly significant.


  Results Top


Our study was conducted on 30 epileptic patients; their mean age was 8.43±3.33 years, besides 30 controls with a mean age of 7.89±2.55 years. The patient group included 16 (53.3%) men and 14 (46.7%) women with 30 healthy controls of same number and male to female percentage.

Age of onset of epilepsy in the case group ranged between 4 and 9 years with a mean age of 5.03±1.88 years; epilepsy duration ranged from 3 to 10 years.

The most prevalent presentation of our patients was generalized epilepsy 40% compared to 36.7% with focal seizures, 16.7% focal with secondary generalization and 6.7% normal, 33.3% of our patients are treated with two AEDs while 60% were treated by one drug, 6.7% belong to nondrug treatment.

Regarding response to treatment 80.0% was controlled, 6.7% was uncontrolled, while 13.3.4% belong to newly diagnosed..

Regarding EEG finding in the patient group 40.0% had generalized activity and 36.6% had focal activity, 16.7% focal with secondary generalization while 6.7% had normal EEG.

We performed receiver operating characteristic curve analysis, when the cutoff value of MMP-9 concentration was more than 4, the sensitivity and specificity for distinguishing epileptic from controls were 62.07 and 96.67%, respectively, and the area under the curve was 0.866.

The positive predictive value is 94.7%. The negative predictive value is 72.5%.

We found that sex and age were insignificant between two groups with a mean age of onset of 3.72 years:
  1. Family history was significant between two groups.
  2. Anthropometric parameters were insignificant between two groups.


We found a statistically significant difference in serum MMP-9 between patients and control groups, it being higher in the patient group with a mean of 6.45±3.33 ng/ml compared with 2.83±1.23 ng/ml in the control group.

[Table 1] shows that among our studied children 53.3% were women, 46.7% were men. Their age ranged between 4 and 17 years, duration of illness was between 3 and 10 months, age of onset of epilepsy ranged between 3 and 14 years, 60% of treatment was monotherapy, and 33.3% was polytherapy; 80% of response to treatment was controlled but 6.7% was uncontrolled.
Table 1 Descriptive clinical data of the studied epileptic children

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According to EEG finding 40.0% in the patient group had generalized activity and 36.6% had focal activity, 16.7% focal with secondary generalization, while 6.7% had normal EEG.

[Table 2] shows that there was no statistically significant difference in demographic data regarding the studied group.
Table 2 Comparison between patient group and control group as regards demographic data

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[Table 3] shows that there was no statistically significant difference regarding anthropometric measures.
Table 3 Comparison between the patient group and control group as regards anthropometric measure (Z score)

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[Table 4] shows that there was statistically significant difference in the patient group in comparison to the control group as regards family history.
Table 4 Comparison between the two studied groups according to family history

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[Table 5] shows that there was statistically significant increase in the patient group in comparison to the control group with MMP-9.
Table 5 Comparison between the patient group and control group as regards matrix metalloproteinase-9

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[Table 6] shows that in MMP-9: The cutoff point of MMP-9 more than 4, its sensitivity is 62.07%.
Table 6 Cutoff point, sensitivity, and specificity of matrix metalloproteinase-9 between two groups

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Its specificity is 96.67%. The positive predictive value is 94.7%. The negative predictive value is 72.5%.

[Table 7] shows no significant correlation between MMP-9 as regards anthropometric measurements in the patient group.
Table 7 Correlation between matrix metalloproteinase-9 as regards anthropometric measurement in the patient group

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[Table 8] shows that MMP-9 has no correlation as regards the type of epilepsy in the patient group.
Table 8 Correlation between matrix metalloproteinase-9 as regards electroencephalogram in the patient group

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[Table 9] shows a significant correlation between MMP-9 and uncontrolled patients, the P value is 0.019.
Table 9 Correlation between matrix metalloproteinase-9 as regards treatment in the patient group

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  Discussion Top


The current study is a cross-sectional case–control study. It was carried out on 30 epileptic children and 30 age-matched and sex-matched healthy children as controls who attended the pediatric outpatient clinic and inpatient department of El-Zahraa hospital, Al-Azhar University during the period from 2018 to 2019.

Among the studied 30 epileptic children 53.3% were men and 46.7% were women. Consistent findings were reported by Mahmoud [18] who reported that the prevalence of epilepsy was higher in boys than girls with a male : female ratio of 2 : 1.

Johnston and Hagberg [19] reported that sex may influence the pathogenesis of developmental brain injuries because immature brain appears to be strongly influenced by the intrinsic difference between male and female brain cells due to their distinct chromosomal complements. Data from adult patients with stroke indicate that sex hormones such as estrogen provide protection against hypoxic–ischemic injury; neonatal brain was also influenced by these hormones.

Various studies published indicate that women have a marginally lower incidence of epilepsy and unprovoked seizures than men. This difference is usually attributed to a greater exposure to risk factors for lesional epilepsy and acute symptomatic seizures in men. Men also have a higher incidence of status epilepticus, with sudden unexpected death in epilepsy [20].

In contrast to our findings, Shakirullah et al. [21] observed a higher prevalence of epilepsy in women than in men. Sampaio et al. [22] observed female predominance in 51.48 and 60% of epileptic children, respectively.

In addition, Serdaroğlu et al. [23], Aydin et al. [24], and Calis¸ir et al. [25] found no significant difference between both sexes.

Regarding AEDs, 60.0% of the epileptic children who received monotherapy and 33.3% received polytherapy, while 6.7% of them did not receive AEDs at the time of involvement in the study. Among the epileptic children 80.0% were controlled on AEDs, while the uncontrolled were 6.7% and the newly diagnosed were 13.3%. Supporting our findings; Shahar and Genizi [26] reported that 77% of children with idiopathic epilepsy gained complete seizure control on AEDs. Both high compliance and proper selection of the type and doses of AEDs can partially explain the high incidence of controlled seizures among our studied patients.

Regarding EEG findings in epileptic children, 40% had generalized activity and 36.7% had focal activity, 16.7% were focal with secondary generalization while 6.7% had normal EEG. This is in agreement with El-Senousey et al. [27] who found generalized discharge in 50%, focal in 13.6%, focal with secondary generalization in 9.7% while normal in 26.7% of children with idiopathic epilepsy. Dahab et al. [28] found that 77.14% of epileptic children have abnormal epileptiform discharge, while 22.85% had normal EEG. Mahmoud [18] reported that 81.1% of epileptic children had abnormal interictal EEG records.

On the other hand, the Sampaio et al. [22] EEG study of epileptic children demonstrated normal findings in 31.18%, focal abnormalities in 48.38%, and generalized abnormalities in 20.43%. Hermann et al. [29] demonstrated that EEG abnormalities were focal in 57% and were generalized in 43%.

EEG was used to recognize and monitor for seizures; on the other hand, normal EEG findings may not necessarily mean that the brain is healthy [30].

On studying the family history of epilepsy, 33.3% of our epileptic children had positive family history of epilepsy. This incidence is in agreement with Taheri et al. [31] who found positive family history in 29.6% of epileptic children. Additionally, other studies on epileptic Egyptian children, Farahat et al. [32] and Hamdy [33] reported positive family history in 22.9 and 20.3% of cases, respectively.

As regards anthropometric and nutritional assessment in our study there were no significant differences among the studied groups. Supporting our findings Tada et al. [34] assessed height in children with epilepsy using Tanner charts and concluded that frequency of seizures had no influence over stature growth. In contrast to our findings, Bertoli et al. [14] observed greater risk of malnutrition in children with epilepsy than in the control group. They noted significant association between epilepsy and low BMI.

There are two different hypotheses, which cause a vicious circle: malnutrition predisposes epilepsy or epilepsy predisposes malnutrition. As malnutrition can be prevented and treated, therefore, a thorough understanding of these interactions can be recommended, in Africa, a greater risk of malnutrition has been observed in children with epilepsy than in the control group. A study in India has shown an association between epilepsy and low BMI [35].

Two other studies carried out in Italy and in the United States showed a higher risk of malnutrition in children with refractory epilepsy, the risk being associated with lower energy intake [15].

On the other hand, Lee and Mattson [36] reported that obesity is noted as the leading factor for maladaptive processes for exacerbating chronic diseases such as epilepsy, multiple sclerosis, and Alzheimer’s disease.

As regards MMP-9 we found a statistically significant difference in serum MMP-9 in between patient and control groups, it being higher in the patient group with a mean of 6.45±3.33 ng/ml compared with 2.83±1.23 ng/ml in the control group.

These results were consistent with the study of Cudna et al. [37], who reported increased levels of MMP-9 in many neurological disorders, including epilepsy, suggesting that it may be involved in the pathogenesis of seizures as MMP-9 mediates the degradation of ECM proteins, and is especially involved in blood–brain barrier maintenance.

Also Suenaga et al. [38] reported that high serum levels of MMP-9 were detected in children following febrile seizures. Prolonged seizures were associated with high serum MMP-9 levels and increases in the ratio of MMP-9 to TIMP-1 in patients with acute encephalopathy with dysfunction and damage of the blood–brain barrier following prolonged febrile seizures.

MMP-9 protein levels were elevated in cortical lesions in patients with focal cortical dysplasia and tuberous sclerosis, which cause chronic epilepsy in children, suggesting a possible pathological role for MMP-9 in these intractable conditions [39].

Elevated MMP-9 immunoreactivity was found in nerve tissue in chronic inflammatory demyelinating polyneuropathy and nonsystemic vasculitic neuropathy, compared with noninflammatory neuropathies [40].

An increase of the MMP-9 level was found in the cerebrospinal fluid of patients with bacterial meningitis who subsequently developed epileptic seizures in comparison to the patients in whom the disease was not complicated by the development of epilepsy [41].

MMP-9 seems to be a key factor in the pathogenesis of epilepsy. It is assumed that impaired plasticity within the synapse and mossy fibers sprouting within the hippocampus, both associated with MMP-9 activity, have an impact on the formation of a new epileptic focus [42].

In the study of Szklarczyk et al. [43], an association between remodeling within the dentate gyri and an increased expression and activity of MMP-9 was reported after the kainate-induced seizures in rats [44]. The study was conducted on rat models and measure activity of MMP-9 in the rat brain influenced by pilocarpine and showed raised MMP-9 activity.

Supporting our findings, Li et al. [45]detected an increase in MMP-9 protein and activity in epileptic patients with generalized tonic–clonic seizures compared with age-matched nonepileptic individuals. Levels of MMP-9 were also increased in serum from patients after seizures

The concept of MMP-9 as a biomarker is not new. In stroke an increase of MMP-9 is regarded to be a marker of increased blood–brain barrier permeability and hemorrhagic transformation of ischemic foci [46].

On the other hand, a decrease in MMP-9 level in the saliva of all children with epilepsy was reported and it was most significant in patients with unsatisfactory control of the disease. The study apart from noting the association of the decrease in MMP-9 level in saliva with the occurrence and activity of epilepsy, also shows a possibility of noninvasive evaluation of MMP-9 level [47].


  Conclusion Top


Epilepsy is a major health burden. We need reliable biomarkers for diagnosis due to a wide range of epilepsy mimics. Our study demonstrated that serum MMP-9 levels were increased in patients with epilepsy. This tool may be a helpful diagnostic biomarker for epilepsy with a good sensitivity and specificity.

Recommendation

  1. MMP-9 is an important tool for the evaluation of epileptic children.
  2. Anthropometric assessment should be part of clinical assessment of children with epilepsy.
  3. We recommend further investigations regarding this issue in children with epilepsy.
  4. Further studies should be made in order to understand which of the anthropometric indexes better define the nutritional status and to decide appropriate programs to improve the nutritional status of these epileptic children.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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Abstract
Introduction
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Patients and methods
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