Menoufia Medical Journal

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 29  |  Issue : 4  |  Page : 954--960

Early detection of attention deficit hyperactivity disorder and/or epilepsy by oxidative stress biomarkers


Fawzy A Ashour1, Maathir K Elshafie2, Yahya M Naguib3, Sameh A Abdelnabi4, Omnia Ameen3,  
1 Department of Medical Physiology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt
3 Department of Medical Physiology, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt
4 Department of Pediatric, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt

Correspondence Address:
Omnia Ameen
Department of Clinical Physiology, Faculty of Medicine, Menoufia University, Shebin Elkom, 32511
Egypt

Abstract

Objectives The objective of this study was early detection of attention deficit hyperactivity disorder (ADHD) and/or epilepsy by oxidative stress biomarkers. Background ADHD is a developmental disorder with an etiopathology not fully understood. According to the prevailing view, oxidative metabolism may be involved. Patients and methods The study sample consisted of 100 children. Children were equally divided into four groups (25 children/group): group I (control group); group II (ADHD group); group III (epilepsy group); and group IV (ADHD with epilepsy group). Each participant was subjected to a multidisciplinary clinical interview using a comprehensively devised semistructured sheet covering sociodemographics, psychiatric and pediatric history, and physical examination. Patients were diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria. Venous blood samples were collected from all groups; serum malondialdehyde and glutathione S transferase levels were assessed. Results The mean value of serum malondialdehyde was significantly increased in the ADHD group, epilepsy group, and ADHD with epilepsy group when compared with the corresponding mean value in the control group. The mean value of serum glutathione S transferase was significantly decreased in the ADHD group, epilepsy group, and ADHD with epilepsy group when compared with the corresponding mean value in the control group. Conclusion Our study points out that changes in oxidative metabolism may have a role in the pathophysiology of ADHD and epilepsy.



How to cite this article:
Ashour FA, Elshafie MK, Naguib YM, Abdelnabi SA, Ameen O. Early detection of attention deficit hyperactivity disorder and/or epilepsy by oxidative stress biomarkers.Menoufia Med J 2016;29:954-960


How to cite this URL:
Ashour FA, Elshafie MK, Naguib YM, Abdelnabi SA, Ameen O. Early detection of attention deficit hyperactivity disorder and/or epilepsy by oxidative stress biomarkers. Menoufia Med J [serial online] 2016 [cited 2020 Apr 3 ];29:954-960
Available from: http://www.mmj.eg.net/text.asp?2016/29/4/954/202497


Full Text

 Introduction



Attention deficit hyperactivity disorder (ADHD) is one of the most common disorders in school-aged children. ADHD is the most prevalent neuropsychiatric disorder worldwide, in both developed and developing countries, affecting between 5 and 15% of school-age children, and it was found to persist through adolescence and adulthood in 30–50% of these individual. This disorder is characterized by developmental inattention, hyperactivity, and impulsivity with onset before the age of 7 years and impaired functioning in two or more settings [1].

These psychogenic impairments are especially evident at school. These children are at a risk for learning difficulties and often demonstrate academic failure and underachievement, especially during elementary schooling [2].

ADHD may carry a financial burden for the community. For example, elevated levels of unemployment and the high turnover of jobs associated with ADHD in adults can lead to lower household income levels. Furthermore, parents of children with ADHD may suffer financially because of reduced efficiency or absence from the work place caused by managing their child's condition. ADHD also represents a burden to society in terms of the increased healthcare resource use that is associated with this disorder, possibly as a result of increased injury rates in patients with ADHD [3].

Many studies have demonstrated that oxidative stress might have a role in the pathogenesis of various psychiatric disorders such as schizophrenia and ADHD. Reactive oxygen species (ROS) can be evaluated indirectly by the measurement of some antioxidant enzyme level such as glutathione S transferase (GST) [4].

Epilepsy is a group of neurological disorders characterized by epileptic seizures. Epileptic seizures are episodes that can vary from brief and nearly undetectable to long periods of vigorous shaking. In many cases the cause of epilepsy cannot be identified; however, factors that are associated include brain trauma, strokes, brain tumor, and drug and alcohol misuse. Epileptic seizures mostly result from abnormal, excessive, or hypersynchronous neuronal activity in the brain [5].

It is estimated that the annual incidence of epilepsy is about 50 cases/100 000 persons (ranging from 40 to 70/100 000/year) in developed countries and 100–190/100 000/year in developing countries [6].

For children with epilepsy, it has been reported that the prevalence of ADHD is much higher than in the general pediatric population, ranging widely between 8 and 77% [7]. The seizures in children with epilepsy can induce hyperactivity, inattention, and impulsivity. There are many seizure-related variables including seizure controllability. Most importantly, multiple seizures can alter a patient's perception. Considerable evidence suggested that seizure control can improve the symptoms of ADHD [8].

ADHD affects a child's performance in school and may lead to academic failure, and thus recognizing ADHD symptoms and seeking help early will lead to better outcomes for both affected children and their families.

Aim

The aim of this study is early detection of ADHD and/or epilepsy by oxidative stress biomarkers.

 Patients and Methods



This study comprised 75 patients with ADHD, epilepsy, and ADHD with epilepsy randomly selected from those attending the pediatric neurology clinic in Menoufia University Hospital and those admitted in pediatric department in Souzane Mubarak hospital, and 25 healthy volunteers (control). Patients and controls had a similar distribution in age from 2 to 10 years. After the controls and patients received a comprehensive description of the study, all provided written informed consents. Ethical approval was obtained from the local research ethics committee in Faculty of Medicine, Menoufia university. Each participant was subjected to a multidisciplinary clinical interview using a comprehensively devised semistructured sheet covering sociodemographics, psychiatric and pediatric history, and physical examination.

Exclusion criteria

Patients with ADHD secondary to neurological diseasesPatients with autism, language delays, learning disabilities, or other psychological disorders were excluded from the study by clinical assessmentPatients having ADHD criteria according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), for less than 6 monthsEpileptic patients who are uncontrolled for at least 3 monthsIQ less than 70.

Patients were equally divided into four groups (25 children/group): group I (control group); group II (ADHD group); group III (epilepsy group); and group IV (ADHD with epilepsy group). Children and their parents in all groups were informed of the study in a detailed manner and consent form was signed.

Patients with ADHD were diagnosed according to history, clinical examination, and DSM-IV criteria. The children had not previously been diagnosed with ADHD and were not on medication. Patients with epilepsy were diagnosed according to history, clinical examination, laboratory investigations (needed to identify underlying conditions such as toxins, infections, drug or alcohol withdrawal, fever (in a child), or hypoglycemia that may be causing seizures, and to distinguish epilepsy from conditions such as fainting or a stroke that may cause some of the same symptoms) and electroencephalogram (EEG). Patients with ADHD and epilepsy were diagnosed according to history, clinical examination, DSM-IV criteria, laboratory investigations, and EEG.

Blood sample collection

Three milliliters of venous blood was collected from all children in a clean graduated EDTA-containing test tube that was left for clotting at room temperature in a water bath for 10 min and then centrifuged at 3000 rpm for 20 min. The supernatant serum was collected in a dry clean Eppendorf tube and was stored frozen at −80° C until used for estimation of serum malondialdehyde (MDA) and GST.

Analytical assay

Serum MDA level was determined by the reaction of MDA with thiobarbituric acid (TBA) at 95°C. In the TBA test reaction, MDA and TBA react to form a pink pigment with an absorption maximum at 532 nm. The reaction was performed at pH 2–3 at 95°C for 15 min. The sample was mixed with 2.5 volumes of 10% (w/v) trichloroaceticacid to precipitate the protein. The precipitate was pelleted by centrifugation and an aliquot of the supernatant was allowed to react with an equal volume of 0.67% TBA in a boiling water bath for 15 min. After cooling, the absorbance was read at 532 nm. Arbitrary values obtained were compared with a series of standard solutions (1, 1, 3, 3 tetramethoxypropane). Results were expressed as nanomol per milliliter [9].

GST activity was measured using 1-chloro-2,4-dinitrobenzene (CDNB), which is a synthetic GST substrate. Briefly, CDNB was added to buffer containing GSH and an aliquot of sample to be tested. Upon the addition of CDNB, the change in absorbance at 340 nm was measured as a function of time. Results are expressed in units per liter [10].

Statistical analysis

SPSS for Windows 11.5 (SPSS Inc., Chicago, Illinois, USA) was used to analyze the data statistically. Student's t-test was used for comparison between means of the different groups of patients. Pearson's χ2 was used for comparison between qualitative variables. P value was used to indicate the level of significance (P ≤ 0.05 is considered significant, P ≤ 0.01 is highly significant, and P ≤ 0.001 is very highly significant).

 Results



Regarding age, the mean age in the ADHD group was 4 ± 2.47 years, which was insignificantly different (P > 0.05) when compared with the corresponding mean value in the control group (5.66 ± 3.99 years). In addition, in the epilepsy group, the mean age was 4.25 ± 1.79 years, which was insignificantly different (P > 0.05) when compared with the corresponding mean value in the control group. Notably, in the ADHD with epilepsy group, the mean age was 4.11 ± 1.72 years, which was insignificantly different (P > 0.05) when compared with the corresponding mean value in the control group ([Table 1]).{Table 1}

The ratio of male: female distribution in the ADHD group was 3.1%, which was significantly higher (P < 0.05) when compared with the corresponding ratio in the control group (1.08%). Furthermore, in the epilepsy group, the ratio of male: female distribution was 1.08%, which was insignificantly different (P > 0.05) when compared with the corresponding ratio in control group. In addition, in the ADHD with epilepsy group, the ratio of male: female was 2.1%, which was significantly higher (P < 0.05) when compared with the corresponding ratio in the control group ([Table 1]).

The number of patients with a positive family history of seizure and neurological disease in the ADHD group was three (12%) patients, which was insignificantly different (P > 0.05) when compared with the corresponding value in the control group (two children, 8%). Furthermore, the number of patients with a positive family history of seizure and neurological disease in the epilepsy group was 16 (64%) patients, which was significantly higher (P < 0.001) when compared with the corresponding values in control and ADHD groups. In addition, the number of patients with a positive family history of seizure and neurological disease in ADHD with epilepsy group was 18 (72%) patients, which was significantly higher (P < 0.001) when compared with the corresponding values in control and ADHD groups ([Table 1]).

Insignificant difference (P > 0.05) was noticed between groups regarding the consanguinity and developmental history ([Table 1]).

The mean value of serum MDA in ADHD was 13.57 ± 1.43 nmol/l/ml, which was significantly higher (P < 0.001) when compared with the corresponding value in the control group (6.72 ± 0.48 nmol/l/ml). In addition, the mean value of serum MDA in the epilepsy group was 12.66 ± 1.60 nmol/l/ml, which was significantly higher (P < 0.05) when compared with the corresponding values in control and ADHD groups. The mean value of serum MDA in the ADHD with the epilepsy group was 14.49 ± 2.51 nmol/l/ml, which was significantly higher (P < 0.05) when compared with the corresponding values in control and epilepsy groups [Figure 1].{Figure 1}

The mean value of serum GST in ADHD was 0.46 ± 0.03 U/l, which was significantly lower (P < 0.001) when compared with the corresponding value in the control group (3 ± 0.07 U/l). In addition, the mean value of serum GST in the epilepsy group was 0.56 ± 0.02 U/l, which was significantly lower (P < 0.001) when compared with the corresponding values in control and ADHD groups. In addition, the mean value of serum GST in the ADHD with epilepsy group was 0.55 ± 0.02 U/l, which was significantly lower (P < 0.001) when compared with the corresponding values in control and ADHD groups [Figure 2].{Figure 2}

 Discussion



ADHD is one of the most common psychogenic disorders in school-age children. It is characterized by persistent pattern of inattention, hyperactivity, and impulsivity. ADHD is usually identified in childhood and persists into adulthood in about 60% of individuals with childhood onset. ADHD has widespread effects on the functioning and development of affected children, as well as having considerable impact on others – including family members, peers, and teachers. It can lead to other disorders, academic difficulties, and social problems [11].

School-age children with epilepsy frequently present with comorbid ADHD. It occurs in 14–31% of children with epilepsy. It seems that the severity of epilepsy enhances the predisposition for having ADHD [12].

A number of studies have addressed the etiology of ADHD focused on imaging and genetics. Relatively, little attention has been given to factors/mechanisms involved in the brain dysfunction and its consequences, such as the oxidative metabolism [13].

The present study was conducted on 100 children. They were divided into four groups: control group, ADHD group, epilepsy group, and ADHD with epilepsy group. The patients were randomly selected from those attending the pediatric neurology clinic in Menoufia University Hospital and those admitted in pediatric department in Souzane Mubarak Hospital. Children and their parents in all groups were informed of the study in a detailed manner and consent form was signed. The diagnosis was based on history, clinical examination, DSM-VI criteria, EEG, and laboratory investigation. Three milliliters of venous blood was collected from all children for the estimation of serum MDA and GST.

The results of the sociodemographic data showed that the ratio of male: female distribution was significantly higher in the ADHD and ADHD with epilepsy groups when compared with the corresponding ratio of the control group. This result was consistent with other studies, which reported that in ADHD the ratio of male to female with ADHD is high in clinic samples (≤10: 1). However, it drops to 2: 1 to 4: 1 in community samples and the majority of studies in adults showed no significant effect of sex on prevalence. This suggests that the biased sex ratios observed in ADHD may result from referral bias rather than a biological mechanism [14–16].

There is persuasive evidence that the sexes differ with respect to their relative vulnerability to disorders of attention and impulsivity. Moreover, these sex differences in neurobiology must be underpinned by genes on the X and Y chromosomes exerting their effects by either direct action in the brain or via intermediary mechanisms such as systemic hormone secretion. In addition, they have reviewed several plausible mechanisms via which genes on the sex chromosomes may influence attention and impulsivity [17].

In general, boys with ADHD have more 'externalizing' symptoms (running, hitting, impulsivity), whereas girls with ADHD have more 'internalizing' symptoms and side effects (depression, anxiety, low self-esteem) [14].

On the other hand, insignificant difference in sex distribution was noticed in the epilepsy group when compared with the control group.

The number of patients with a positive family history of seizure or neurological problem was significantly higher in epilepsy and ADHD with epilepsy group when compared with a corresponding number of patients in the control group. This result matched with those of other researches that have found that there are elements of hereditability in epilepsy disease [18],[19].

A research has provided a molecular mechanism of epileptogenesis. A large number of genetic disorders are recognized to cause recurrent seizures [20]. There are many epilepsy-related genes that have been identified among the critical genes; each one may determine different aspects of the phenotype, including age of onset, seizure type, and seizure focus [21].

Insignificant differences were noticed between groups regarding age, consanguinity, and developmental history.

The mean value of serum MDA level was significantly higher in the ADHD group when compared with the corresponding mean value of the control group. This result agreed with a study that reported that serum MDA level was significantly elevated in ADHD patients [22]. In addition, the mean value of serum GST level was significantly lower in the ADHD group when compared with the corresponding mean value of the control group. This result was consistent with other studies, which found a significant decrease in serum GST in ADHD patients when compared with controls [13],[23].

Oxidative stress is generally considered as a condition underlying many diseases, and it is defined as an increase in ROS or a decrease in antioxidant defense [24]. MDA is one of the end products of lipid peroxidation that is a well-known source of ROS causing oxidative stress. Increased MDA could have an important role in the pathophysiology of psychiatric diseases [13],[22]. GST enzymes are involved in the metabolism of xenobiotics that include environmental carcinogens and ROS. The great majority of catalyzing reactions between glutathione and electrophilic compounds results in detoxification products [25].

Dopamine is a key element of ADHD pathophysiology. Dopamine may play a central role because of its association with the modulation of psychomotor activity and executive functions, which are the main clinical features of individuals with ADHD [26]. Dopamine is very susceptible to auto-oxidation when antioxidant defense is weak. This condition may contribute to the occurrence of ADHD [27].

The strongest assumption regarding this mechanism stems from the interaction between oxidants and cell membrane proteins. This interaction leads to the obstruction of cellular uptake of enzymes and/or neurotransmitters, which functions as a predisposing factor for ADHD. It has been reported that deterioration of the membranes of neurons that are targeted by increased oxidative stress may lead to abnormalities in the binding affinities of neurotransmitters including serotonin, norepinephrine, opiates, and dopamine, which lead to dysregulation of neurotransmission. Moreover, it has been suggested that impairment in the integrity of the membrane induces potential deterioration in both the structure and function of neuronal receptor [28].

It was previously found that nitric oxide synthase and xanthine oxidase activities of the patients with ADHD were significantly higher than those of the controls. In addition, GST and paraoxonase-1 activities of ADHD patients were significantly lower than those of the controls, which support our results in the role of oxidative stress in ADHD [13].

Moreover, in the present study, the mean value of serum MDA level was significantly higher in the epilepsy group when compared with the corresponding mean value of the control group. In addition, the mean value of serum GST level was significantly lower when compared with the corresponding mean value of the control group. These results agreed with many studies, which concluded that there is oxidative stress in epileptic patients [29],[30].

It has been suggested that an increase in the free radicals may cause neuronal degeneration through peroxidation and decrease in the glutathione peroxidase levels. These free radicals have been implicated in the development of many acute and chronic diseases of the brain, such as epilepsy, cerebrovascular disease, and Alzheimer's disease [30].

Seizure-like activity at the cellular level initiates significant influx of calcium via voltage-gated and N-methyl-d-aspartate dependent ion channels. Elevated intracellular ions lead to biochemical cascades, which trigger acute neuronal death after status epilepticus. In addition, high levels of intracellular calcium can induce ROS [31].

Generalized epilepsy is characterized by recurrent seizures, which can increase the content of ROS in the brain and can in turn induce seizures activity by direct inactivation of glutathione synthatase, thereby permitting an abnormal build-up of excitatory neurotransmitter glutamic acid [32].

Brain injury resulting from seizures is a dynamic process that comprises multiple factors contributing to neuronal cell death. These may involve genetic factors, excitotoxicity-induced mitochondrial dysfunction, altered cytokine levels, and oxidative stress [33].

Many researches discussed the role of antiepileptic drugs on oxidative stress. Antiepileptic drugs seriously increase lipid peroxidation at the expense of protective antioxidants, leading to an increase in seizure recurrence and idiosyncratic drug effect [34].

The children with idiopathic epilepsy treated with valporate and/or carbamazepine had disturbance in the oxidant–antioxidant balance, and thus they need adequate supply of antioxidants for brain protection and prevention of neurological disturbance. In addition, long-term use of valporate could lead to lack of selenium, copper, and zinc, which are cofactors of GST activity, and thus long administration of antiepileptic drugs in epileptic children leads to decreased GST [35].

Antioxidant melatonin has been found to decrease seizure activity or delay the development of epileptic discharges in ferric chloride-induced seizure models in rodents. This phenomenon was also found to accompany decreased levels of lipid peroxidation [36].

In the present study, in the ADHD with epilepsy group the mean value of serum MDA level was significantly higher, whereas the mean value of serum GST was significantly lower when compared with the corresponding values in the control group. The peroxidation of long-chain polyunsaturated fatty acids mediated by ROS may affect membrane excitability and normal neurotransmission particularly dopaminergic and serotonergic systems that may cause ADHD [37]. Moreover, the antiepileptic drugs may increased lipid peroxidation leading to an increase in seizure recurrence [34].

 Conclusion



Our study points out that changes in oxidative metabolism may have a role in the pathophysiology of ADHD and epilepsy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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