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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 1  |  Page : 37-42

Soluble intercellular adhesion molecule-1 as a marker for the possible role of Toxoplasma gondii in the pathogenesis of cryptogenic epilepsy


1 Department of Parasitology, Faculty of Medicine, Benha University, Benha, Egypt
2 Department of Pediatrics, Faculty of Medicine, Benha University, Benha, Egypt

Date of Submission05-Jan-2016
Date of Acceptance12-Apr-2016
Date of Web Publication25-Oct-2016

Correspondence Address:
Maysa A Eraky
Department of Parasitology, Faculty of Medicine, Benha University, Benha 13518
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7942.192989

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  Abstract 

Background
Congenital toxoplasmosis may be without an obvious clinical picture at birth and later present with variable signs and symptoms, mostly related to the central nervous system. Cryptogenic epilepsy in children is one of those conditions without obvious etiology and in which latent toxoplasmosis may be implicated. Soluble cell adhesion molecules (sICAM-1) are circulating biomarkers of DNA shed by living organisms and of pathogenic processes.
Aim
The present study aimed to investigate the possible association of Toxoplasma gondii infection with cryptogenic epilepsy and to determine the increase in sICAM-1 level as an indicator of the possible role of T. gondii in the pathogenesis of cryptogenic epilepsy.
Materials and methods
Ninety children (40 with cryptogenic epilepsy, 30 with noncryptogenic epilepsy, and 20 healthy controls) were evaluated to determine exposure to T. gondii by means of specific immunoglobulin (Ig) G seropositivity and the corresponding sICAM-1 serum levels. Respective specific enzyme-linked immunosorbent assay kits were used.
Results
The level of T. gondii IgG antibody seropositivity was significantly higher among children with cryptogenic epilepsy (20%) than among noncryptogenic epileptic children (0%). In healthy controls, seropositivity was 10%. sICAM-1 was recorded with variable levels, in all cases and controls (90%). In the cryptogenic group, the level ranged from 3.13 to more than 50 ng/ml, whereas it was lower in the noncryptogenic control group, with a maximum sICAM-1 level of 25 ng/ml. In the healthy control group, only one case presented a sICAM-1 level of 25–50 ng/ml. In addition, among IgG-seropositive cases, five cases showed a high sICAM-1 level of 25–50 ng/ml, whereas the remaining three IgG-seropositive cases showed lower sICAM-1 level (12.6–25 ng/ml). In healthy children, the two Toxoplasma IgG-seropositive cases showed a sICAM-1 level of 3.13–25 ng/ml.
Conclusion
The statistically significant results of IgG positivity among the crytptogenic cases supported the possible association between toxoplasmosis infection and cryptogenic epilepsy and revealed the associated upregulation of sICAM-1 level in this condition, thus suggesting that toxoplasmosis should be taken into consideration as a predisposing factor in cryptogenic epilepsy.

Keywords: cryptogenic epilepsy, soluble intercellular adhesion molecule-1, Toxoplasma gondii immunoglobulin G


How to cite this article:
Eraky MA, Abdel-Hady S. Soluble intercellular adhesion molecule-1 as a marker for the possible role of Toxoplasma gondii in the pathogenesis of cryptogenic epilepsy. Parasitol United J 2016;9:37-42

How to cite this URL:
Eraky MA, Abdel-Hady S. Soluble intercellular adhesion molecule-1 as a marker for the possible role of Toxoplasma gondii in the pathogenesis of cryptogenic epilepsy. Parasitol United J [serial online] 2016 [cited 2021 May 12];9:37-42. Available from: http://www.new.puj.eg.net/text.asp?2016/9/1/37/192989


  Introduction Top


Several studies have suggested the possible association between parasitic infections and epilepsy, especially as the main target for Toxoplasma gondii parasite infection is the central nervous system (CNS) [1]. The prevalence of T. gondii seropositivity varies from one country to another. Besides foodborne transmission due to ingestion of raw or undercooked meat containing the parasite in tissue cysts [2], or through ingestion of food, soil, or water contaminated by oocysts, intrauterine transmission from infected pregnant mother to her fetus occurs when the infection takes place during or just before pregnancy [3]. Congenital infection can be complicated by abortion, stillbirth, adverse effects, or severe disease in the newborn. These include developmental delays, blindness, and epilepsy [4]. However, many newborns with congenital toxoplasmosis are asymptomatic at birth and develop complications later in their life most often ocular disease, but also neurologic symptoms and developmental disabilities [5].

Neurological disorders characterized by epileptic seizures [6],[7] are of two types: primary or idiopathic epilepsy mainly of unknown etiology, and secondary epilepsy, which originates from cerebral lesions that may be traumatic, hypoxic, or infectious in origin [8],[9]. It is recorded that about 1% of the world's population suffers from epilepsy [10], with considerably higher rates in poor countries, as nearly 80% of cases occur in developing countries [11]. In high-income countries, traumatic head/brain injuries and stroke are the main causes of epilepsy [12],[13], whereas in low and middle income countries, CNS infections due to viral, bacterial, and parasitic infections are the main contributors [14]. Toxoplasmosis has been implicated either as a cause or a potential risk factor for epilepsy [15]. Cerebral toxoplasmosis causing seizures in about 25% of infected cases [16] has been reported as diffuse encephalitis or due to the formation of dormant cysts in the brain [6]. However, the evidence for such an association is not conclusive.

The blood–brain barrier (BBB) prevents most intravascular leukocytes from entering the parenchyma of the normal brain. However, leukocytes are able to migrate from blood vessels into the brain when infection, ischemia, or an autoimmune disease occurs [17]. As an early step in an inflammatory condition, adhesion between leukocytes and vascular endothelium is facilitated through soluble intercellular adhesion molecule-1 (sICAM), also known as CD54 [18],[19]. This molecule is a membrane-bound protein with five extracellular domains (D1–D5) expressed on many cell types and can be considered as an early indicator for immune activation [20]. Its expression by endothelial cells and leukocytes, and mediation of leukocyte adhesion and migration to inflamed sites occur by binding to LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) [21]. sICAM-1 is a general molecule and not specific to a particular pathogen (similar to other cytokines such as interleukins, interferon, and tumor necrosis factor), and has been detected in different body fluids, including serum, cerebrospinal fluid, urine, and bronchoalveolar lavage fluid. It is continuously present in low concentrations in the membranes of leukocytes and endothelial cells. Upon cytokine stimulation, the concentrations greatly increase [19]. Studies indicate that sICAM-1 plays a role in host cell invasion by Plasmodium falciparum, either as receptors or as crucial accessory molecules [22],[23], causing severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Vascular cell adhesion protein (VCAM-1) and sICAM-1 were reported to be the vascular endothelial adhesion molecules whose expression is upregulated in the brains of mice during chronic infection with T. gondii [24],[25]. Severity of toxoplasmic encephalitis in C57BL/6 mice was found to be associated with increased sICAM-1 and VCAM-1 expression in the CNS [26]. In addition, T. gondii was proved to increase the level of sICAM-1 on the surface of endothelial brain cells [27]. El-Sayed et al. [28] approached this concept and were able to demonstrate a higher level of sICAM-1 among T. gondii-seropositive schizophrenic patients.

The present study aimed to investigate the association between T. gondii infection and cryptogenic epilepsy and evaluate the upregulation of sICAM-1 level, which may support the possible role of T. gondii in the pathogenesis of cryptogenic epilepsy.


  Materials and methods Top


Study design and population

The current cross-sectional study was carried out between June 2014 and March 2015. Ninety children between 9 months and 18 years of age were investigated. The children were divided into three groups. Group 1 included 40 cryptogenic epileptic children who presented with recurrent epileptic fits of unknown etiology. All selected patients had no past history of head trauma, brain surgery, or previous meningitis, or encephalitis, and had normal brain MRI scan and no family history of epilepsy. The second group included 30 epileptic children who presented with recurrent epileptic seizures with known cause such as head trauma, family history of epilepsy, brain surgery, previous encephalitis, or meningitis. The third group included 20 completely healthy children. The epileptic cases were selected from those attending the pediatric outpatient clinic of Benha University Hospital, the Pediatrics Neurology Unit, and from Benha Specialized Hospital for children.

Serological assay

Three milliliters of blood was drawn from all children, centrifuged at 1000 rpm, and the sera were stored at −20°C until analysis. T. gondii immunoglobulin (Ig) G antibody level was determined using commercially available quantitative enzyme-linked immunosorbent assay kit DRG Toxoplasma IgG (TORCH) catalog no. EIA-1798; DRG International Inc., USA) following the manufacturer's instructions, with cutoff calibrator: 32 IU/ml (optical density=1.040). For the determination of sICAM-1 serum level, a commercially available enzyme-linked immunosorbent assay (Quantikine Human sICAM-1/CD54 Immunoassay R&D Systems) was conducted according to the manufacturer's instructions. This assay uses the quantitative sandwich enzyme immunoassay technique. Values of samples were calculated from a standard curve generated from seven standards of known concentrations (<1.56, 1.56–3.13, 3.13–6.26, 6.26–12.5, 12.6–25, 25–50, >50 ng/ml).

Statistical analysis

The collected data were tabulated and analyzed using SPSS, version 16 software (SPSS Inc., Chicago, Illinois, USA). Categorical data were presented as number and percentages. The χ2-test, Fisher's exact test,and Student's t-test were used as tests of significance. The accepted level of significance was stated at 0.05.

Ethical considerations

The present study was approved by the Ethical Committee of Faculty of Medicine, Benha University, Egypt (2014). On behalf of all children participating in the study, written consent was obtained from parents or legal guardians. Control sera were collected after obtaining consent from the volunteers or patients.


  Results Top


Seropositivity of T. gondii IgG antibodies was significantly higher (P < 0.05) in cryptogenic epileptic children (20%) when compared with children with noncryptogenic epilepsy (0%) and with healthy controls (10%) ([Table 1]). sICAM-1 was recorded with variable levels, in all cases and controls (90%) ([Table 2]). The level of sICAM-1 in the cryptogenic group ranged from 3.13 to more than 50 ng/ml and was lower in the noncryptogenic control group with a maximum sICAM-1 level of 25 ng/ml. In the healthy control group, only one case had sICAM-1 level of 25–50 ng/ml. The level of specific IgG antibody was significantly higher (≥300 IU/ml) in seven of the eight cryptogenic cases, and the level ranged between 100 and 300 IU/ml in the eighth case ([Table 3]). In the seropositive healthy control group, only one positive case had less than 100 IU/ml and the other had between 100 and 300 IU/ml ([Table 1]). In addition, among IgG-seropositive cases, there were five cases that had high sICAM-1 level more than 25, whereas the remaining three IgG-seropositive cases showed lower sICAM-1 level (12.6–25 ng/ml). In healthy children, the two Toxoplasma IgG-seropositive cases showed a sICAM-1 level of 3.13–25 ng/ml ([Table 3]).
Table 1 Anti-Toxoplasma gondii IgG seropositivity level among the studied groups

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Table 2 Recorded sICAM-1 levels among the studied groups

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Table 3 Relation between sICAM level and Toxoplasma IgG-positive cases

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  Discussion Top


In the present study, there was a significant association of T. gondii seropositivity with cryptogenic epilepsy, as 20% of the epileptic cryptogenic group was seropositive compared with 10% in the healthy control group (P = 0.017). In addition, seven of the eight IgG-positive cases in the cryptogenic epileptic group had a high titer (>300 IU/ml) and the two positive cases in the control group had a moderate titer (>100–300 IU/ml). This result indicates that Toxoplasma IgG seropositivity is expressed strongly in Toxoplasma -positive cryptogenic cases, which supports the possibility that cryptogenic epilepsy may be a consequence of latent toxoplasmosis [6],[29],[30],[31]. In support of this hypothesis, other studies have reported a decreased incidence of cryptogenic epilepsy and toxoplasmosis with time [32]. This significant correlation can be explained by the presence of dormant Toxoplasma cysts that can cause epileptic foci and epilepsy. The cryptogenic epilepsy patients could also be more susceptible than others to such infections [6],[32], for reasons unrelated to epilepsy, or due to intrinsic immunologic differences that predispose them to epilepsy.

The current results are consistent with many other studies [15],[30],[31],[33], in which the percentage of Toxoplasma IgG-positive antibody in cryptogenic epilepsy patients was found to be greater than that in epilepsy patients with a known cause and nonepileptic healthy volunteers. Despite wide variations in the percentage of Toxoplasma IgG seropositivity among the studied groups, these results indicate a statistically significant difference between the cryptogenic epilepsy group and the other two groups. In contrast, Akyol et al. [34] reported no relationship between cryptogenic epilepsy and Toxoplasma IgG seropositivity.

The diversity in seropositivity rates between the previous reports and the current work can be attributed to the timing of infection, either congenital infection with recurrences many years later, or postnatally acquired infection [35], or host immune function, host genetic factors [36], and variations in virulence of T. gondii strains. Such differences in virulence may be associated with differences in incidence or clinical manifestations [37].

The mechanism of brain damage in epileptic seizures may be explained by the effect of leukocytes and leukocyte adhesion molecules [38], wherein several neurological disorders have been associated with increased levels of adhesion molecules [39]. In drug-refractory epilepsy compared with newly diagnosed and drug-responsive epilepsy, Luo et al.[40] reported higher serum levels of sICAM-1, suggesting its possible role in the drug-refractory epilepsy.

In response to infection with T. gondii, the host provokes a cellular immune reaction through helper T lymphocytes [41]. Upon cytokine stimulation of cerebral endothelial cells, released adhesion molecules enhance the organism invasion into the deep tissues [42],[43]. With this in mind, the present study determined the frequency of T. gondii infection among patients with cryptogenic epilepsy that could be caused by toxoplasmosis, and also whether sICAM-1 is implicated in the pathogenesis of toxoplasmic encephalitis. The results showed that sICAM-1 exhibited a significantly higher level of T. gondii IgG in the seropositive cryptogenic group compared with the healthy control group and the noncryptogenic group. Meanwhile, there was a higher level of sICAM-1 in the IgG-seropositive cryptogenic cases compared with the seronegative cryptogenic and control cases. These results suggested that sICAM-1 is highly linked to the IgG-seropositive epileptic cryptogenic patients. This suggestion might be acceptable because many investigators have reported a possible role of sICAM-1 in infection with T. gondii [27],[42].

It is well documented that T. gondii crosses the BBB, thereby gaining access to tissues where it most likely causes marked pathologic lesions [44]. The severity of toxoplasmic encephalitis in mice was found to be associated with elevated ICAM-1 expression in the CNS and higher BBB permeability [26]. In addition, Barragan et al. [42] found that sICAM-1 antibodies inhibited the migration of Toxoplasma across cellular barriers.

As regards the higher levels of the sICAM-1 in cryptogenic epileptic Toxoplasma IgG-positive cases enrolled in this study, this upregulation of sICAM-1 expression is believed to be a specific response to the interaction between host cells and the parasite at different stages of parasite infiltration, parasite intracellular replication, and/or release of parasite secretion and degradation products. In those Toxoplasma -seropositive cases, serum levels of ICAM-1 varied from one case to another probably correlating with the severity of pathological changes. Moreover, the higher levels of sICAM-1 in the cryptogenic epileptic Toxoplasma -seropositive group is a reflection of more intense inflammation associated with toxoplasmic encephalitis. In addition, the current study showed low sICAM-1 levels in the Toxoplasma -seropositive healthy control group. This could be explained by the presence of a minimal inflammatory response and cell damage at this stage of infection due to latency of the disease resulting from the existing balance between the host immune response and the parasite.

El-Sayed et al. [28] and El-Sayed and Ismail [45] investigated the role of ICAM-1 in the pathogenesis of Toxoplasma -associated schizophrenia and toxoplasmic retinochoroiditis, respectively. They reported a statistically significant correlation between sICAM-1 level and anti-Toxoplasma seropositivity in both clinical diseases.

If these results are verified with a greater number of epileptic patients by other researchers, there may be new approaches for the treatment of cryptogenic epilepsy. These results present another important reason to increase efforts for preventing toxoplasmosis. Additional studies are needed to fully elucidate the relationship between T. gondii infection and neurological illness, and how the parasite strain affects this relationship.


  Conclusion Top


Our results demonstrated possible serological evidence of T. gondii exposure in children suffering from seizures of unknown cause (cryptogenic epilepsy). The findings of the present study also suggested that sICAM-1 expression might be implicated in the pathogenesis of toxoplasmic encephalitis. The results of the current study re-emphasize the importance of public health measures to prevent and control exposure of pediatric age-susceptible population to such parasitic infections.

Author contribution

MA Eraky and S Abdel Hady contributed equally to the research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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