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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 1  |  Page : 157-161

Probable relationship between Toxoplasma gondii and children with cryptogenic epilepsy


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission16-Sep-2018
Date of Decision04-Nov-2018
Date of Acceptance10-Nov-2018
Date of Web Publication25-Mar-2020

Correspondence Address:
Sally S. M El-Dabaa
Shebeen El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_263_18

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  Abstract 

Objective
The aim was to determine the association between Toxoplasma gondii infection and cryptogenic epilepsy.
Background
Cryptogenic epilepsy is defined as a group of epilepsy syndromes for which etiology is unknown, but an underlying brain disease is suspected. We selected patients in this subgroup of epilepsy and investigated the seropositivity rate for antitoxoplasma immunoglobin (Ig)G antibodies by enzyme-linked immunosorbent assay. T. gondii is found in up to 20% of the US population, forming dormant brain cysts in the latent bradyzoite form. We investigated the probable relationship between T. gondii infection and cryptogenic epilepsy.
Materials and methods
This was a case–control prospective study conducted on 70 children in the time period between 1/2017 and 4/2018 from those attending the outpatient clinic of pediatric neurology at Menoufia University Hospital and Shebein El-Kom teaching hospital. We selected 30 patients with cryptogenic epilepsy, 20 patients with known-cause epilepsy, and 20 healthy children sex-matched and age-matched with epileptic children who served as a control group. We investigated the seropositivity rate for antitoxoplasma IgG antibodies by enzyme-linked immunosorbent assay.
Results
The seropositivity rate for antitoxoplasma IgG antibodies among patients with cryptogenic epilepsy (40%) was found to be higher than healthy volunteers (10%) and patients with known-cause epilepsy (10%), with statistical significance (χ2 = 8.006, P = 0.014). This significance persists after adjustment for subjects' sex and age in a multiple logistic regression model.
Conclusion
Our results suggest that chronic T. gondii infection may be a cause of cryptogenic epilepsy.

Keywords: case–control study, cryptogenic epilepsy, seroprevalence, Toxoplasma gondii infection


How to cite this article:
Khatab AA, Soliman MA, El-Naby SA, El-Dabaa SS. Probable relationship between Toxoplasma gondii and children with cryptogenic epilepsy. Menoufia Med J 2020;33:157-61

How to cite this URL:
Khatab AA, Soliman MA, El-Naby SA, El-Dabaa SS. Probable relationship between Toxoplasma gondii and children with cryptogenic epilepsy. Menoufia Med J [serial online] 2020 [cited 2020 Aug 14];33:157-61. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/157/281286




  Introduction Top


Childhood epilepsy is one of the commonest neurological disorders in pediatrics affecting no fewer than 50 million patients worldwide[1].

Cryptogenic epilepsy is a syndrome in which there is no underling structural brain lesion or other neurological signs or symptoms. It is presumed to have a genetic background and is usually age dependent[2]. It comprises ∼20% of all epilepsy syndromes[3].

Epidemiological links suggest an association between helminthes infestation and epilepsy, particularly in the poorer areas of the world. Toxoplasma gondii can form asymptomatic dormant cysts in the brain and have the potential to cause epilepsy[4].

Toxoplasma infections are implicated to have an association with epilepsy either as a cause or a potential risk factor for its occurrence. There has been a long-standing interest in investigating this possible association. However, as yet the evidence for such a relationship is far from conclusive[5].

Antimicrobial treatment of infants who have congenital toxoplasmosis during the first year of life dramatically reduces the risk of adverse neurologic outcomes. Before the current treatment regimens were established, the risks of seizures, mental retardation, and motor abnormalities were each ∼75%. After implementation of the current treatment regimens, the risks have been reduced to ∼30% for each neurodevelopmental handicap[6].

The aim of this study was to investigate the frequency of Toxoplasma infection among patients with cryptogenic epilepsy and the epidemiological factors associated with the disease.


  Materials and Methods Top


Before initiation of our study, the study protocol was approved by the local ethical committee of the Menoufia University, and written consent was obtained from the parents. This case–control study was carried out at Pediatric Department of Menoufia Faculty of Medicine and Shebin El-Kom teaching hospital inpatient and outpatient clinics.

It was conducted on two groups: the patient group included 50 children with epilepsy, who were subdivided into two groups, group I (cryptogenic group, 30 children) and group II (noncryptogenic group, 20 children), and the control group, which included 20 healthy children with same age and sex. All children were subjected to the following: careful history taking including main complaint of the patient, socioeconomic status, history of contact with animals, and clinical examination according to the standard clinical sheet, with special stress on neurologic examination.

Inclusion criteria children whose age between 9 months and 16 years old, both sexes, and epilepsy as a disease. Diagnosis of cryptogenic epilepsy was based on negative family history epilepsy, no history of head trauma, previous bacterial or viral meningitis/encephalitis or brain surgery, and normal MRI study finding.

A written informed consent was obtained from parents of patients and controls before including in the study.

Laboratory methods included routine investigations. Specific investigations included brain imaging: computed tomography or MRI. Serology included the following: 3 ml of venous blood samples was taken from each case and control, and serum was separated by centrifugation and stored at −20°C until tested. It was used to estimate anti-T. gondii IgG antibodies by enzyme-linked immunosorbent assay technique[7].

Statistical analysis

The collected data were tabulated and analyzed using IBM SPSS software package version 20.0 (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, standard deviation, and median. χ2-Test/Fisher's test or Monte Carlo correction/Student 't' test/Kruskal–Wallis test (KW χ2) and logistic regression test. Logistic regression measures the relationship between the categorical dependent variable and one or more independent variables/affecting factor by estimating probabilities. The accepted level of significance in this work was stated at 0.05 (P < 0.05 was considered significant)[8].


  Results Top


A total of 70 children met the study criteria and were divided into the following: the patient group consisted of 50 epileptic children who were subdivided into two groups: group I (cryptogenic group, 30 children) and group II (noncryptogenic group, 20 children), and the control group, which consisted of 20 age-matched and sex-matched healthy children. We have found that incidence of epilepsy is statistically significantly higher in rural areas in comparison with urban areas, with P of 0.035* [Table 1]. We have found that there was a statistically significant increase in history of contact with animals in cryptogenic epilepsy group compared with noncryptogenic (epilepsy and control groups; P = 0.013*). We have found a statistically significant elevation of the seropositivity rate for antitoxoplasma immunoglobin (Ig) G antibodies among patients with cryptogenic epilepsy (40%) compared with noncryptogenic (10%), with P of 0.014*. [Table 2]. In the univariable and multivariable analyses [Table 3], the findings of elevation of the seropositivity rate for antitoxoplasma IgG antibodies and contact with animals among patients with cryptogenic epilepsy persisted significantly even after adjustment for subjects' sex and age in a multiple logistic regression model (Table 4).
Table 1: Descriptive data for residence of epileptic cases

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Table 2: Comparison between the three studied groups according to contact with animals and immunoglobin G

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Table 3: Results of logistic regression analysis predicting cryptogenic epilepsy

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  Discussion Top


In a case–control prospective study, we have demonstrated an association between chronic toxoplasmosis and cryptogenic epilepsy.

Epidemiological links suggest an association between helminthes infection and epilepsy, particularly in the poorer areas of the world. T. gondii can form asymptomatic dormant cysts in the brain and have the potential to cause epilepsy[4].

Toxoplasma infections are implicated to have an association with epilepsy either as a cause or a potential risk factor for its occurrence. There has been long-standing interest in investigating this possible association. However, as yet, the evidence for such a relationship is far from conclusive[5].

Antimicrobial treatment of infants who have congenital toxoplasmosis during the first year of life dramatically reduces the risk of adverse neurologic outcomes. Before the current treatment regimens were established, the risks of seizures, mental retardation, and motor abnormalities were each ∼75%. After implementation of the current treatment regimens, the risks have been reduced to ∼30% for each neurodevelopmental handicap[6].

Regarding residence in our study, 74% of epileptic groups were residing in rural areas and 26% were residing in urban ones. This significant difference indicates that epilepsy is more common in rural areas. This agrees with Abdallah et al.[9] who reported that epilepsy is more common in rural areas, but does not match with what was recorded by some other studies[5],[10],[11]. They reported no significant relation between epilepsy and residence. This may be owing to negligence, decrease in parent's care, and low socioeconomic standards that make children at risk of exposure to epilepsy-predisposing factors such as head trauma, cerebral infections, and perinatal problems.

Regarding contact with animals, there was a significant increase in history of contact with animals among cryptogenic epilepsy compared with controls. This agrees with Mendonça et al.[12] who stated that cryptogenic epilepsy is more common in patient who have contact with animals, but El-Tantawy et al.[5] detected no significant relation between epilepsy and contact with animals.

Regarding T. gondii seropositivity, 12 (40%) cases of the cryptogenic group and two (10%) cases of the control group were toxoplasma IgG positive, with P of 0.014, which is statistically significant. These values indicate significant relation between toxoplasma infection and cryptogenic epilepsy.

This significant correlation can be explained by either (a) dormant T. gondii cysts containing bradyzoites may cause epileptic foci and cryptogenic epilepsy in animal models, and it is proposed that some tissue cysts rupture and in doing so cause marked inflammation of that area and hence triggers microglial formation which may represent the 'tombstones' of toxoplasma cysts and lead to scar tissue formation[13] or (b) patients with cryptogenic epilepsy could be more susceptible to this infections[14].

Our results are consistent with El-Tantawy et al.[5], as they also found a significant relation. In their study, 60.6% of the cases and 43.3% of controls were toxopositive.

Moreover, the results are consistent with Zibaei et al.[11], where 12 (14.1%) patients with epilepsy had positive antitoxoplasma antibodies, as compared with four (4.7%) among the control group. This was statistically significant.

Moreover, the results are consistent with Yazar et al.[15], who reported that the level of T. gondii IgG showed a statistically significantly high value in a study of cryptogenic epilepsy. In their study, the percentage of anti-T. gondii IgG positive antibody in patients with cryptogenic epilepsy (54%) was found to be greater than patients with known-cause epilepsy (22%) and nonepileptic healthy volunteers (18%). Thus, the results indicate a statistically significant difference between the cryptogenic epilepsy group and the other two groups.

In addition, the results are consistent with Stommet et al.[4], as they suggested that chronic T. gondii infections with brain cysts may be a cause of cryptogenic epilepsy. The authors thought that the cryptogenic epilepsy population could be more susceptible to the parasitic infection, for reasons unrelated to epilepsy, or owing to intrinsic immunologic differences that predispose them to epilepsy. In this study, the frequency of toxoplasma infection in epileptic patients was 14.1%, which was significantly higher than the healthy controls (4.7%). They identified 22 patients with cryptogenic epilepsy, and on the basis of the enzyme-linked immunosorbent assay values, 75% of the 22 patients had greater T. gondii antibody titers than the median titer observed among the 23 controls.

Moreover, Shehata et al.[16] reported a statistically significant association between IgG seropositivity and neurodevelopmental disorders.

On the contrary, Akyol et al.[10] reported no relationship between cryptogenic epilepsy and positive T. gondii serology in their study, which was carried on 100 patients with cryptogenic epilepsy and 50 healthy volunteers who had no history of epilepsy in their first-degree relatives. In their study, 31% of the cases and 20% of the controls were toxoplasma IgG positive, which was considered statistically insignificant.

To eliminate the effects of confounding factors such as age and sex, our data have been analyzed by logistic regression and revealed that these factors were comparable in the study and control groups and did not influence the interactions of serology and disease state.

This result confirms the relation between toxoplasma infection and cryptogenic epilepsy in our study.

There are some limitation of our study in its design and data analysis. It is often contended that the burden of epilepsy moves proportionately with that of toxoplasmosis (e.g., more toxoplasmosis and more epilepsy), but this may not be logically correct because of the large number of causes of epilepsy; one single factor like toxoplasmosis, about the epileptogenicity of which little is known, cannot explain such epidemiological shifts of a disease like epilepsy in any given population.

Moreover, there is always a possibility of an influence of variables such as 24-h electroencephalographies supervised by an epileptologist or diagnosis by simple history taking by family physician, etc., which may cause some influence in the diagnosis of epilepsy, hence on the results of some of these studies.

Good quality epidemiological research will further help to draw broad conclusion on this important subject. These good quality studies may at least be population based with samples representative of all age groups, and taking case–controls from the same source population, with at least 70% power. These studies should also use standard criteria to define various parameters and taking active epilepsy in account with clear description of procedures.

Further research is still required to understand and clarify the role of T. gondii in its diverse routes of transmission, as well as to design better control measures that focus on minimization of the risk of infection. The purpose of such studies should be to aid in the monitoring of changes in the epidemiology of T. gondii infection and to strengthen educational effort to avoid transmission of infection in population that cannot controlled by drugs alone.


  Conclusion Top


From this study, we can conclude that there was a statistically significant association between T. gondii seropositivity and cryptogenic epilepsy. The results of the current study reemphasize the importance/significance of public health measures to prevent and control exposure of pediatric age/susceptible population to such parasitic infestation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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2.
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Wam EC, Sama LF, Ali IM, Ebile WA, Aghangu LA, Tume CB Seroprevalence of Toxoplasma gondii IgG and IgM antibodies and associated risk factors in women of child-bearing age in Njinikom, NW Cameroon. BMC Res Notes 2016; 9:406.  Back to cited text no. 7
    
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Abdallah KF, Eraky MA, Hady SA. Seropositivity of Toxoplasma gondii and Toxocara spp. in children with cryptogenic epilepsy, Egypt. Korean J Parasitol 2016; 54:335–338.  Back to cited text no. 9
    
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Zibaei M, Zamani Z, Esfahani AC, Anbari K, Nazer MR. Toxoplasma infection and epilepsy: A case-control study in Iran. Neurology Asia 2011; 16:299–302.  Back to cited text no. 11
    
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Mendonça LR, Figueired CA, Esquivel R, ML Barretto, Alcantara-Neves NM, et al. Seroprevalence and risk factors for Toxocara infection in children from an urban large setting in Northeast Brazil. Acta Trop 2013; 128:90–95.  Back to cited text no. 12
    
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Frenkel JK, Escajadillo A. Cyst rupture as a pathogenic mechanism of toxoplasmic encephalitis. Am J Trop Med Hyg 1987; 36:517–522.  Back to cited text no. 13
    
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Woodruff AW, Bisseru B, Bowe JC. Infection with animal helminths as a factor in causing poliomyelitis and epilepsy. Br Med J 1996; 1:1576–1579.  Back to cited text no. 14
    
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Yazar S, Arman F, Yalcin S, Yaman. O, Sahin N, Demirtas F, et al. Investigation of probable relationship between Toxoplasma gondii and cryptogenic epilepsy. Seizure 2003; 12:107–109.  Back to cited text no. 15
    
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Shehata AI, Hassanein FI, Abdul-Ghani R. Seroprevalence of Toxoplasma gondii infection among patients with non-schizophrenic neurodevelopmental disorders in Alexandria, Egypt. Acta Tropica J 2015; 154:155–159.  Back to cited text no. 16
    



 
 
    Tables

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



 

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