|Year : 2017 | Volume
| Issue : 1 | Page : 41-48
Early-onset versus late-onset obsessive–compulsive disorder: an immunological comparative study
Sahar El Emam Gad MD 1, Wafaa Mohamed El Emshaty2, Hanan El-sayed Hussein1, Osama Ahmed El-Boraie1, Mohammed Ali Ezzat El-Hadid1
1 Department of Psychiatry, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||17-Oct-2016|
|Date of Acceptance||03-Aug-2016|
|Date of Web Publication||22-Feb-2017|
Sahar El Emam Gad
Psychiatry, Lecturer of Psychiatry Mansoura University, Postal code: 35744
Source of Support: None, Conflict of Interest: None
This study was conducted to investigate the possible role of streptococcal infection in obsessive–compulsive disorder (OCD) and to clarify whether the age of onset could affect its clinical presentation and immunological results.
Participants and methods
The study was carried on 96 participants. They were divided into 46 OCD patients with a mean age of 30.76 years and 50 healthy controls with a mean age of 28.94 years. The patients group was subdivided according to the age of onset into the early-onset group include 21 patients with onset age of 18 years or less and the late-onset group include 25 patients with onset age above 18 years. All participants were subjected to psychometric and serological assessments of serum antibasal ganglia autoantibodies (ABGA) and antistreptolysin O titer (ASOT).
Rates of ABGA positivity were 26.1% in the OCD group compared with 30% in the control group, with no significant difference (P=0.670). ASOT positivity were 6.5% in the OCD group, whereas none of the controls had positive ASOT (P=0.160). Positivity for ASOT and ABGA was not associated with the age of onset as 95.2 and 71.4% of the early-onset group had positive ASOT and ABGA results against 92 and 76% in the late-onset group, respectively, with no significant differences (P≥0.05) or clinical variables. Positivity for ASOT was not associated with ABGA positivity.
The negative results of this study do not exclude the role of autoimmunity in OCD pathogenesis. Further investigations are needed to establish this role.
Keywords: antibasal ganglia autoantibodies, antistreptolysin O titer, early onset, late onset, obsessive–compulsive disorder, streptococcal infection
|How to cite this article:|
Gad SE, El Emshaty WM, Hussein HE, El-Boraie OA, Ezzat El-Hadid MA. Early-onset versus late-onset obsessive–compulsive disorder: an immunological comparative study. Egypt J Psychiatr 2017;38:41-8
|How to cite this URL:|
Gad SE, El Emshaty WM, Hussein HE, El-Boraie OA, Ezzat El-Hadid MA. Early-onset versus late-onset obsessive–compulsive disorder: an immunological comparative study. Egypt J Psychiatr [serial online] 2017 [cited 2017 Sep 20];38:41-8. Available from: http://new.ejpsy.eg.net/text.asp?2017/38/1/41/200719
| Introduction|| |
Obsessive–compulsive disorder (OCD) is a severe and disabling mental illness, with a lifetime prevalence of 2–3% in the general population ((Abramowitz et al., 2009)). The core features of OCD involve anxiety-provoking intrusive thoughts (obsession) and/or repetitive ritualistic behaviors (compulsion) aimed at reducing anxiety ((Stein et al., 2016)). OCD is ranked as the second most prevalent psychiatric disorder, although it is still underestimated ((Ameringen and Patterson, 2014)) worldwide due to its ego dystonic nature that enforces the sufferer to disguise or be ashamed of their symptoms, so that they do not reveal their obsessive and or compulsive symptoms. Over the past few decades, convergent evidence from genetics, neuroimaging, and pharmacology point towards a neurobiological basis for this disorder, involving specific brain regions, particularly the orbitofrontal cortex and basal ganglia ((Esposito et al., 2014)). Also, the association of OCD with extrapyramidal movement disorders such as Tourette syndrome, Huntington’s disease, Parkinson’s disease, and Sydenham’s chorea further strengthens the neuroanatomical association with the basal ganglia (Shanahan et al., 2011)). There is now growing evidence for a range of neuropsychiatric disorders associated with poststreptococcal autoimmunity. The main laboratory evidence supporting this group of disorders comes from the identification of increased titers of antibasal ganglia autoantibodies (ABGA) and/or antistreptolysin O (ASO) antibodies ((Singer et al., 2012)). Sydenham chorea was the first disorder in which these antibodies were detected. However, a broad range of conditions have been found to be associated with ABGA: from discrete neurological conditions such as dystonia to ‘classical’ neuropsychiatric disorders such as Tourette syndrome and the rarer syndromes of encephalitis lethargic and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection ((Stagi et al., 2014)). High rates of obsessive–compulsive symptoms have been described in these syndromes.
Rationale of the study
The rationale of this study is based on the hypothesis that poststreptococcal autoimmunity may contribute to OCD pathogenesis. Few studies have been conducted in this field, but their findings were contradicting and not satisfactory; hence the need for our study to answer the question about the possible role of streptococcal infection in OCD pathogenesis and to clarify whether the age of onset could affect the immunological results and clinical presentations.
| Participants and methods|| |
A case–control study was carried out in the outpatient clinic ‘OPC’ of the Psychiatry Department in cooperation with the Department of Clinical Pathology in Mansoura University Hospital ‘MUH’. The study was conducted during the period from 2012 to 2016.
The total number of participants included in this study was 96 adult individuals divided into 46 patients fulfilling the criteria for diagnosis of OCD matched with 50 healthy control individuals with regard to age and sex. The patients were subdivided according to the age of onset into early-onset (EO) (onset age≤18 years) and late-onset (LO) groups (onset age>18 years). Informed written consent was obtained from all participants after explanation of the procedures, which were approved by the Ethical Committee at Mansoura University, Faculty of Medicine. The sample size was limited by the kit’s requirement.
Inclusion criteria for the patients group
Patients who fulfilled the diagnosis of OCD according to DSM-IV-TR were included in the study. Their age ranged from 18 to 60 years, and IQ was more than 80; both sexes were included.
Patients with mental retardation or with neurological, specific medical condition, autoimmune diseases, and medications were excluded from the study. Comorbid axis I DSM-IV-TR disorders including alcohol or any other drug abuse were also included as exclusion criteria.
Inclusion criteria for controls
Controls were recruited from the attendants accompanying their siblings for evaluation in the surgery clinic at Mansoura University Hospital, who had no history of psychiatric or neurological diseases. Controls included both sexes and were matched for age (range between 18 and 60 years). All were subjected to the same scales and tools as the patients group.
- Structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) Axis I disorders clinical version (SCIDI-CV) ((First et al., 1997)).
- Yale–Brown Obsessive–Compulsive Scale (YBOC-S) ((Goodman et al., 1989)).
- Yale–Brown Obsessive–Compulsive Symptoms Checklist ((Goodman et al., 1989)).
- Insight (item was added to Yale–Brown Obsessive–Compulsive Scale) ((Goodman et al., 1989)).
- A scale for measuring family socioeconomic status for health research in Egypt ((El-Gilany et al., 2012)).
Venous blood samples were collected from patients and control participants by clean vein puncture using plastic disposable syringe on plain tubes. Sera were separated from the plain tubes after coagulation at room temperature for 20 min by centrifugation at 3000 rpm for 20 min and distributed into aliquots that were used for detection of serum AB-Ab using the human ABGA (BG-Ab) ELISA kit (Catalog #B5412; Glory Science Co. Ltd., USA; www.Glorybioscience.com) and ASO using the latex agglutination kit (Omega Diagnostics, 5026 south service road Burlington, Ontario).
Antistreptolysin O titer
ASO antibodies, if found in sera of patients in response to infection with hemolytic streptococci of groups A, C, or G, react with the purified and stabilized streptolysin-O-coated latex particles, and clear agglutination was seen within 2 min (concentration of 200 IU/ml or more). For positive samples, a series of doubling dilutions of the patient’s serum in isotonic saline were prepared and the test procedure was repeated for each dilution. The serum ASO concentration was calculated by multiplying the dilution factor by the detection limit (200 IU/ml).
Human antibasal ganglia autoantibody (BG-Ab)
This Sandwich-ELISA method utilizes a microelisa strip-plate precoated with an antigen specific to BG-Ab. Standards or samples are added to the appropriate microelisa strip-plate wells and combined to the specific antigen. Then, a horseradish peroxidase-conjugated antigen specific for BG is added to each microelisa strip-plate well and incubated. Free components are washed away. The TMB substrate solution is added to each well. Only wells that contain BG-Ab-conjugated and horseradish peroxidase-conjugated BG antigen will appear blue in color and then turn yellow after the addition of the stop solution. The optical density (OD) is measured spectrophotometrically at a wavelength of 450 nm. The cutoff was calculated by adding 0.15 to the average absorbance of the negative control. AB-Ab-negative samples were samples with OD less than calculated cutoff, whereas AB-Ab-positive samples were those with OD at least calculated cutoff.
Statistical analysis of the data was performed using Excel program (Microsoft Office, 2013, USA) and SPSS (Statistical Package for Social Science) program (SPSS Inc., Chicago, Illinois, USA) version 20. The Kolmogorov–Smirnov test was used to test the normality of data distribution. Quantitative data were presented as mean, SD, or median and range. For comparison between two groups, the Student t-test and the Mann–Whitney test (for nonparametric data) were used. Qualitative data were presented as number and percentage. χ2 and Fisher exact tests were used to compare categorical groups. Correlation coefficients were used to examine the correlations between parameters. Logistic and ordinal regression was used for the prediction of risk factors. P value is significant if 0.05 or less at confidence interval 95%.
| Results|| |
The study included 96 participants. They were divided into 46 patients and 50 healthy controls. The mean age of OCD patients was 30.76±9.677 years with range of 18–60 years, whereas the mean age of the control group was 28.94±8.336 years. The mean age of onset was 19.2±4 years. Regarding sex distribution, there were 20 male patients with a percentage of 43%. Five and 26 female patients with a percentage of 56.5% compared with 22 male (44%) and 28 female (56%) patients in the control group. No significant differences were found with regard to the sociodemographic comparison of both groups except for the educational level and the family history of illness. Regarding the family history of illness, a significant difference was found between OCD patients and the healthy control group (P=0.049). Regarding the educational level, primary education (P≤0.001) was more reported in OCD patients and secondary (P=0.004) level of education was more reported in controls ([Table 1]).
The mean age in the LO group was older (34.44±10.300) than in the EO group (26.38±6.808 years). This difference was significant at P value of 0.004. No significant differences were found with regard to the sex distribution, family history, residence, educational level, and socioeconomic status in both groups ([Table 2]).
|Table 2 Comparison of sociodemographic data in early-onset and late-onset obsessive–compulsive disorder groups|
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The median duration of illness was 10 years (range 1–44 years). No significant difference was found between the EO and LO groups (P=0.611). According to the Yale–Brown Obsessive–Compulsive Symptoms Checklist Scale (Y-BOCS-C), the total number of obsessions was 44, with the percentage of 95.7% and with a higher number for contamination obsession (n=22), which represented 47.8% of the total obsessions, followed by religious (n=15), somatic (32.6%), aggressive, the sexual and miscellaneous obsessions at a lower percentage. Although the total number of patients with compulsions was 35 (76.1%), the highest number was for cleaning compulsion 22 (45.7%), followed by checking 20 (43.5%), and the least number and percentage were for repeating and miscellaneous compulsions. The total number for mixed type was 33, with a percentage of 71.7%. Regarding the severity of illness, the mean Y-BOCS score was 20.9±5.1 (within moderate severity). No significant differences was found between EO and LO groups with regard to the symptoms profile and severity of illness ([Table 3]). The numbers of patients with somatic, religious aggression, sexual, cleaning, checking, repeating, miscellaneous compulsion, and miscellaneous obsessions were 7 (15.2%), 22 (47.8%), 10 (21.7%), 4 (8.7%), 2 (4.3%), 21 (45.7%), 18 (39.1%), 1 (2.2%), 1 (2.2%), and 2 (4.3%), respectively (data not shown in the table) ([Table 4]).
|Table 4 Serological results in obsessive–compulsive disorder and control groups|
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No significant differences were found in both OCD group and controls with regard to ABGA and antistreptolysin O titer (ASOT) results. Rates of positivity of ASOT were three (6.5%) in the OCD group, whereas none of the controls had positive results. This difference was not significant (P=0.160). Moreover, rates of positivity of ABGA were 26.1% (n=12) in the OCD group compared with 30% (n=15) in the control group. This difference was not significant (P=0.670). With regard to the OD as a rough measure of the concentration of antibasal ganglia, no significant differences were found between the OCD and control groups (P=0.317) as the median value and range were 0.145 (0.089–1.121) in the OCD group and 0.137 (0.088–2.331) in the control group.
As shown in [Table 5], no significant associations were found between ABGA and ASOT positivity and the age of onset of OCD. Rates of ASOT positivity were 4.8% in the EO group compared with 8% in the LO patients. This difference was not significant (P=1). The rates of positivity of ABGA were 28.6% (n=6) in the EO group compared with 24% (n=6) in the LO group. This difference was also not significant (P=0.725). With regard to OD, no significant differences were found in both EO and LO groups (P=0.559). In EO, the median OD value was 0.141 with a range of 0.089–1.121, whereas in the LO, the group median value was 0.149 with a range of 0.099–0.731.
|Table 5 Comparison of serological results in early-onset and late-onset obsessive–compulsive disorder patients|
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No significant associations were found between ABGA positivity and symptoms dimensions, severity, and age of onset of OCD ([Table 6]).
|Table 6 Clinical findings of obsessive–compulsive disorder patients according to the presence of antibasal ganglia autoantibodies and its relation to the age of onset|
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| Discussion|| |
The results of our study showed that no significant difference existed between OCD patients and healthy controls regarding the presence of the ASOT and ABGA. The rates of positivity of ABGA were 26.1% in the OCD group compared with 30% in the control group and only 6.5% of OCD patients had positive ASOT.
The presence of ABGA and ASOT in a small percentage of OCD patients can be explained by the higher rate of old age in the present study sample of patients (the mean age was 30.76±9.677 years) and the long duration passed since the onset of illness (median 10 years), during which the infected individuals may be exposed to variable strains of streptococcus that influence the autoimmune response. Also, it is possible that the produced antibodies may be transient, and so highly present at the onset of illness only.
It is possible that the occurrence of these specific ABGA is rare in control populations, although rates of exposure to streptococci, which are postulated to stimulate antibody production, are relatively common. In our study, it is surprising that the rate of ABGA positivity was higher than expected. These results may be attributed to the difference in the serological methods and parameters that were used for the detection of autoantibodies. The heterogeneous nature of illness reflect that no single etiology is related to it, and so it is expected that multiple factors help in its occurrence; also, genetic background, in conjunction with exposure to streptococcal infection, represents one trajectory for the development of OCD. For these reasons, the negative results of our study could not exclude the role of streptococcal infection in OCD pathogenesis even with a low rate of positivity of both ASOT and ABGA in OCD patients compared with negative ASOT in the control group.
In agreement with our study, the first study that was conducted by (Black et al., 1998) to assess autoimmune markers in adult OCD including neuron-specific, other organ-specific, and non-organ-specific autoantibodies found no humoral evidence of autoimmunity.
No significant associations were found between either ABGA or ASOT positivity and sex, family history of OCD, residence, educational level, and socioeconomic status. This is in agreement with the study that was conducted by (Nicholson et al., 2012).
Regarding symptom profile and severity, no significant associations were found between ABGA or ASOT positivity in terms of symptom dimensions and severity. These findings were consistent with the cross-sectional study by (Nicholson et al., 2012) that was conducted on 96 participants with OCD who were tested for the presence of ASOT and the presence of ABGA compared with those in a control group of individuals with depression and schizophrenia. They showed that no clinical variables were associated with ABGA positivity. Positivity for ASOT was not associated with ABGA positivity.
In the present study, no significant association between ASOT or ABGA positivity and the age of onset of illness were found. This is in agreement with the study that was conducted by (Nicholson et al., 2012).
In contrast to our study, (Morer et al., 2006) showed that only adult OCD patients with childhood onset had higher ASLO titers, whereas no other immune parameters were found to be different. This can explain the role of autoimmunity in children in the pathogenesis of at least some forms of OCD or Tourette’s syndrome. Our results may have explained by the nearly small number of patients with EO and LO OCD. This small number does not provide a significant statistical difference between both groups, and hence a lager sample size is recommended.
In a study by (Dale et al., 2005), an increased incidence of ABGA (42%) was found in 50 children with OCD, particularly in those with comorbid Tourette syndrome or tics, compared with multiple control groups. A smaller study of 32 children found some consistent but nonsignificant findings ((Morer et al., 2008)) and another study found no increase in antibrain antibodies in 13 children with OCD alone or in 23 children with OCD plus chronic tic disorder, but found some evidence for increased incidence in 20 children with both OCD and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection ((Gause et al., 2009)). These different results can explain the role of comorbidity in autoimmune reaction, which was not a point of focus in our study.
The first systematic review and meta-analysis was conducted by (Pearlman et al., 2014) to assess the relationship between ABGA positivity and OCD by pooling data from seven studies that assessed sera and/or cerebrospinal fluid (CSF) samples of 844 participants, which showed that a significantly greater proportion of those with primary OCD were ABGA seropositive compared with various controls. There were no significant differences in ABGA seropositivity for comparisons between primary OCD and Tourette syndrome, attention-deficit hyperactivity disorder, or pediatric acute-onset neuropsychiatric syndrome. Results of one study testing CSF samples showed that a significantly greater proportion of participants with primary OCD were ABGA CSF positive compared with healthy controls (P=0.045).
The discrepancies in the findings with regard to the presence of antibrain antibodies in the sera of patients with OCD are likely because there is no accepted standardized methodology for assessing anti-BG antibodies. Different centers have differed with regard to substrates of brain tissue utilized, ranging from immortalized neuronal cell lines to animal and human brains, as well as their preparation. Also, the use of different sensitivities of techniques such as immunofluorescence, ELISA, and western blotting as well as different dilutions of sera used in determining the presence of antibodies across the studies could also account for the discrepant findings.
The negative results of this study could not exclude the role of autoimmunity as criteria other than the presence of autoantibodies must be fulfilled for diagnosing the disorder as autoimmune: for example, the presence of antibodies in target tissue, induction of disease in animal model by passive transfer of antibody, induction of disease in animal model by autoantigen immunization, and improvement of clinical symptoms after removal of antibodies with plasma exchange. None of these factors applied in our study. In contrast, because streptococcal infections are widespread, it is worth remembering that an association with OCD and/or OC symptoms can also occur by chance. Also, correlating timing and certainty of a streptococcal infection with the onset of OCD symptoms is often difficult. Further exploration of markers other than ASOT, especially if the onset of illness was many years ago, as in our sample, is needed as the assessment of exposure to streptococcal bacteria by single measurements is thought to be highly problematic.
Limitations and strength of the study
Strength of the study
To our knowledge, this is the first study in the Arab World that investigates the possible role of streptococcal infection in OCD pathogenesis, and also clarifies the effect of demographic factors, age of onset, symptoms profile, and severity of illness and their correlation to serological results.
Limitations of the study
This study is limited by the small sample size. Consequently, the participants might not be representative of the general population. Also, the young age group is not represented in this study. This decreases our chance for applying the serological tests on a high number of patients with EO of illness.
Inclusion of a larger sample size will strengthen the statistical significance of the study. Participants of younger age are recommended to be included based on the fact that ASOT is higher in childhood, adolescence, and early adulthood.
Assessment of the patient groups at onset of illness is better for significant immunological findings, as it is possible that the antibodies involved in OCD may be transient and highly present at the onset of the illness only.
Further studies using standardized immunological parameters are needed.
As the assessment of exposure to streptococcal bacteria by single measurements such as ASOT is thought to be highly problematic, especially if the onset of illness was many years ago, the need for explorations of other immunological marker is essential.
Longitudinal follow-up prophylactic antibiotic treatment trials in OCD patients may prove the relationship to streptococcal infection.
| Conclusion|| |
The majority of the OCD patients do not seem to have autoimmunity disturbances or elevations in ASLO titers as compared with a control group. The role of autoimmunity in OCD pathogenesis cannot be excluded, and further investigations are needed to establish this role. Also, if exposure to streptococcal infection is established as a risk factor for the development of OCD in certain susceptible individuals, there may be potential for novel or modified treatments including prophylactic antibiotics and plasmapheresis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]