Obsessive Compulsive Disorders and The Immune System
According to the model that is emerging from research literature, prolonged "immunologic stress" may be a risk factor for OCD. That is, immunologic stress may compromise the blood-brain barrier (BBB) and permit the influx of antineuronal antibodies into the central nervous system (CNS). Additionally, in PANDIS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) antibodies cross-react with basal ganglia neurons following streptococcus infection. This autoimmune reaction disrupts a basal ganglia-thalamocortical circuit and generates obsessive- compulsive symptoms. Thus, even viral infections might trigger the autoimmune process leading to OCD.
- Analysis of 50 cases established that compulsive symptoms and/or tics appeared relatively abruptly following streptococcal illness. In addition, a number of case studies report significant therapeutic response following immunomodulatory therapy in treatment-resistance pediatric OCD.
- The relationship between OCD and Sydenham's chorea is strengthened by clinical observations showing that more that 80% of children with this condition show obsessions and compulsions both before, and concomitantly with, choric movements.
- Compared with adults, children with OCD are more likely to be male and to have comorbid Tourette's syndrome.
- The prevalence of PANDAS is unknown. There is one report on the prevalence of streptococcal-induced exacerbations in a group of children presenting with tics, 11 % of whom had a history of exacerbations within 6 weeks of a streptococcal infection.
- Interpreted as indices of disturbances at the level of interaction between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis.
- Patients with rheumatic fever show a high level of antineural antibodies against the caudate (Husby et al 1997) and a particular antigen in B lymphocytes reacting with a monoclonal antibody called D8/D17 (Zabriskie 1986;Gibofsky et al 1991). Such an antigen has been shown to be stable in different populations and over time and, more interestingly, it is also present in patients with childhood OCD, Tourette syndrome, and chronic tic disorder (Murphy et al 1997); preliminary data are available also in subjects with autism (Hollander et al 1998).
- Various reports have indicated the presence of immune system alterations in adult OCD patients (Maes et al 1994; Weizman et al 2996; Brambilla et al 1997; Khanna et al 1997) including increased cortisol production.
- The number of relapses of multiple sclerosis during the stress period was significantly lower than expected, suggesting that not all stress conditions invariably increase the risk of exacerbations of autoimmune diseases.
- Tourette's syndrome compared with controls, and in both of these studies significantly elevated titers were observed in the subjects with Tourette's syndrome. Antistreptococcal antibody levels were found to correlate with severity of symptoms in one report.
Allergic Syndromes in OCD, Anxiety Disorders, and Dysthymia
- Clinical features of IgA-D include recurrent sinopulmonary infections (e.g., recurrent bronchitis, sinusitis, and acute pneumonia); allergic diseases (e.g., asthma); gastrointestinal tract disease (e.g., celiac disease, ulcerative colitis, regional enteritis); and autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosis (SLE), and hemolytic anemia).
- Although many IgA-deficient individuals are asymptomatic, at least 50 percent present with a history of recurrent respiratory tract infections, acute diarrheal illness, or bronchitis.
- Symptoms typically emerge during the first decade of life and there is an elevated incidence of allergic diseases including asthma, eczema, and allergic rhinitis (often treatment-resistant). Recurrent sinopulmonary infection is the most frequent clinical manifestation of IgA-D. Selective IgA-D patients demonstrate a marked decrease or absence of serum IgA. The lack of IgA in mucosal secretions renders the patient susceptible to respiratory and gastrointestinal tract disease.
- Pediatric OCD and Tourette's syndrome (TS) patients exhibit a high incidence of recurrent infections, asthma, allergy, and gastrointestinal tract disease. Based on this clinical observation, they screened OCD/TS patients for immunodeficiency disorders and found that approximately 10 percent of OCD/TS subjects demonstrated selective immunoglobin A deficiency (IgA-D). The incidence of IgA-D in the general population is approximately 1 in 600.
Specific Immune Alterations
- The following empirical findings have been reported: significantly elevated antineuronal antibodies in children with PANDAS and related neuropsychiatric disorders increased basal ganglia volumes on volumetric MRI in subjects with PANDAS and higher antistreptococcal antibodies that correlated with increased basal ganglia volumes in subjects with either attention deficit hyperactivity disorder or OCD.
- A monoclonal antibody called D8/D17 characterizing a B-lymphocyte antigen, present in almost all patients with rheumatic fever, has been found in children affected by OCD, Tourette syndrome, and chronic tics to a greater degree than in healthy control subjects. D8/17 antibodies may represent a marker of susceptibility to PANDAS.
- Results showed that OCD patients had increased CD8 T-suppressor cells, as compared with health control subjects, both in terms of percent values (mean + SD,33+6 vs. 27 + 4; p = .002) and absolute number (mean +SD,789 + 186 vs. 403 + 114; p = .001), and decreased CD4 T cells (mean + SD, percent values, 43 + 8 vs. 49 + 1; p =.003), while the CD3, CD19, and CD56 lymphocyte subpopulations were unchanged. CD8 lymphocyte increase has been reported in association specifically, with psychologically frustrating situations. (Knapp et al 1992; Hoffman-Goetz and Pedersen 1994). It may be that the obsessive ideation and compulsive behavior represent the substrate of frustration provoked by the efforts made to cope with and to resist them (Brosschot et al 1992).
- The findings of increased CD8 and decreased CD4 cells seem to be peculiar to OCD, since they are at variance with what is reported in depression.
- Different signs of immune activation have been reported, in particular, leukocytes, an increased number of CD4, CD7/CD25, HLA-DR cells, and an increased CD4/CD8 ratio, while the number of CD8 lymphocytes appears to have decreased (Irwin et al 1990; Muller et al 1993; Maes et al 1996).
- In other studies the CD8 lymphocytes were significantly increased in OCD patients. Patients with adult OCD showed increase CD8 (i.e., suppressor T lymphocytes) as compared with a similar group of healthy control subjects - peculiar to patients with OCD and suggestive of an immunologic imbalance. (May be artifact of the stress deriving from the frustrating situation determined by the disorder itself.)
- Decreased CD4 cells have been observed also in patients with autism (Warren et al 1986).
- The role of immune factors in OCD is also supported by the report of increased CSF levels of immunoglobulin G antibodies against herpes virus of type 1, suggestive of a chronic infection.
- Immunologic alterations appear to be different in children and adult patients and probably reflect different pathophysiology mechanisms, such as autoimmune and possibly, primary processes in the first case, and perhaps, secondary alternations in adulthood.
- An association between OCD and an increased incidence of disorders associated with immunodeficiency leaves open the direction of causality. Immunopathology and OCD may stem from a shared biological vulnerability. It is also possible that the stress associated with OCD impairs immune function.
- Initial investigations in children with a history suggestive of streptococcal infection or a strong family history of rheumatic fever, or both, should include throat cultures and antistreptolysin O titers. These titers should be repeated after an interval of approximately 3-4 weeks, because a correlation of symptom severity with changes in antibody levels is far more informative than an isolated antistreptolysin O titer We recommend antistreptolysin O titer, because the other antistreptococcal test reported in the PANDAS literature, namely, antideoxyribonuclease-B (antiDNAse B), is expensive and not widely available in Canada. The D8/17 marker is an experimental assay that is not available for routine clinical use.
- If post-infectious, immune-mediated disruption of a basal-ganglia thalamocortical circuit contributes to the generation of OCD, then the development of immunomodulatory interventions may offer treatment alternatives for OCD patients, particularly those who fail to respond to traditional therapeutic modalities.
- Both plasma exchange and intravenous immunoglobulin were associated with striking improvements on standardized scales that measure obsessive-compulsive symptoms, anxiety and overall functioning.
- Plasma exchange and intravenous immunoglobulin are highly invasive, require admission to hospital and have not been directly compared with more traditional therapies such as serotonergic medications and cognitive behavioral therapy.
- The US National Institute of Mental Health to issue a warning to parents and clinicians that plasma exchange and intravenous immunoglobulin are not to be used outside research protocols.
Fig. 1: Assessment and treatment of children presenting with abrupt-onset obsessive-compulsive disorder (OCD) or tic disorders.