Immunotherapy for Infection-Triggered TS and OCD in Children
abstract & commentary
Source: Perlmutter SJ, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorder in childhood. Lancet 1999;354: 1153-1158.
Tourette syndrome (ts) and the closely related condition, obsessive compulsive disorder (OCD), are highly prevalent neuropsychiatric disorders of childhood. A proportion of children with tics disorders (including TS) and OCD appear to have onset or marked exacerbation of their symptoms following various infections, in particular infections with group A b-hemolytic streptococci (GABHS).
During the past decade, Swedo and colleagues at the National Institutes of Mental Health have developed the concept of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) to cases of tics and OCD in which a post-streptococcal trigger is apparent (Swedo SE, et al. Am J Psychiatry 1998;155:264-271). Children with PANDAS share clinical features and immunological abnormalities with patients with Sydenham chorea, a cardinal component of GABHS-triggered rheumatic fever. Sydenham chorea has long been believed to involve molecular mimicry of GABHS antigens, resulting in production of serum and cerebrospinal fluids to brain-reactive antigens. Thus, it was reasonable to suppose that patients with PANDAS might be effectively treated by immunotherapy.
Perlmutter and colleagues have now tested this hypothesis by examining the response of patients with severe, infection-triggered tics to two forms of potent immunotherapy. Perlmutter et al randomized 29 children (aged 5-14) in a partially double-blinded fashion to three treatment arms: intravenous immunoglobulin (IVIG), IVIG placebo (saline infusion), and plasmapheresis. There was no placebo control for plasmapheresis therapy in this study, and it was therefore not possible to blind this group. Patients were then studied with a battery of neuropsychiatric tests performed pretreatment, at one month following treatment, or one year following treatment.
The severity of obsessive-compulsive symptoms was gauged by the children’s Yale-Brown Obsessive Compulsive Scale (YBOCS). At one month, YBOCS scores improved 45% in the IVIG group (n = 9), but only 3% in the saline placebo group (n = 10). Patients with plasmapheresis (n = 10) had an even more robust response, with a 58% reduction in YBOCS scores. Of the 19 treated patients, 17 were available for follow-up at one year; interestingly, YBOCS scores remained 58% below baseline with IVIG treatment and 70% below baseline with plasmapheresis treatment. Of note, 14 of 17 patients available at one-year follow-up had received only a single course of treatment one year prior.
Tic scores were also improved: reduced 19%, 49%, and 12% for IVIG, plasmapheresis, and saline placebo groups at one month. Reduction in tic scores was sustained at one year, at 15% for IVIG, and 53% for plasmapheresis. There appeared to be a much higher efficacy of plasmapheresis, as compared to IVIG in treating postinfectious tics; the efficacy of both treatments appears comparable in treating obsessive-compulsive symptoms.
Importantly, many other psychometric variables, such as measures of anxiety, depression, and emotional lability, markedly improved in these patients, and the improvement was sustained at one-year follow-up.
Comment by Rosario Trifiletti, MD
This is a landmark paper in psychoneuroimmunology, just as important for its "proof of concept" as its therapeutic implications. This paper could be severely criticized for its small sample size (only 19 treated patients) but one should consider that this group recruited patients nationwide for four years. The finding of strong statistical significance of benefit of IVIG and plasmapheresis as compared to placebo, despite the small sample size, implies the effects of therapy are large. Clearly, this study focused only on severe cases, several of whom had failed conventional therapies; this makes the strongly beneficial effects of IVIG or plasmapheresis even more dramatic.
Another important and commonly used immuno-modulatory therapy, corticosteroids, was not considered in this study. Perlmutter et al state that "tics and OCD may worsen during steroid administration," but this point has not been clearly demonstrated in a large controlled study. Indeed, there have been several case reports of marked and rapid efficacy of corticosteroids (Kondo K, et al. Ann Neurol 1978;4:387; Allen AJ, et al. J Am Acad Child Adolesc Psychiatry 1995;34:307-311). The possible efficacy of corticosteroid therapy, which may be much less costly than IVIG or plasmapheresis, should probably be more carefully studied before this option is rejected.
What "toxic antibodies" or other immune abnormalities might be modified by these therapies? As is the case with several neurological diseases that seem to respond to IVIG or plasmapheresis therapy (a notable exception being myasthenia gravis), we do not yet know. However, it is known that patients with TS do have serum antibodies that cross react with specific brain proteins (Singer HS, et al. Neurology 1998;50: 1618-1624). Our laboratory has discovered a specific brain protein of 83kd apparent molecular weight (ts83) that is enriched in the globus pallidus. It is recognized by the serum of 80-90% of patients with TS or OCD, but only 10-20% of controls (Trifiletti R, et al. Ann Neurol 1998;44:561); furthermore, levels of anti-ts83 antibodies are reduced by IVIG or corticosteroid therapy (Trifiletti R, et al. Ann Neurol 1998;44:561). Perlmutter et al did not report levels of antibrain antibodies or other potential immunological markers, such as D8/17 (Murphy TK, et al. Am J Psychiatry 1997;154:402-407) in their patients. Clearly, Perlmutter et al’s study greatly increases the interest in possible autoimmune basis for some cases of TS or OCD, and characterization of potential target antigens is a worthwhile research goal.
Although the findings of the Perlmutter et al study are restricted to infection-triggered tics or OCD, there is reason to believe that these therapies might be efficacious in cases where an infectious trigger is not apparent. For example, both infectious triggered and idiopathic patients share similar immunological abnormalities (Murphy TK, et al. Am J Psychiatry 1997;154:402-407; Trifiletti R, et al. Ann Neurol 1998;44:561). Perlmutter et al state that they plan to broaden their studies to examine idiopathic cases, so this mode of therapy may apply to a much broader spectrum of children. Also, this therapy might not also be beneficial to adults with severe tic disorders or OCD.
Clearly, most patients that neurologists or psychiatrists encounter with these disorders could be adequately controlled with currently available medications (clonidine or neuroleptics for tics; cognitive-behavioral psychotherapy and selective serotonin release in-hibitors for OCD). However, there are many young patients with severe, debilitating, and drug-refractory tics and OCD for which immunotherapy may prove to be an important new therapeutic option. (Dr. Trifiletti is Assistant Professor of Neurology & Pediatrics, Department of Neurology, Weill Medical College of Cornell University, New York City.)
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