Antibiotic Treatment Trial for the PANDAS/PANS Phenotype

Accumulating evidence suggests that a subset of children with obsessive compulsive disorder (OCD) have a symptom course that is temporally associated with infections (group A Streptococcus, Mycoplasma, Borrelia burgordfi, etc.). The intent of this proposal is to test the hypotheses that: 1) this subset of children with OCD known as Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) and the specific subset associated with Streptococcus, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus), experience symptom onset and exacerbations due to autoimmune/inflammatory responses to infectious triggers and, 2) antibiotic treatment will reduce symptom severity. Investigators have reported improvement in neuropsychiatric symptoms of patients presenting with PANDAS following antibiotic treatment (Murphy & Pichichero, 2002; Snider, Lougee, Slattery et al., 2005). Difficulties with study design and small sample size of early antibiotic trials limit the influence of their findings (Kurlan & Kaplan, 2004) although anecdotally, many families report often dramatic improvements in OCD symptoms after antibiotic therapy.

The proposed study is a 4 week double-blind placebo-controlled study of the efficacy of azithromycin once daily on OCD symptom severity in children ages 4-14 years presenting with the PANS phenotype. An 8 week open label phase will be offered to all subjects completing the 1-month trial to assess longer term efficacy and tolerability (12 weeks total antibiotics for those on active, 8 weeks for those on placebo). At the end of week 8, the child can transition to best clinical care practice (cognitive behavioral therapy, additional medication trials, etc) if not fully remitted. The rate and timing of any relapse will be assessed but are not the primary outcome variables. Evaluations will consist of: 1) semi-structured psychiatric diagnostic interviews and rating scales to establish psychiatric diagnoses and monitor severity of psychiatric symptoms, particularly obsessive compulsive behavior and tics; 2) parent and child-report questionnaires to elicit information regarding infections and clinical correlates of PANS attributes; 3) physical and neurological examinations; and 4) laboratory studies.

Aim 1: To compare, in randomized controlled fashion, placebo vs. antibiotic on changes in overall symptom severity for obsessive-compulsive symptoms among children with PANS phenotype. Changes from baseline and clinical status at end of study will be compared for the study arms. Primary endpoint will be change on the Children's Yale Brown Obsessive Compulsive scale (CY-BOCS). Secondary measures of interest include severity and improvement measures on the Clinical Global Impression Severity/Improvement scale, quality of life measures, and weekly ratings of mood, anxiety, attention deficit hyperactivity and tic symptoms. Hypothesis: Children receiving antibiotic will show significantly greater overall improvement in severity compared with placebo. Children that meet PANDAS/PANS criteria and have current OCD symptoms of less than 6 months duration will be enrolled in a double-blind placebo-controlled randomized trial of azithromycin for 4 weeks. Subjects will be followed weekly during the 3 months (4-week antibiotic treatment trial, 8 weeks open label treatment). Although earlier trials have had mixed results, these studies have primarily enrolled subjects with longer illness durations and used traditional prophylactic doses in contrast to the standard treatment dose of this study. Since treatment doses of antibiotic decrease antigenic load, one can speculate that treatment level doses, rather than prophylactic doses, may best attenuate neuropsychiatric sequelae. Secondary neuromodulating or immune modulating properties at higher dose of antibiotics may also be a possible mode of therapeutic action. The timing of treatment response and moderators and predictors of response will also be assessed.

Aim 2: To assess immune risk factors in children with PANDAS/PANS. The data and biological specimens (blood, cultures, etc) for all subjects consented for Aim 1 will, be entered into a database and repository to assess further these clinical phenotypes. Subjects that do not qualify for randomization (medication allergy or current long term antibiotic therapy) or decline randomization (e.g. travel required for future visits) will be permitted to contribute to Aim 2, i.e. collection of baseline symptom severity and immune marker assessment. Hypothesis: It is hypothesized that children with sudden onset of OCD and whose subsequent course shows dramatic fluctuations will have evidence of immune risk factors that predisposes to this presentation. Certain subject characteristics such as age, duration of illness, characteristics of exacerbation episodes, type and number of prior infections, and co-occurring disorders may influence treatment response. Immunologic markers that may help with determining pathobiology and treatment response will be explored including pathogen detection array to identify potential infectious triggers, cytokine array to explore inflammatory processes and specific antibody assay to assess potential mediators. In order to differentiate those children that may most benefit from antibiotic prophylaxis from those that do not benefit, analytic strategies to refine an antibiotic-responsive phenotype will be explored.

Rationale: Based on the PI's observations from research and clinical patients being referred for PANDAS (60 patients per year), patients have had most improvement when higher doses of antibiotics are used, often relapsing on prophylactic doses. The best response rates have been antibiotics designed to treat beta lactamase co-pathogens such as azithromycin, cephalosporins or amoxicillin/clavulanic acid. Observed response rates are typically within 3 weeks although some subjects appear to take longer to gain response. These observations deserve further study. Azithromycin was chosen due to improved tolerance, once daily dosing regimen, coverage against other microbes implicated in PANS and low risk for allergic reaction or exclusion.