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Z. Farhood et al. / International Journal of Pediatric Otorhinolaryngology 89 (2016) 149 e 153

postoperatively [3] . Similarly, Heubi & Shott reported a similar experience with two siblings; one with Tourette's syndrome (TS) and one with obsessive-compulsive disorder (OCD) [4] . The child with OCD discontinued sertraline 1 year postoperatively and no longer required follow-up with a psychiatrist. The child with TS was symptom-free 2 months postoperatively and had his clonidine dosage reduced. Murphy, Storch et al. examined a cohort of children with OCD and found that PANDAS cases had a high association of undergoing surgery compared to those with OCD without PANDAS [5] . Of note, they also observed that PANDAS subjects were more likely to have remission of symptoms when receiving antibiotic therapy. In another study, Murphy, Lewin et al. examined a group of 43 PANDAS patients, 20 of whom had tonsillectomy and/or adenoi- dectomy [6] . They found no difference in streptococcal titer levels or symptom severity between the surgical and nonsurgical groups. Moreover, a majority of the patients had symptom onset more than 2 years after surgery and so the authors concluded that surgery does not prevent disease onset. This study corroborates the previ- ous study that those with PANDAS were more likely to have surgery compared to non-PANDAS subjects with OCD. In a prospective study of 120 PANDAS patients, 56 underwent adenotonsillectomy [7] . There were no differences in symptom severity or titer elevation (i.e. antistreptolysin O, anti- deoxyribonuclease B, and antineural antibodies) following surgery compared to the nonsurgical group. Timing of surgery did not affect time to fi rst relapse (mean ¼ 45.1 ± 17.8 days). The authors concluded that PANDAS is not an indication for adenotonsillectomy. Finally, Demesh et al. recently conducted a retrospective review of 10 PANDAS patients who received antibiotic therapy followed by tonsillectomy in 9 patients [8] . The parents of the subjects were also contacted and administered a questionnaire regarding the severity of their child's symptoms. Half of the children responded to anti- biotic treatment per the parents but symptom resolution was not noted. All nine children who underwent tonsillectomy were noted to have symptom improvement with 3 experiencing complete resolution of OCD symptoms. However, the retrospective nature of the study and post-treatment screening limit the conclusions, as the interpreted results are susceptible to recall bias. Three articles were selected involving the use of antibiotic therapy (ABX) [10 e 12] . In a double-blind randomized control trial (DB RCT), 37 patients were given oral penicillin V or placebo fol- lowed by crossover after 4 months [10] . The authors found no dif- ference in infection rate or symptom severity by treatment phase. Sixteen of the children were also on neuropsychiatric medications at various points during the study. One prospective study evaluated antibiotic therapy for acute infections and exacerbations in 12 patients over a 3-year period [11] . Antibiotics (either penicillins or cephalosporins) for treatment of GABHS infection alleviated neuropsychiatric symptoms, although half of the patients experienced a recurrence in symp- toms. Again, when the recurrence was treated with antibiotics there was improvement in symptoms. One DB RCT examined the utility of azithromycin or penicillin prophylaxis in a PANDAS cohort of 23 patients [12] . The patients served as their own controls and decreased rates of infection and neuropsychiatric exacerbations were noted in both groups compared to pretreatment. A limitation of this study was retro- spective collection of medical history. Finally, a case report of 2 patients that received benzathine penicillin showed potential bene fi t of antibiotics [13] . One 9 year 3.2. Antibiotic therapy

old patient who had a favorable response received monthly in- jections. The dosing frequency was tapered over time, and the patient was symptom-free at 16 years of age. Another showed improvement but was eventually lost to follow up after 6 months.

3.3. Intravenous immunoglobulin therapy

Two selected articles described the use of IVIG: one RCT and one retrospective study [14,15] . Perlmutter et al. in a partially DB RCT, examined the ef fi cacy of IVIG or plasma exchange [14] . In- vestigators and participants were blinded if IVIG or placebo was administered, but not plasma exchange. Both treatment groups showed signi fi cant improvement compared to the placebo group at 1 month and 1 year follow up. Adverse events reported included headache, fever, pallor, dizziness, nausea, and vomiting. Later, Kovacevic et al. retrospectively presented 12 patients that received IVIG [15] . Follow up ranged from 4 months to 7 years and patients reported signi fi cant improvement or complete recovery in all instances. Several patients were also on antibiotic prophylaxis. Additionally, seven patients were retreated with a second course of IVIG due to recurrence or no response to initial treatment with a noted improvement in symptoms. One prospective study examined cognitive-behavioral therapy (CBT) in seven patients, with 6 concurrently taking selective sero- tonin reuptake inhibitors (SSRIs) [16] . Subjects underwent 3 weeks of intensive CBT and were evaluated at 4 weeks prior to treatment, before the fi rst session, before the fi nal session, and 3 months after the fi nal session. There was signi fi cant and sustained reduction in symptom severity, however 2 patients experienced complete relapse and one partial relapse. This systematic review examined treatment modalities for a rare pediatric disease occasionally evaluated by an Otolaryngologist. The pathophysiology of this disease is still poorly understood, though it has been likened to Sydenham's chorea given the com- mon link with GABHS. Autoimmune theories propose molecular mimicry in which an acute infection triggers the generation of antineuronal antibodies that cross-react with the basal ganglia [17] . However, such antibodies have not been demonstrated and used to identify patients with PANDAS [18,19] . Other alterations in the immune system are also debatable as one study recently demon- strated distinct differences in cytokine levels among these patients [20] . Another found no differences in B-Cell expression between the tonsils of PANDAS and non-PANDAS patients [21] . In light of these fi ndings, it is still dif fi cult to establish a true immunologic link. Most of the included studies graded symptom severity using a variety of scales, including the Yale Global Tic Severity Scale (YGTSS) and the Yale-Brown Obsessive Compulsive Scale (YBOCS). Some studies used questionnaires that were more arbitrary and asked the parents their overall perception of their child's well- being. Others simply reported whether the child continued to experience symptoms. The YGTSS or YBOCS would be the most appropriate tools to use in symptom evaluation, as they are quite reliable and valid, although they may not be readily familiar to Otolaryngologists [22,23] . The bene fi t of tonsillectomy is uncertain due to con fl icting re- sults. In theory, removing the tonsils would serve to reduce the rate of infection and therefore exacerbation frequency. Overall, 3.4. Cognitive behavioral therapy 4. Discussion

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