Additional PANDAS Studies Including Treatment Trials

Reference	Findings/ Critique
[Prus2022]	Therapeutic plasma exchange in adolescent and adult patients with autoimmune neuropsychiatric disorders associated with streptococcal infections In our cohort, no available test value appeared to predict TPE response (Table 1). Improvement was noted in over half of the patients with available follow-up information and no adverse reactions to TPE were documented. TPE appears to be a safe and potentially efficacious treatment option for symptomatic adolescent and adult PANDAS/PANS patients. Limitations of this study include the retrospective nature and incomplete data availability, including post-treatment ASO and Cunningham Panel results.
[Prasad2021]	Role of tonsillectomy and adenoidectomy in parental satisfaction of treatments for PANDAS Caregivers reported a decreasing frequency of symptoms over time regardless of treatment and had no difference in satisfaction. T&A was the most preferred treatment and the most impactful on symptoms for surgical patients. Given the challenges of immunologic therapies, T&A in combination with antibiotics should be considered as an early intervention for PANDAS.
[Melamed2021]	Evaluation of Intravenous Immunoglobulin in Pediatric Acute-Onset Neuropsychiatric Syndrome The final cohort consisted of 21 subjects (7 per site) with moderate to severe PANS. The mean age was 10.86 years (range: 4–16 years). Results demonstrated statistically significant reductions in symptoms from baseline to end of treatment in all six assessments measured. CY-BOCS results demonstrated statistically significant reductions in obsessive compulsive symptoms (p < 0.0001), resulting in >50% improvement sustained for at least 8 weeks after the final infusion and up to 46 weeks in a subset of subjects.
[Brown2017]	Pediatric Acute-Onset Neuropsychiatric Syndrome Response to Oral Corticosteroid Bursts: An Observational Study of Patients in an Academic Community-Based PANS Clinic Patients experienced shorter flares when treated with oral corticosteroids (6.4 ± 5.0 weeks vs. 11.4 ± 8.6 weeks) than when not treated (p < 0.001), even after controlling for presumed confounding variables, including age at flare, weeks since onset of PANS illness, sex, antibiotic treatment, prophylactic antibiotics, previous immunomodulatory treatment, maintenance anti-inflammatory therapy, psychiatric medications, and cognitive behavioral therapy (p < 0.01). When corticosteroids were given for the initial PANS episode, flares tended to be shorter (10.3 ± 5.7 weeks) than when not treated (16.5 ± 9.6 weeks) (p = 0.06). This difference was statistically significant after controlling for the relevant confounding variables listed earlier (p < 0.01). Earlier use of corticosteroids was associated with shorter flare durations (p < 0.001). Longer courses of corticosteroids were associated with a more enduring impact on the duration of neuropsychiatric symptom improvement (p = 0.014).

[Brown2017]

Effect of Early and Prophylactic Nonsteroidal Anti-Inflammatory Drugs on Flare Duration in Pediatric Acute-Onset Neuropsychiatric Syndrome: An Observational Study of Patients Followed by an Academic Community-Based Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic
NSAID use was associated with a significantly shorter flare duration. Flares not treated with NSAIDs had a mean duration of approximately 12.2 weeks (95% CI: 9.3–15.1). Flares that occurred while the child was on NSAID maintenance therapy were approximately 4 weeks shorter than flares not managed with NSAIDs (95% CI: 1.85–6.24; p < 0.0001). Flares treated with NSAIDs within 30 days of flare onset were approximately 2.6 weeks shorter than flares not managed with NSAIDs (95% CI: 0.43–4.68; p = 0.02). Flares treated prophylactically and those treated early with NSAIDs did not differ in duration (p = 0.26). Among the flares that received NSAID treatment within the first 30 days, earlier intervention was modestly associated with shorter flare durations (i.e., for each day that NSAID treatment was delayed, flare duration increased by 0.18 weeks; 95% CI: 0.03–0.33; p = 0.02), though it was not statistically significant after controlling for covariates (p = 0.06).

[Spartz2017]

Course of Neuropsychiatric Symptoms After Introduction and Removal of Nonsteroidal Anti-Inflammatory Drugs: A Pediatric Observational Study
Seventy-seven patients were included in the current study. Of the 52 trials in which NSAID addition was the sole change in treatment, 16 (31%) coincided with an improvement in patients’ neuropsychiatric symptoms. Of the 57 trials in which removal of NSAID treatment was the sole change in treatment, 20 (35%) coincided with escalation in patients’ neuropsychiatric symptoms. Thirty patients (39%) experienced side effects, mainly mild gastrointestinal symptoms, which self-resolved after removal of NSAID, reduction of dose, or change in NSAID.

[Murphy2017]

A Double-Blind Randomized Placebo-Controlled Pilot Study of Azithromycin in Youth with Acute-Onset Obsessive-Compulsive Disorder
Participants in the azithromycin group (n = 17) showed significantly greater reductions in OCD severity on the CGI-S OCD than the placebo group (n = 14) posttreatment (p = 0.003), although there were no significant differences on the CY-BOCS. Significantly more participants in the azithromycin condition met treatment responder criteria on the CGI-I OCD at the end of week 4 (41.2%, n = 7) in comparison to the placebo group (7.1%, n = 1; p = 0.045). Tic severity moderated treatment response, with greater tic severity being associated with enhanced treatment response on the CGI-S OCD. Azithromycin was well tolerated with minimal adverse effects and no study dropouts due to side effects. However, the azithromycin group showed a trend toward significantly greater electrocardiography QTc (p = 0.060) at the end of week 4, and significantly more reports of loose or abnormal stools (p = 0.009).

[Mahony2017]

Improvement of psychiatric symptoms in youth following resolution of sinusitis
10/150 (6.6%) patients had isolated sinusitis at the time of their neuropsychiatric deterioration. Eight patients received antibiotics to treat sinusitis, three of whom also received sinus surgery. Neuropsychiatric symptoms improved in all eight patients concurrent with resolution of sinusitis per parent report and clinician assessment. One patient did not follow through with recommended sinus surgery or antibiotics and her psychiatric symptoms persisted. One patient was lost to follow-up.


[Wong2016]	Impact of Immunoglobulin Therapy in Pediatric Disease: a Review of Immune Mechanisms Wong, P.H. & White, K.M. Clinic Rev Allerg Immunol (2016) 51: 303. doi:10.1007/s12016-015-8499-2


[Kovacevic2015]	Kovacevic M, Grant P, Swedo SE. Use of Intravenous Immunoglobulin in the Treatment of Twelve Youths with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):65-69. doi:10.1089/cap.2014.0067.


[Demesh2015]	Demesh D, Virbalas JM, Bent JP. The Role of Tonsillectomy in the Treatment of Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS). JAMA Otolaryngol Head Neck Surg. 2015;141(3):272-275. doi:10.1001/jamaoto.2014.3407


[Latimer2015]	Latimer ME, L’Etoile N, Seidlitz J, Swedo SE. Therapeutic Plasma Apheresis as a Treatment for 35 Severely Ill Children and Adolescents with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):70-75. doi:10.1089/cap.2014.0080.


[Nadeau2015]	A Pilot Trial of Cognitive-Behavioral Therapy Augmentation of Antibiotic Treatment in Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome-Related Obsessive-Compulsive Disorder.

[Hachiya2013]

Autoimmune neurological disorders associated with group-A beta-hemolytic streptococcal infectionFindings: (N=3) This report describes three case studies of patients meeting the diagnostic criteria for ADEM, PANDAS and subacute encephalitis associated with GABHS. All three cases showed psychiatric behavioral disorders and elevated homovanillic acid levels in the cerebrospinal fluid. Immunotherapy treatment was effective in all three cases. Authors recommend immunohistochemistry as a sensitive screening method for the detection of anti-neuronal autoantibodies in CNS disorders associated with GABHS infection.
Critique: small sample size

[Murphy2011]

Maternal history of autoimmune disease in children presenting with tics and/or obsessive-compulsive disorderFindings: (N=107) Mothers of children with OCD and/or tic disorders are more than 3x more likely to have reported autoimmune disorder (17.8% vs 5% in US). Mothers of children considered “likely PANDAS” were 5x more likely to report autoimmune disorder (25% vs 5% in US).
Critique: It is unclear what the autoimmune rate would be for mothers of children who do not have tic and/or OCD. The self-reporting of immune disease may also over-report as parents may have significant knowledge of autoimmune presumption in PANDAS.

[Lewin2011]

Neurocognitive functioning in youth with pediatric autoimmune neuropsychiatric disorders associated with streptococcus.Findings: (N=26, 18 boys) Marked performance issues on neurocognitive/executive ability, visuospatial memory and fine motor speed tests were observed despite having average to above average academic performance and other neurocognitive measures. Increased titers to GABHS antibodies were correlated with increased OCD symptoms but not correlated to test performance issues.
Critique: study lacked control for non-PANDAS OCD

[Hirschtritt2009]

Executive and Attention Functioning Among Children in the Pandas SubgroupFindings: (N=67, C=98) Study found that children with PANDAS subtype exhibit neuropsychological profiles similar to the primary psychiatric diagnosis (e.g., subjects with TS or OCD with tics exhibited a delayed response time compared to controls or subjects with OCD-only symptoms). While many of the medicated subjects were taking neuroleptics, medication did not appear to impact neuropsychological tests such as WCST.
Critique: Some tests lacked sufficient power due to unavailability of subjects.

[Gabbay2008]

Pediatric autoimmune neuropsychiatric disorders associated with streptococcus: comparison of diagnosis and treatment in the community and at a specialty clinic.Findings: (N=31, C=176) This retrospective study at a Tourette and Tic Disorder specialty clinic evaluated the diagnostic agreement between referred patients who were externally diagnosed with PANDAS (by community doctors) and patients diagnosed internally (by the specialty clinic). The paper concludes that referred patients are more than twice as likely to be misdiagnosed as PANDAS by non-specialists. The authors raise concern that PANDAS may be over-diagnosed and over-treated in the community.
Critique:There are multiple issues with this retrospective. 1)the authors are assuming their internal evaluation is correct creating exposure to type II errors. 2) the authors have incorrectly linked a complaint on the thoroughness of a PANDAS diagnosis workup to a statement that treatment of an active GABHS infection is unwarranted. An active GABHS infection requires treatment. 3) There is selection bias in that the cases studied are ones referred to a tic/tourettes specialty clinic and therefore are likely not representative of sudden onset OCD. 4) The sample size is extraordinarily small for the broad statements/conclusions.

[Storch2006]

Cognitive-behavioral therapy for PANDAS-related obsessive-compulsive disorder: findings from a waitlist controlled open trial.Findings: (N=7) Subjects fitting the PANDAS subtype were enrolled in a 3-week intensive CBT program. Six of seven participants showed much or very much improved at posttreatment and three of seven remained improved at 3 months.
Critique:Six of seven participants were taking SSRI’s clouding the issue of whether CBT alone was helping. Antibiotics usage during the trial was not monitored.

[Snider2004]

Echocardiographic findings in the PANDAS subgroupFindings: (N=60) In acute rheumatic fever, there is often mitral valve involvement with or without the Sydenham Chorea. Author sought to understand whether this finding existed in the PANDAS subtype. The result was that there was no echocardial involvement in the subjects selected. One patient was found to have minor mitral regurgitation. Lack of evidence of mitral valve involvement indicates that PANDAS subtype is distinct from SC/ARF.
Critique: sample remains small and unclear if OCD symptoms of SC are the same as mitral valve involvement in non-SC ARF.

[Giedd2000]

MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infectionFindings: (N=34, C=82) Authors assessed basal ganglia involvement in children who exhibited OCD and/or tic disorders believed associated with GABHS infection. Average sizes of the cudate, puramen and globuspallidus were greater in the group of children with GABHS associated OCD/tics. Differences were similar to those found in SC versus healthy children. MRI is not, however, diagnostic for PANDAS as only the weighted average size could be compared.
Critique: It was unclear how the association with streptococcal infection or the episodic course of PANDAS was determined.

[Perlmutter1999]

Therapeutic Plasma Exchange and Intravenous Immunoglobulin for Obsessive-Compulsive Disorder and Tic Disorders in ChildhoodFindings: (N=19, C=10). From an initial screening of 200, 29 children were selected who exhibited abrupt onset tic and/or OCD symptoms consistent with PANDAS diagnosis. 10 received plasma exchange, 9 receive IVIG, and 10 placebo IVIG. Both Plasma Exchange and IVIG were markedly better than placebo on both short term (1 m) and long term (1 yr) followup.
Critique: Startling paper. It is, however, unclear how effective the blinding was given the side effects of IVIG.

[Allen1995]

Case Study: A New Infection-Triggered, Autoimmune Subtype of Pediatric OCD and Tourette’s SyndromeFindings: (N=4) Four boys, one with OCD, two with Tourette’s syndrome, and one with OCD and Tourette’s syndrome were treated with immunotherapy. Two had evidence of a recent GABHS infection and the others had evidence of recent viral infection. Two were treated with plasmapheresis, one with IVIG, and one with immunosuppressive doses of prednisone. All had clinically significant response immediately after treatment. Authors define a new acronym PITAND to describe this subtype of responsive OCD/TS.
Critique: There was no control for the significant placebo effect.