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Published on January 12, 2009

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PANDAS : PANDAS Lee Hampton Yale Pediatric Residency February 25, 2008 PANDAS : PANDAS Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections Specifically Group A Streptococcus Proposed in 1998 Analogous to behavior and movement changes seen with Sydenham’s Chorea in Acute Rheumatic Fever PANDAS Criteria : PANDAS Criteria Tic disorder or Obsessive Compulsive Disorder meeting DSM criteria Symptoms first evident between 3 years of age and the beginning of puberty Episodic course of symptom severity Explosive onset of symptoms with significant improvement and occasional resolution between episodes Swedo SE, Leonard HL, Garvey M, et al. PANDAS: Clinical Description of the First 50 Cases. American Journal of Psychiatry 1998; 155: 264-271. PANDAS Criteria : PANDAS Criteria Association with Group A Beta-hemolytic streptococcus (GAS) infection 6-9 month delay between 1st infection and 1st PANDAS symptoms possible Recurrences may have shorter time lag, e.g. days to weeks Infection ideally confirmed with throat culture or elevated anti-GAS antibody titers Anti-GAS titers should ideally be followed for peaks and declines with time Need at least 2 exacerbations after GAS infection to qualify Swedo SE, Leonard HL, Garvey M, et al. PANDAS: Clinical Description of the First 50 Cases. American Journal of Psychiatry 1998; 155: 264-271. PANDAS Criteria : PANDAS Criteria Association with neurological abnormalities Motor hyperactivity, tics, and choreiform movements are common Chorea indicates ARF Swedo SE, Leonard HL, Garvey M, et al. PANDAS: Clinical Description of the First 50 Cases. American Journal of Psychiatry 1998; 155: 264-271. Overview : Overview Criteria Controversies Epidemiological Evidence Neurological and Autoimmune Possible Etiologies Prophylaxis and Treatment Psychiatric Diagnostic Criteria : Psychiatric Diagnostic Criteria OCD and tics may not be the only psychiatric diagnoses linked to PANDAS Late onset ADHD, separation anxiety disorder have also been proposed Original paper also discusses subclinical OCD Murphy ML, Pichichero ME. Prospective Identification and Treatment of Children with PANDAS. Archives of Pediatric and Adolescent Medicine 2002; 156: 356-361. Age of Onset Criteria : Age of Onset Criteria 1-3% of children have OCD 10-25% of school age children have tics 75% of Tourette’s patients have onset before 11 years of age Increases likelihood that an association between GAS sx and psych sx is a coincidence Excludes cases of sudden onset OCD after pharyngitis in older patients Kurlan R, Kaplan EL. PANDAS Etiology for Tics and OC Sx: Hypothesis or Entity? Practical Considerations for the Clinician. Pediatrics 2004; 113: 883-886. Abrupt Exacerbation Criteria : Abrupt Exacerbation Criteria Since tics are either present or not, onset will always seem abrupt Patients with tics often seem to have sudden, explosive worsening of tics even without meeting PANDAS criteria Kurlan R, Kaplan EL. PANDAS Etiology for Tics and OC Sx: Hypothesis or Entity? Practical Considerations for the Clinician. Pediatrics 2004; 113: 883-886. GAS Infection Criteria : GAS Infection Criteria Neurological symptom exacerbation could be due to stress from infections in general, not just GAS Longitudinal history of GAS infection and OCD or tic sx can be difficult to establish Family reports subject to recall bias King RA. PANDAS: To Treat or Not to Treat. In: 179-183 GAS Infection Criteria : GAS Infection Criteria GAS infections relatively common among PANDAS age group GAS colonization also fairly common, ca. 10% Sx of pharyngitis not needed to meet criteria of GAS infection, just culture or serologies Many past claims of GAS causation of autoimmune diseases have not panned out E.g. Kawasaki’s and Henoch-Schonlein Purpura Kurlan R, Kaplan EL. PANDAS Etiology for Tics and OC Sx: Hypothesis or Entity? Practical Considerations for the Clinician. Pediatrics 2004; 113: 883-886. Neurological Sx Criteria : Neurological Sx Criteria Choreiform may be difficult to identify, may mask mild chorea Swedo SE, Leonard HL, Rapoport JL. The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Subgroup: Separating Fact from Fiction. Pediatrics 2004; 113: 907-911. Overview : Overview Criteria Controversies Epidemiological Evidence Neurological and Autoimmune Possible Etiologies Prophylaxis and Treatment PANDAS Original Case Series : PANDAS Original Case Series Most studies are case series Initial 1998 paper typical 50 patients referred by local support groups, esp. Tourette’s Syndrome Association 28 patients met DSM IV OCD criteria, 40 patients with tics OCD average age of onset – 7.4 yrs Tic average age of onset – 6.3 years Many patients with comorbid disorders, e.g. ADHD (20), ODD (20), or MDD (18) At least one GAS infection <= 6 wks prior to a symptomatic episode Swedo SE, Leonard HL, Garvey M, et al. PANDAS: Clinical Description of the First 50 Cases. American Journal of Psychiatry 1998; 155: 264-271. PANDAS Case Control Study : PANDAS Case Control Study Seattle HMO records Children 4 to 13 years old Case: 1st diagnosis of OCD, TS, or tic disorder between Jan. 1992 and Dec. 1999 Controls matched by birth date, gender, primary physician, and tendency to seek health care Case and control prior GAS and GBS infections were confirmed by throat culture Mell LK, Davis RL, Owens D. Association Between Streptococcal Infection and OCD, TS, and Tic Disorder. Pediatrics 2005; 116: 56-60. PANDAS Case Control Study : PANDAS Case Control Study 144 cases analyzed (75,000 children in HMO) 37 other cases rejected because no matched controls 112 possible cases rejected because no specific diagnosis recorded although given relevant ICD-9 code 71% of patients were male 81% of patients were <10 years old Mell LK, Davis RL, Owens D. Association Between Streptococcal Infection and OCD, TS, and Tic Disorder. Pediatrics 2005; 116: 56-60. PANDA Case Control Study : PANDA Case Control Study Mell LK, Davis RL, Owens D. Association Between Streptococcal Infection and OCD, TS, and Tic Disorder. Pediatrics 2005; 116: 56-60. PANDAS Longitudinal Study : PANDAS Longitudinal Study 47 children aged 7-17 years old with tic disorder, OCD or both. Average age 11.7 years old Followed on average for 12.7 months 19 children used as controls Participants assessed monthly by staff and then by family Most patients had clinical assessment, throat and blood cultures samples taken every 4 months and during symptomatic exacerbations Luo F, et al. Prospective Longitudinal Study of Children with Tic Disorders and/or OCD: Pediatrics 2004; 113: e578-e585. PANDAS Longitudinal Study : PANDAS Longitudinal Study 8 patients met criteria for probable PANDAS at baseline 16 patients had 23 acute exacerbations of OCD or TS symptoms No significant difference in rates of new GAS infections between cases and controls No power calculations Temporal association between infection and symptom exacerbation no better than chance Luo F, et al. Prospective Longitudinal Study of Children with Tic Disorders and/or OCD: Pediatrics 2004; 113: e578-e585. GAS Exposure and PANDAS : GAS Exposure and PANDAS 814 patient cohort followed for 12 weeks No history of PANDAS. Community peds practice GAS Exposure and PANDAS : GAS Exposure and PANDAS Treated GAS infection did not increase risk of developing PANDAS sx or mild PANDAS variant compared to viral or no infection Ill children did have more PANDAS symptoms than well children at baseline, but there was no difference between GAS and viral infection Underpowered for standard PANDAS Earlier study in same practice found 12 PANDAS in 4000 patients Perrin EM et al. Does Group A Beta-Hemolytic Streptococcal Infection Increase Risk for Behavioral and Neuropsychiatric Symptoms in Children? Archives of Pediatric and Adolescent Medicine 2004; 158: 848-856. Overview : Overview Criteria Controversies Epidemiological Evidence Neurological and Autoimmune Possible Etiologies Prophylaxis and Treatment PANDAS Pathogenesis : PANDAS Pathogenesis Swedo SE, Leonard HL, Rapoport JL. The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Subgroup: Separating Fact from Fiction. Pediatrics 2004; 113: 907-911. Sydenham’s Chorea - Clinical : Sydenham’s Chorea - Clinical Affects ca. 25% of patients with Acute Rheumatic Fever Chorea usually involves face and extremities May feature involuntary ballistic movements Speech, behavior, handwriting, muscle strength and gait changes common Motor and vocal tics uncommon 25-80% with carditis Ca. 70% of cases are female Pavone P, Parano E, Rizzo R, et al. Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection: Sydenham Chorea, PANDAS, and PANDAS Variants. Journal of child Neurology 2006; 21: 727-736. Sydenham's Chorea - Etiology : Sydenham's Chorea - Etiology Antibodies to GAS antigens attack host proteins in various organs, including brain One study found antibodies against human caudate and subthalamic nucleus tissue in 46% of patients with Sydenham;s chorea and 1.8% to 4% of patients without it Severity of chorea correlates with levels of antineuronal antibodies Husby G, van de Rijn I, Zabriskie JB, et al. Antibodies Reacting with Cytoplasm of Subthalamic and Caudate Nuclei Neurons in Chorea and Acute Rheumatic Fever. The Journal of Experimental Medicine 1976; 114: 1094-1110. Criteria for Autoantibodies Causing Disease : Criteria for Autoantibodies Causing Disease Identification of autoantibodies Autoantibodies at the pathologic site Induction of symptoms with autoantigens Passive transfer of the disorder to animal models Positive response to immunomodulatory therapy Harris K, Singer HS. Tic Disorders: Neural Circuits, Neurochemistry, and Neuroimmunology. Journal of Child Neurology 2006; 21: 678-689. Fulfillment of Autoantibody Etiology Criteria : Fulfillment of Autoantibody Etiology Criteria Identification of autoantibodies Mixed results for studies investigating possible increased anti-neuronal antibody levels in PANDAS vs. control patients using ELISA and Western blot methods Autoantibodies at the pathologic site No post-mortem studies yet Harris K, Singer HS. Tic Disorders: Neural Circuits, Neurochemistry, and Neuroimmunology. Journal of Child Neurology 2006; 21: 678-689. Fulfillment of Autoantibody Etiology Criteria : Fulfillment of Autoantibody Etiology Criteria Induction of symptoms with autoantigens No animal studies yet Studies to pre-empt autoimmune response with ABX prophylaxis have been mostly negative Passive transfer of the disorder to animal models Rat studies mixed, on balance no effect Harris K, Singer HS. Tic Disorders: Neural Circuits, Neurochemistry, and Neuroimmunology. Journal of Child Neurology 2006; 21: 678-689. Fulfillment of Autoantibody Etiology Criteria : Fulfillment of Autoantibody Etiology Criteria Positive response to immunomodulatory therapy 1 study using IVIG and plasmapheresis treatment and an IV fluid placebo did show improvement Harris K, Singer HS. Tic Disorders: Neural Circuits, Neurochemistry, and Neuroimmunology. Journal of Child Neurology 2006; 21: 678-689. Overview : Overview Criteria Controversies Epidemiological Evidence Neurological and Autoimmune Possible Etiologies Prophylaxis and Treatment Penicillin Prophylaxis : Penicillin Prophylaxis 37 patients who met PANDAS criteria placed on PCN or placebo prophylaxis Double blind, balanced cross-over study No power calculations Rate of infection same in both groups No difference in OCD or tic symptoms Lack of PCN effect may in part be due to poor compliance, low serum levels Garvey MA, Perlmutter SJ, Allen AJ, et al. A Pilot Study of Penicillin Prophylaxis for Neuropsychiatric Exacerbations Triggered by Streptococcal Infections. Biological Psychiatry 1999; 45: 1564-1571. Azithromycin Prophylaxis : Azithromycin Prophylaxis 23 patients who met PANDAS criteria placed on PCN or azithromycin for 12 months Double blind randomized control trial PCN designated “active placebo” No power calculations Streptococcal infections and neuropsychiatric exacerbations same in both groups Infections and exacerbations decreased compared to baseline year based on medical records Snider LA, Lougee L, Slattery M, et al. Antibiotic Prophylaxis with Azithromycin or Penicillin for Childhood-onset Neuropsychiatric Disorders. Biological Psychiatry 2005; 57: 788-792. Treatment : Treatment Case series of 12 patients aged 5-11 who met PANDAS criteria reported resolution of sx with ABX Patients only had OCD symptoms Consensus that standard psychiatric treatments should be used SSRIs and CBT for OCD Alpha agonists and antipsychotics for tics Murphy ML, Pichichero ME. Prospective Identification and Treatment of Children with PANDAS. Archives of Pediatric and Adolescent Medicine 2002; 156: 356-361. Kurlan R, Kaplan EL. PANDAS Etiology for Tics and OC Sx: Hypothesis or Entity? Practical Considerations for the Clinician. Pediatrics 2004; 113: 883-886. Immunotherapy : Immunotherapy 29 children with PANDAS randomized equally to plasmapheresis, IVIG and IVF placebo IVIG group had 45% improvement on Yale-Brown OCD scale and 19% improvement on TS unified rating scale at 1 month Plasmapheresis had 58% improvement on OCD, 49% improvement with tics at 1 month Placebo had 3% improvement on OCD, 12% improvement on tics Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic Plasma Exchange and Intravenous Immunoglobulin for Obsessive-Compulsive Disorder and Tic Disorders in Childhood. Lancet 1999; 354: 1153-1158. Immunotherapy : Immunotherapy Trial criticized for recruitment methods, lack of plasmapheresis placebo, size, and lack of severity matching 2/3 of patients had side effects Pallor, dizziness, nausea, headache Kurlan R, Kaplan EL. The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Etiology for Tics and Obsessive-Compulsive Symptoms: Hypothesis or Entity? Practical Considerations for the Clinician. Pediatrics 2004; 113: 883-886. Conclusion- PANDAS Hypothesis : Conclusion- PANDAS Hypothesis PANDAS evidence mixed and weak Diagnostic criteria coherent but vulnerable to coincidental timing of GAS infections/colonization and neuropsychiatric symptoms Epidemiological evidence interesting but very limited Plausible model for pathogenesis but supportive evidence lacking Covers only fraction of patients with tics and OCD Conclusion – PANDAS Treatment : Conclusion – PANDAS Treatment Treatment and prophylaxis with ABX are relatively low risk but evidence does not really support them Some supportive evidence for much riskier/costlier IVIG and plasmapheresis Suspected PANDAS patients still need standard treatment for OCD and tics Diagnosis requires close attention by pediatrician and/or close cooperation between pediatrician and psychiatrist National Institutes of Mental Health Recommendations : National Institutes of Mental Health Recommendations Children with an explosive OCD or tic exacerbation should have a throat culture. If sx present for more than 1 week, serial anti-streptococcal titers could be followed instead Antibiotics should only be used to treat GAS infections diagnosed by a positive throat culture or rapid strep test. Prophylactic antibiotics are currently not indicated Swedo SE, Leonard HL, Rapoport JL. The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Subgroup: Separating Fact from Fiction. Pediatrics 2004; 113: 907-911. National Institutes of Mental Health Recommendations : National Institutes of Mental Health Recommendations Children with PANDAS should receive standard treatment for OCD and/or tics. ABX and other PANDAS tx are an addition to, not substitute for, standard treatments IVIG and plasmapheresis are options for acutely, severely ill children who meet standard PANDAS criteria Swedo SE, Leonard HL, Rapoport JL. The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Subgroup: Separating Fact from Fiction. Pediatrics 2004; 113: 907-911. References : References Garvey MA, Perlmutter SJ, Allen AJ, et al. A Pilot Study of Penicillin Prophylaxis for Neuropsychiatric Exacerbations Triggered by Streptococcal Infections. Biological Psychiatry 1999; 45: 1564-1571. Harris K, Singer HS. Tic Disorders: Neural Circuits, Neurochemistry, and Neuroimmunology. Journal of Child Neurology 2006; 21: 678-689. Husby G, van de Rijn I, Zabriskie JB, et al. Antibodies Reacting with Cytoplasm of Subthalamic and Caudate Nuclei Neurons in Chorea and Acute Rheumatic Fever. The Journal of Experimental Medicine 1976; 114: 1094-1110. King RA. PANDAS: To Treat or Not to Treat. In: 179-183. Kurlan R, Kaplan EL. The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Etiology for Tics and Obsessive-Compulsive Symptoms: Hypothesis or Entity? Practical Considerations for the Clinician. Pediatrics 2004; 113: 883-886. Luo F, Leckman JF, Katsovich L, et al. Prospective Longitudinal Study of Children with Tic Disorders and/or Obsessive Compulsive Disorder: Relationship of Symptom Exacerbations to Newly Acquired Streptococcal Infections. Pediatrics 2004; 113: e578-e585. References : References Mell LK, Davis RL, Owens D. Association Between Streptococcal Infection and Obsessive Compulsive Disorder, Tourette’s Syndrome, and Tic Disorder. Pediatrics 2005; 116: 56-60. Mercadante MT, Busatto GF, Lombroso PJ, et al. The Psychiatric Symptoms of Rheumatic Fever. American Journal of Psychiatry 2000; 157: 2036-2038. Murphy ML, Pichichero ME. Prospective Identification and Treatment of Children with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Group A Streptococcal Infection (PANDAS). Archives of Pediatric and Adolescent Medicine 2002; 156: 356-361. Murphy TK, Snider LA, Mutch PJ, et al. Relationship of Movements and Behaviors to Group A Streptococcus Infections in Elementary School Children. Biological Psychiatry 2007; 61: 279-284. Pavone P, Parano E, Rizzo R, et al. Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection: Sydenham Chorea, PANDAS, and PANDAS Variants. Journal of child Neurology 2006; 21: 727-736. References : References Perrin EM, Murphy ML, Casey JR, et al. Does Group A Beta-Hemolytic Streptococcal Infection Increase Risk for Behavioral and Neuropsychiatric Symptoms in Children? Archives of Pediatric and Adolescent Medicine 2004; 158: 848-856. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic Plasma Exchange and Intravenous Immunoglobulin for Obsessive-Compulsive Disorder and Tic Disorders in Childhood. Lancet 1999; 354: 1153-1158. Singer HS, Hong JJ, Yoon DY, et al. Serum Autoantibodies Do Not Differentiate PANDAS and Tourette Syndrome from Controls. Neurology 2005; 65: 1701-1707. Snider LA, Lougee L, Slattery M, et al. Antibiotic Prophylaxis with Azithromycin or Penicillin for Childhood-onset Neuropsychiatric Disorders. Biological Psychiatry 2005; 57: 788-792. References : References Swedo SE, Leonard HL, Garvey M, et al. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections: Clinical Description of the First 50 Cases. American Journal of Psychiatry 1998; 155: 264-271. Swedo SE, Leonard HL, Rapoport JL. The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Subgroup: Separating Fact from Fiction. Pediatrics 2004; 113: 907-911. Zomorrodl A, Wald ER. Sydenham’s Chorea in Western Pennsylvania. Pediatrics 2006; 117: e675-e679.

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