Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
3/8/2010 DISCLAIMER PANDAS: A Case Discussion NEITHER THE PUBLISHER NOR THE AUTHORS ASSUME ANY LIABILITY FOR ANY INJURY AND OR DAMAGE TO PERSONS OR PROPERTY ARISING FROM THIS WEBSITE AND ITS CONTENT. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus Suzanne Collier, MD ETSU Psychiatry Resident PGY-III March 5, 2010 Case Study: CJ 7 year old Caucasian male One month prior to admission, would repeat himself compulsively, i.e. “I love you Mom, okay, okay, okay, okay, okay” etc. More “clingy” clingy than normal One week prior to admission began praying incessantly. Cannot answer questions without interrupting himself in order to pray. God is talking to him. Sleep disturbance Would not step on certain colored tiles on the floor Odd hand gestures 1 3/8/2010 Further collateral information reveals: No clear precipitant to worsening of symptoms in last one week Started an allergy medication in October that made him more agitated One month prior to presentation, difficulty hearing FP noted enlarged tonsils ENT referral – PE tubes and tonsillectomy scheduled No Strep screen, no antibiotics initiated Let’s review Rheumatic Fever – Requires 2 major criteria or 1 major and 2 minor criteria Major criteria: Migratory polyarthritis (usually starts in legs and migrates upward) Carditis Subcutaneous nodules (painless collagen nodules on back of wrist, outside elbow, and front of knees) Erythema marginatum Sydenham’s chorea (a.k.a. St. Vitus’ dance, characteristic series of rapid, purposeless movements of face and arms) Differential Diagnosis OCD, possibly related to medical reason, r/o PANDAS Psychosis NOS Bipolar disorder with psychotic features Tic disorder, Tourette’s syndrome Anxiety disorder Psychosis NOS Sydenham’s chorea (rheumatic fever) Rheumatic fever, continued Minor criteria Fever Arthralgia Laboratory abnormalities (increased ESR, C reactive protein,, leukocytosis) p y ) Electrocardiogram abnormalities (prolonged PR interval) Evidence of Group A streptococcal infection (elevated or rising titers of Antistreptolysin O titre, or DNAase, though by clinical illness onset cultures for streptococci will be negative) Previous rheumatic fever or inactive heart disease 2 3/8/2010 “So what’s your point?” Basal ganglia dysfunction = neuropsychiatric symptoms in some cases, particularly in Sydenham’s chorea and OCD What’s the connection? Observations of patients with rheumatic fever who had Sydenham’s chorea and classic OCD symptoms BG also anatomic target for Tourette’s syndrome, ADHD SC patients often display motor and vocal tics, OCD, and ADHD symptoms Possible link between GABHS in subset of OCD patients Suggested by Swedo in 1994 that there may some autoimmune link to neuropsychiatric disorders GABHS also implicated in development of Tourette syndrome and autism in children NIMH 1998 – research group to characterize a subgroup of children with OCD and tic disorders Defined PANDAS and diagnostic criteria Swedo, Susan. “Sydenham’s chorea: a model for childhood autoimmune neuropsychiatric disorders”, JAMA. 1994;272:1788-91. PANDAS Diagnostic Criteria Also watch for: Presence of obsessive-compulsive disorder and/or tic disorder Pediatric onset of symptoms (age 3 years to puberty) Episodic course of symptom severity Association with group A Beta-hemolytic streptococcal infection (a positive throat culture for strep. or history of Scarlet Fever.) Association with neurological abnormalities (motoric hyperactivity, or adventitious movements, such as choreiform movements) Also now accepted that you need at least two exacerbations after GABHS infection to meet criteria ADHD symptoms (hyperactivity, inattention, fidgety) Separation anxiety (Child is "clingy" and has difficulty separating from his/her caregivers.) Mood changes (irritability (irritability, sadness sadness, emotional lability) Sleep disturbance Night- time bed wetting and/or day- time urinary frequency Fine/gross motor changes (e.g. changes in handwriting) Joint pains Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases [published correction appears in Am J Psychiatry. 1998;155(4):578]. Am J Psychiatry. 1998;155 (2):264 –271 3 3/8/2010 Psychiatric comorbidity “Saving Sammy” ADHD – 40% Affective disorders – 42% Anxiety y disorders – 32% “Today” show September 24, 2009 Today Show Video Clip Swedo, Susan E., et al. Am J Psychiatry 155:2, February 1998 Clinical Controversy o Age of onset criteria o 1-3% of children have OCD o 10-25% school age children have tics o 75% Tourette’s Tourette s patients have onset prior to 11 y/o o Increases possibility that association between GABHS and psych symptoms is coincidence 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 (4):883 –886 4 3/8/2010 Controversy, continued Controversy, continued o Abrupt exacerbation criteria o GABHS infection criteria o Neurological symptom exacerbation could be due to stress from infections in general, not just GABHS o Longitudinal history of GABHS infection and OCD or tic symptoms can be difficult to establish o Since tics are either present or not, onset could always seem abrupt o Patients with tics often seem to have sudden worsening of tics even without meeting PANDAS criteria o Family reports subject to recall bias 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 (4):883 –886 Fig 1. Model of pathogenesis for PANDAS 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 (4):883 –886 Proposed Theory of Pathogenesis Immune-mediated model of molecular mimicry Autoimmune attack on tissues such as joints, j i h heart valves, l b brain i Antibodies cross-react with neuronal tissue of the CNS (basal ganglia) BG is responsible for movement and behavior Swedo, S. E. et al. Pediatrics 2004;113:907-911 Copyright ©2004 American Academy of Pediatrics 5 3/8/2010 Pathogenesis, continued Pathogenesis, continued o Yet another theory: immune-mediated altered neuronal signaling o Involves the dominant epitope of GABHS o Monoclonal antibodies reacted with lysoganglioside GM1 o This lysoganglioside influences neuronal signal transduction o Also found an autoantibodyy that induces CaM kinase II activity y o CaM kinase II could be an intracellular mediator of behavioral and motor manifestations in some neuropsychiatric disorders o CaM kinase II activation at low levels: non-PANDAS OCD o CaM kinase II activation at high levels : rheumatic chorea Kirvan, CA, Swedo, SE. Antibody-mediated neuronal cell signaling in behavior and movement disorders. J Neuroimmunology. 2006;179:173-179. Peripheral markers Trait marker D8/17 that has been associated with rheumatic fever can also be used to identify children with PANDAS This is a non-HLA B-cell marker D8/17 found on subset of DR+ cells in peripheral circulation Frequency of D8/17 positive individuals: • Sydenham's chorea – 89% • PANDAS – 85% • Healthy volunteers - 17% Swedo, Susan E., et al. “Identification of Children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections by a Marker Associated with Rheumatic Fever”, Am J Psychiatry 1997; 154:110-112. A Recent Example – “Sneezing Girl” Lauren Johnson, 12 year old “Today” show November 11, 2009 and again on December 11, 2009 Today Show Lauren Johnson Video Clip Today Show Update Video Clip 6 3/8/2010 Diagnostic studies Check for Strep! Two tests available: ASO titer: rises 3-6 weeks postinfection Anti DNAase-B titer: rises 6-8 weeks post-infection If negative, get throat culture Back to our Case Study, CJ: Initial rapid Strep test was negative (this was at least one month postinfection) Throat Th culture l was negative i ((patient i was uncooperative with obtaining culture, likely inadequate culture) Further titers not obtained due to expense of tests and also results would not have changed treatment Therapeutic Strategies – To use antibiotics or not? o Prospective longitudinal study of 12 children with PANDAS o 5 were given penicillin or amoxicillin o 1 was given amoxicillin and clavulanate (Augmentin) o 6 were given i cephalosporin h l i o In all patients, resolution of OCD, anxiety symptoms, and tics within average 14 days Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002;156:356–61. 7 3/8/2010 Antibiotics or not? Antibiotics or not? o First controlled trial on antibiotic prophylaxis for PANDAS o Were Garvey’s negative results due to inefficacious prophylaxis against GABHS infection or lack of association between GABHS infection and neuropsychiatric symptoms? o Snider compared penicillin (“active placebo”) with azithromycin o 23 patients - continued meds for 12 months o In contrast to previous studies, both effectively decreased GABHS infections and neuropsychiatric exacerbations. o They concluded that antibiotic prophylaxis may be useful in the management of children with PANDAS o Others later pointed out limitations of study o 37 children with PANDAS were randomized to 4 months of penicillin V (250mg PO BID) followed by 4 months of placebo, or placebo followed by penicillin o Oral penicillin failed to provide adequate prophylaxis for GABHS and subsequently for neuropsychiatric symptom exacerbations Garvey MA, Perlmutter SJ, et al. A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry. 1999;45:1564-1571. Snider LA, et al. Antibiotic prophylaxis with azithromycin or penicillin for childhoodonset neuropsychiatric disorders. Biol Psychiatry. 2005;57:788-792. Treatment Plan CJ's Treatment: Treat any suspected active Strep infection with antibiotics! Accepted standard of care for Strep – but there are no set guidelines for if/how long to continue antibiotics as prophylaxis for PANDAS More research needed OCD, anxiety: SSRIs Tic disorders/Tourette's: typical and atypical antipsychotic meds Option for severely ill patients is IVIG or plasma exchange Erythromycin 250mg PO QID x 7 days Risperdal Cogentin g Gradual improvement during hospitalization Strongly considered SSRI (Zoloft) for anxiety Nicolson R, Swedo SE, et al. An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without poststreptococcal exacerbations. J Am Acad Child Adolesc Psychiatry. 2000;39:1313-1315. Not clear if anxiety secondary to PANDAS or innate anxiety disorder Perlmutter, Susan J., et al. Therapeutic Plasma Exchange and Intravenous Immunoglobulin for Obsessive Compulsive Disorders and Tic Disorders in Childhood. The Lancet 1999;345 (9185):1153-58. 8 3/8/2010 Special Thanks: Dr. Jill McCarleyy References References Ashbar, FR, et al. “Obsessive-compulsive and related symptoms in children and adolescents with rheumatic fever with and without chorea: a prospective 6-month study.” Am J Psychiatry. 1998;155:1122-1124. Pavone, P, et al. Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatric Neurology. 2004;30:107-10. Gabbay V, Coffey BJ, Babb JS, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcus: comparison of diagnosis and treatment in the community and at a specialty clinic. Pediatrics. 2008;122 (2):273 –278 Perlmutter, Susan J., et al. Therapeutic Plasma Exchange and Intravenous Immunoglobulin for Obsessive Compulsive Disorders and Tic Disorders in Childhood. The Lancet 1999, 345 (9185):1153-58 Garvey MA, Perlmutter SJ, et al. A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry. 1999;45:1564-1571. Geidd JN, Rapoport JS, Garvey MA, Perlmutter S, Swedo SE. MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal Am J Psychiatry. 2000;157:281–283. Kirvan, CA, Swedo, SE. Antibody-mediated neuronal cell signaling in behavior and movement disorders. J Neuroimmunology. 2006;179:173-179. 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 (4):883 –886 Snider LA, et al. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders. Biol Psychiatry. 2005;57:788-792. Swedo, Susan. “Sydenham’s chorea: a model for childhood autoimmune neuropsychiatric disorders”, JAMA. 1994;272:1788-91. Swedo, Susan E., et al. “Identification of Children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections by a Marker Associated with Rheumatic Fever”, Am J Psychiatry 1997; 154:110-112. Kurlan R, Johnson D, Kaplan EL; Tourette Syndrome Study Group. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics. 2008;121 (6):1188 –1197 Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases [published correction appears in Am J Psychiatry. 1998;155(4):578]. Am J Psychiatry. 1998;155 (2):264 –271 Nicolson R, Swedo SE, et al. An open trial of plasma exchange in childhood-onset obsessivecompulsive disorder without poststreptococcal exacerbations. J Am Acad Child Adolesc Psychiatry. 2000;39:1313-1315. Swedo SE, Leonard HL, Rapoport JL. The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. Pediatrics. 2004;113 (4):907 –911 Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002;156:356–61. 9