Immune Pathogenesis of Pediatric
Autoimmune Neuropsychiatric Disorders Associated with Group A
b-Hemolytic Streptococcal Infections (PANDAS)
David
S Younger, Denis A Bouboulis
David S. Younger, Department of Neurology, New York
University Langone Medical Center, New York University School of Medicine, and
the Global Institute of Public Health, New York University, New York, the
United States
Denis D Bouboulis, Advanced Allergy, Immunology &
Asthma, PC, Darien, CT, and Stamford Hospital, Center for Allergy and
Immunology, Stamford, CT, the United States
Correspondence to: Denis Bouboulis, MD, Advanced Allergy,
Immunology & Asthma, PC. 125 Strawberry Hill
Avenue, Suite 101, Stamford, Connecticut 06902, the United States
Email: advanced-allergy.com
Telephone: +1-203-323-7744
Fax:
+1-203-323-1525
Received: November 30,
2014 Revised: December 26, 2014
Accepted: December 30, 2014
Published online: February 2, 2015
ABSTRACT
Pediatric
autoimmune neuropsychiatric disorders associated with group A -hemolytic streptococcal infections or
PANDAS, is a well characterized autoimmune disorder that affects the central
nervous system producing childhood-onset obsessive-compulsive disorder and tic
disorders, and a spectrum of psychiatric comorbidity accompanying
exacerbations. Recent advances in the understanding of the postulated
pathophysiology had led to effective interventions with immune modulatory
therapy. This article reviews the current understanding, diagnosis and
management of PANDAS.
© 2015 ACT. All
rights reserved.
Key words: PANDAS; IVIg; Therapeutics
Younger DS, Bouboulis DA. Immune Pathogenesis of Pediatric Autoimmune Neuropsychiatric Disorders
Associated with Group A ¦Â-Hemolytic Streptococcal Infections (PANDAS). International
Journal of Neurology Research 2015; 1(1): 5-7 Available from: URL: http://www.ghrnet.org/index.php/ijnr/article/view/928
INTRODUCTION
From 1989 to 1992, Swedo and investigators in the
Children Psychiatry Branch of the National Institute of Mental Health (NIMH) in
Bethesda, Maryland[1-3] were characterizing the long-term course of
children and adolescents with obsessive-compulsive disorders revealing the
episodic course of a subgroup characterized by dramatic and acute symptom
exacerbations interspersed with long periods of relative symptom quiescence
noting that in some, the exacerbations were associated with group A -hemolytic streptococcal (GABHS) infections. In 1998, Swedo and
colleagues[4] described the clinical neuropsychiatric clinical and
laboratory features 50 children all of whom met the criteria of prepubertal
onset of obsessive compulsive disorder (OCD) or tic disorder, episodic course,
and association with GABHS infections and neurological abnormalities. Children
with known rheumatic fever, or overt chorea by history and physical examination
leading to suspicion of Syndenham chorea, also a known variant of rheumatic
fever requiring antibiotic prophylaxis against GABHS, were disqualified from
participation. Their studies showed a striking association between the abrupt
onset of OCD, tics and comorbid psychiatric symptoms, and a documented GABHS
infection and increase in anti-streptococcal titers. Like rheumatic fever, the
authors[4] postulated that the pathogenesis of PANDAS was due to
exposure of GABHS infection in a genetically and developmentally susceptible
host with a resulting central nervous system (CNS) extrapyramidal immune
response.
Despite past controversy regarding
PANDAS as concerns conflicting epidemiologic studies regarding the risk for
behavioral and neuropsychiatric symptoms in affected children[5],
the validity of the clinical criteria for PANDAS[6], criticisms of
the measurement of antineuronal antibodies and other biomarkers to identify
affected patients[7], there has been recent extraordinary progress
in the understanding of PANDAS since their report more than fifteen years ago[4],
particularly in the role of immune modulatory therapy employing plasma exchange
(PE) and intravenous immune globulin (IVIg).
Autoantibodies
Elevated anti-streptolysin (ASO) antibodies distinguished cases versus
non-cases respectively in 59% and 37% (p=0.03) of cases providing
evidence of antecedent streptococcal infection, however they are not diagnostic
of PANDAS since other factors may mitigate their appearance. Whereas a limited
prior exposure to GABHS, hyperlipidemia, treatment with antibiotics and the
host ability to mount a strong immune response may lead to false negative
titers in a given child[8], sustained high titers result from
reinfection, slower rates of the decline in the antibody rise and a more potent
immune response may be responsible for inordinately elevated titers providing
evidence of repeated exposure[9-11]. A ¦Â-cell alloantigen identified by
monoclonal antibodies as D8/D17[12] which attaches to the surface of
B cells as a susceptibility factor for rheumatic fever, was found in 85% of
patients with PANDAS, 89% of those with Syndenham chorea (SC) but in only 17%
of controls[13]. The GNcNAc epitope expressed in SC monoclonal
antibodies (mAb) is capable of provoking a strong humoral response during
active streptococcal infection and in post-infectious sequela[14,15]
presumably due to terminal O-linked GLcNAc residues bearing structural
similarity to many host glycoconjugates. Experimental animals immunized with
GlcNAc mAb leads to T-cell dependent antibody responses and persistently high
titers to streptococcal carbohydrate[16]. Lysoganglioside
GM1-specific antibodies present in the cerebrospinal fluid (CSF) of patients
with active disease blocks SC chorea mAb in acute sera that bind to human
caudate-putamen tissue suggested the presence of innate neuronal cell surface
determinate capable of altering neuronal physiological homeostasis in SC
patients. Anti-ganglioside antibodies affect signal transduction pathways in
neuroblastoma cells[17,18] and trigger calcium/calmodulin-dependent
protein (CaM) kinase II activation in the catecholamine-secreting neuroblastoma
cell line SK-N-Sh[19]. Active but not convalescent PANDA serum IgG
reacts with GlcNAc epitope of the streptococcal GAC and lysoganglioside GM1 as
in SC, and induces CaM kinase II activity in SK-N-SH human neuroblastoma cells
with significant increases in CaM kinase II activity[14] suggesting
a role for antibody-mediated neuronal cell signaling in the immunopathogenesis
of PANDAS.
Immune
Modulatory Therapy
The most compelling support for an immune-mediated pathogenesis in
PANDAS derives from the results of randomized, placebo-controlled trials (RCT)
of IVIg and PE. Both immune modulatory therapies have been associated with
significant improvement in neuropsychiatric symptoms severity leading to 45%
and 58% reductions respectively, with sustained improvements at one year
followup[20]. Among 29 children with OCD and tic disorders randomly
assigned five PE over two weeks (10 patients), 1 gram per kilogram daily for
two days of IVIg (nine patients), or saline solution placebo (10 patients)[21],
there were mean improvement of 45% and 58% respectively following IVIG and PE
OCD symptoms on the children's Yale-Brown obsessive compulsive scale score; and
a 49% mean improvement in the Tourette syndrome rating scale following PE.
These gains were maintained at 1 year, with 14 (82%) of 17 children
"much" or "very much" improved over baseline including 7/8
treated by PE and 7/9 children treated by IVIg therapy. A multi-site double-blind
placebo-controlled, parallel assignment treatment trial of the efficacy of 2
grams per kilogram of Gamunex over 2 days versus normal saline placebo
commenced in PANDAS begun in 2011 at the NIMH (ClinicalTrials.gov identifier
NCT01281969) finished recruiting subjects ages 4 to 12 years, and is due to
reach primary completion by 2016. In addition to outcome measures of
improvement in obsessions, compulsions, and other neuropsychiatric symptoms,
the investigators will by exploring the impact of treatment on reduction of titers
of cross-reactive antibodies, resolution of basal ganglia inflammation as
measured by pre- and post-changes in magnetic resonance imaging (MRI)
volumetric scans and inflammatory sequences, and normalization of selected
serum and CSF cytokines.
CONFLICT OF INTERESTS
Dr. Younger is a consultant to Innovative Research Associates, Sharon
Hill, PA.
REFERENCES
1
Swedo SE, Rapoport JL, Leonard HL,
Lenane M, Cheslow D. Obsessive-compulsive disorder in children and adolescents:
clinical phenomenology of 70 consecutive cases. Arch Gen Psychiatry 1989; 46:
335-341.
2
Leonard HL, Lenane MC, Swedo SE, Rettew
DC, Gershon ES, Rapoport JL. Tics and Tourette¡¯s syndrome: a 2 to 7-year
followup of 54 obsessive-compulsive children. Am J
Psychiatry 1992; 149: 1244-1251.
3
Rettew DC, Swedo SE, Leonard HL, Lenane
MC, Rapoport JL. Obsessions and compulsions across time in 79 children and
adolescents with obsessive compulsive disorder. J Am Acad Child Adolesc
Psychiatry 1992; 31: 1050-1056.
4
Swedo SE, Leonard HL, Garvey M,
Mittleman B, Allen AJ, Perlmutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK.
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal
infections: clinical description of the first 50 cases. Am
J Psychiatry 1998; 155: 264-271.
5
Perrin EM, Murphy ML, Casey JR,
Pichichero ME, Runyan DK, Miller WC, Snider LA, Swedo SE. Does group A beta-hemolytic streptococcus infection increase the risk
for behavioral and neuropsychiatric symptoms in children? Arch Pediatr Adolesc
2004; 158: 848-856.
6
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 clinical. Pediatrics 2004; 113: 883-886.
7
Martino D, Dale RC, Gilbert DL,
Giovannoni G, Leckman JF. Immunopathogenic mechanisms in Tourette syndrome: A
critical review. Mov Disord 2009; 24: 1267-1279.
8
Murphy TK, Storch EA, Lewin EA, Edge PJ,
Goodman WK. Clinical factors
associated with PANDAS. J Pediatr 2012; 160: 314-319.
9
Murphy TK, Sajid M, Soto O, Shapira N,
Edge P, Yang M, Lewis MH, Goodman WK. Detecting pediatric autoimmune
neuropsychiatric disorders associated with streptococcus in children with
obsessive-compulsive disorder and tics. Biol Psychiatry 2004; 55: 61-68.
10
Lee LH, Ayuob E, Pichichero ME. Fewer
symptoms occur in the same-serotype recurrent streptococcal
tonsillopharyngitis. Arch Otolaryngol Head Neck Surg 2000; 126: 1359-1362.
11
Bombaci M, Grifantini R, More M, Reguzzi
V, Petracca R, Meoni E, Balloni S, Zingaretti C, Falugi F, Manetti AG, Margarit
I, Musser JM, Cardona F, Orefici G, Grandi G, Bensi G. Protein array profiling
of tic patient sera reveals a broad range and enhanced immune response against
Group A streptococcus antigens. J Am Acad Child
Adolesc Psychiatry 2000; 39: 1120-1126.
12
Zabriskie JB, Lavenchy D, Williams RC
Jr, Fu SM, Yeadon CA, Fotino M, Braun DG. Rheumatic fever associated with B
cell alloantigens as identified by monoclonal antibodies. Arthritis Rheum 1985;
28: 1047-1051.
13
Mabrouk AA, Ezpen V. Challenges in the
identification and treatment of PANDAS: a case series. J Tropical Pediatrics
2008; 55: 46-48.
14
Kirvan CA, Swedo SE, Kurahara D,
Cunningham MW. Streptococcal mimicry and antibody-mediated cell signaling in
the pathogenesis of Sydenham¡¯s chorea. Autoimmunity 2006; 39: 21-29.
15
Froude J, Gibofsky A, Buskirk DR, Khanna
A, Zabriskie JB. Cross-reactivity between streptococcus and human tissue: A
model of molecular mimicry and autoimmunity. Curr Top Microbiol Immunol 1989;
145: 5-26.
16
Dudding BA, Ayoub EM. Persistence of
streptococcal group A antibody in patients with
rheumatic valvular disease. J Exp Med 1968; 128: 1081-1098.
17
Quattrini A,
Lorenzetti I, Sciorati C, Corbo M, Previtali SC, Feltri ML, Canal N, Wrabetz L,
Nemni R, Clementi E. Human IgM and
anti-GM1 autoantibodies modulate intracellular calcium hemeostasis in
neuroblastoma cells. J Neuroimmunol 2001; 114: 213-319.
18
Kasahara K, Watanabe K, Takeuchi K,
Kaneko H, Oohira A, Yamamoto T, Sanai Y. Involvement of gangliosides in
glycosylphosphatideylinositol-anchored neuronal cell adhesion molecule TAG-1
signaling in lipid rafts. J Biol Chem 2000; 275: 34701-34709.
19
Kirvan CA, Swedo SE, Heuser JS,
Cunningham MW. Mimicry and autoantibody-mediated neuronal cell signaling in
Syndenham chorea. Nat Med 2003; 9: 914-920.
20
Snider LA, Swedo SE. PANDAS: current
status and directions for research. Molecular Psychiatry 2004; 9: 900-907
21
Perlmutter SJ, Leitman SF, Garvey MA,
Hamburger S, Feldman E, Leonard HL, Swedo SE. Therapeutic plasma exchange and
intravenous immunoglobulin for obsessive-compulsive disorders tic disorders in
childhood. Lancet 1999; 354: 1153-1158.
Peer reviewer: Giorgia Quadrato, PhD,
Dept. of Stem Cell and Regenerative Biology, Harvard University,
Sherman-Fairchild Building, 7 Divinity Avenue, 02138 Cambridge, MA, USA.
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