Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies (original) (raw)
Related papers
Journal of Child and Adolescent Psychopharmacology, 2010
Obsessive-compulsive disorder (OCD) and related conditions including Tourette's disorder (TD) are chronic, relapsing disorders of unknown etiology associated with marked impairment and disability. Associated immune dysfunction has been reported and debated in the literature since the late 80s. The immunologic culprit receiving the most interest has been Group A Streptococcus (GAS), which began to receive attention as a potential cause of neuropsychiatric symptoms, following the investigation of the symptoms reported in Sydenham's chorea (SC) and rheumatic fever, such as motor tics, vocal tics, and both obsessive-compulsive and attention deficit/hyperactivity symptoms. Young children have been described as having a sudden onset of these neuropsychiatric symptoms temporally associated with GAS, but without supporting evidence of rheumatic fever. This presentation of OCD and tics has been termed pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS). Of note, SC, OCD, and TD often begin in early childhood and share common anatomic areas-the basal ganglia of the brain and the related cortical and thalamic sites-adding support to the possibility that these disorders might share a common immunologic and/or genetic vulnerability. Relevant manuscripts were identified through searches of the PsycINFO and MedLine databases using the following keywords: OCD, immune, PANDAS, Sydenham chorea, Tourette's disorder Group A Streptococcus. Articles were also identified through reference lists from research articles and other materials on childhood OCD, PANDAS, and TD between 1966 and December 2010. Considering the overlap of clinical and neuroanatomic findings among these disorders, this review explores evidence regarding the immunobiology as well as the relevant clinical and therapeutic aspects of TD, OCD, and PANDAS. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus Dr. Laurence Selling made one of the earliest reported cases of this potential correlation between the onset of tics and infectious disease in 1929 when he described three cases of tics associated with sinusitis (Selling 1929). Subsequently, psychoanalytic theories of TD prevailed (Kushner and Kiessling 1996). Just before the medicalization of TD in 1965, Langlois and Force described a 6-year-old child with TD and SC symptoms following several infectious illnesses that were successfully treated with antibiotics and neuroleptics (Langlois and Force 1965). They argued that Tourette was wrong to say TD was incurable and separate from SC but that
Molecular Psychiatry, 2010
Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A b-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and a-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood-brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (Review)
Experimental and Therapeutic Medicine, 2020
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are clinically characterized by the sudden onset of obsessive-compulsive manifestations, motor and verbal tics, as well as other behavioral symptoms in a group of children with B-hemolytic streptococcal infection. PANDAS are considered autoimmune diseases because the streptococcal infection and response can be demonstrated. The most frequent physiopathological mechanism is molecular mimicry: A foreign antigen shares sequence or structural similarities with self-antigens. A thorough review of the literature was carried out using the PubMed database and SCOPUS, searching for immunological, clinical and microbiological aspects, as well as the treatment of the PANDAS syndrome. The diagnosis is clinical and it requires a careful medical history and a thorough physical examination, while the treatment is complex. Untreated or unrecognized manifestations of PANDAS can increase the risk of obsessive-compulsive manifestations and tics during adulthood. Taking this into consideration, further studies are required to establish the best method of therapy. Contents 1. Introduction 2. Methods 3. Results 4. Conclusions
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus in Identical Siblings
Journal of Child and Adolescent Psychopharmacology, 2011
OBJECTIVES-This study aimed to examine whether pediatric autoimmune neuropsychiatric disorders associated with streptococcus were appropriately diagnosed in the community and to determine subsequent rates of unwarranted use of antibiotic treatment for tics and obsessivecompulsive symptoms without the identification of an infection. METHODS-The design was a retrospective, cross-sectional, observational study of 176 children and adolescents who were evaluated in a specialty program for tics, Tourette's disorder, and related problems. Previously published diagnostic criteria were used to establish the diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus in our clinic. RESULTS-Subjects were significantly less likely to receive a diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus at the specialty clinic than in the community. In the community, subjects were significantly more likely to be treated with antibiotics or immunosuppressant medication if they received a diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus. Of the 27 subjects with a community diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus who were treated with antibiotics, 22 (82%) were treated without laboratory evidence of an infection; 2 were treated with immunomodulatory medications. CONCLUSIONS-Our results support our hypothesis that pediatric autoimmune neuropsychiatric disorders associated with streptococcus are frequently diagnosed in the community without the application of all working diagnostic criteria. This phenomenon has resulted in unwarranted use of antibiotic treatment for tics/obsessive-compulsive disorder without evidence of laboratory infection.
Frontiers in Psychiatry, 2016
A 9-year-old girl with Tourette syndrome (TS) and increased antibody levels against Streptococcus pyogenes was monitored longitudinally for the presence of nasopharyngeal bacteria, specific antibody titers, and autoimmunity directed against brain antigens. Microbiological monitoring indicated that the child was an intermittent Staphylococcus aureus nasopharyngeal carrier. Clinical improvements in motor tic frequency and severity were observed during the S. aureus colonization phase and were temporally correlated with the downregulation of anti-streptococcal and anti-D1/D2 dopamine receptor antibody production. After decolonization, clinical conditions reverted to the poor scores previously observed, suggesting a possible role of the immune response in bacterial clearance as a trigger of symptom recrudescence. These findings imply that a causeeffect relationship exists between S. aureus colonization and tic improvement, as well as between bacterial decolonization and tic exacerbation. Understanding the impact of S. aureus on the host adaptive immune response and the function of autoantibodies in the pathogenesis of TS may alter approaches for managing autoimmune neuropsychiatric and tic disorders.
2019
Background: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a rare neuropsychiatric disorder in children. Obsessive-compulsive symptoms, tics and other neuropsychiatric disorders may occur after a group A beta-hemolytic streptococcal infection. Treatment is still unclear and debate still continues. The objective of this case report is to describe the clinical presentation and the management of PANDAS at Sanglah General Hospital. Case Presentation Summary: An 8-year-old boy complained of involuntary movement of his head and eyes since 5 days before admission. There was history of sore throat and fever for 3-4 days one month before admission. Physical examination showed symptom of nystagmus with tic on the face. Laboratory test revealed ASO 400 IU/ml, ECG and MRI were normal. Blood culture and throat swab were performed and showed no bacterial growth. We treated with ampicillin 100 mg/kg/day orally, haloperidol 0.5 mg BID orally, an...
Cureus
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) have attracted a lot of interest and discussion since it was originally characterized in 1998. The role of streptococcal infection in children with abrupt-onset obsessive-compulsive disorder (OCD) and new-onset tics, the natural history of this entity, and the role of symptomatic and disease-modifying therapies, such as antibiotics, immunotherapy, and psychoactive drugs, are still unresolved issues. Alternative therapies for acute-onset OCD have been developed based on this postulated pathophysiology, including antibiotics and immunomodulatory therapy. The literature on PANDAS therapy is varied but there is no clinical consensus on the treatment of choice. While there is no convincing evidence for the autoimmune rationale for PANDAS, given the increased attention to this entity and the apparent growth in usage of this diagnostic category, it is critical to address concerns about the condition's diagnosis, treatment, and pathogenesis. We conducted a multi-language literature search on Medline, Cochrane, Embase, and Google Scholar for a period spanning until October 2021. The following search strings and Medical Subject Heading (MeSH) terms were used: "PANDAS," "Group A Streptococcus," "OCD," and "tics." We explored the literature on PANDAS in terms of its epidemiology, pathophysiology, the role of group A streptococcal infection, associated complications, and prophylactic and treatment modalities. We examined current working definitions of PANDAS, analyzed differential diagnoses, and published pieces of evidence for therapies associated with this entity, with a view to proposing a therapeutic strategy for children with acute symptoms that meet PANDAS criteria, in this review article.
Biological Psychiatry, 2001
Methods: To test this hypothesis, we looked for the presence ot total and IgG antibodies against neural, nuclear, cytoskeletal and streptococcal epitopes using indirect immunofluorescent assays and Western blot techniques in three patient groups: TS (n ϭ 81), SC (n ϭ 27), and a group of autoimmune disorders (n ϭ 52) and in normal controls (n ϭ 67). Subjects were ranked after titrations of autoantibodies from 0 to 227 according to their level of immunoreactivity. Results: TS patients had a significantly higher mean rank for total antineural and antinuclear antibodies, as well as antistreptolysin O titers. However, among children and adolescents, only the total antinuclear antibodies were increased in TS patients compared to age matched controls. Compared to SC patients, TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, significantly lower IgG class anticytoskeletal antibodies, and a significantly higher rank for total antinuclear antibodies. Compared to a mixed group of autoimmune disorders, the TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, total and IgG class antinuclear antibodies, IgG class anticytoskeletal antibodies, and a significantly higher rank for antistreptococcal antibodies. Conclusions: TS patients had significantly higher levels of total antineural and antinuclear antibodies than did controls. Their relation to IgG class antineural and antinuclear antibodies, markers for prior streptococcal infection, and other clinical characteristics, especially chronological age, was equivocal.
Future Neurology, 2016
Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham's chorea (SC) and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust Th17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS.