- Neuroanatomical features and its usefulness in classification of patients with PANDAS. [Journal Article]
- CSCNS Spectr 2018 Nov 15; :1-11
- CONCLUSIONS: The results of this integrative study allow a better understanding of the neural substrates in this OCD subtype, suggesting that the anatomical gray matter characteristics could have an immune origin that might be helpful in patient classification.
- Tic Disorders and PANDAS. [Review]
- SPSemin Pediatr Neurol 2018; 25:25-33
- Tics are the most common movement disorder in childhood and are a frequent reason for referral to child neurology clinics. The purpose of this review is to examine the phenomenology of tics, discuss …
Tics are the most common movement disorder in childhood and are a frequent reason for referral to child neurology clinics. The purpose of this review is to examine the phenomenology of tics, discuss what is known regarding their genetic and pathophysiological causes and to evaluate current treatment options. The evidence for the evaluation and treatment of the controversial diagnosis of pediatric autoimmune neuropsychiatric disorders associated with group A streptococci (PANDAS) will also be reviewed. With improved understanding of tic disorders, their etiology and response to current treatment options, we may be able to more effectively diagnose them and identify novel treatment strategies.
- Tonsillectomy remains a questionable option for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). [Review]
- GCGMS Curr Top Otorhinolaryngol Head Neck Surg 2016; 15:Doc07
- Background: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a disease attributed to children with obsessive compulsive disorders (OCD) or tic dis…
Background: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a disease attributed to children with obsessive compulsive disorders (OCD) or tic disorders associated with streptococcal infections. Because otolaryngologists examine a large number of pediatric patients with recurrent streptococcal infections, tonsillectomy (TE) is a common option of therapy. This study was conducted to evaluate the efficacy of TE in patients presenting with verified PANDAS. Material and methods: A PubMed review was performed using search terms "tonsillectomy" and "PANDAS", "OCD", "compulsive" "pediatric autoimmune", "chorea" and "tic" limited by publication date of January 1, 1995, to July 31, 2015. Reviews without patients were not included in the review. Results: Nine papers matched our search criteria, including 6 case reports with 8 patients and 3 case series. Most case reports were in favor of TE, but this was by far not supported by the findings in the case series. The follow-up ranged from 2 to 36 months in case reports and from 24 to 36 in case series. Conclusion: Establishing the diagnosis of PANDAS is complicated because of underlying comorbidities in the field of neurology-psychiatry and the lack of a reliable biomarker. The positive outcome after TE as reported in case studies may be influenced by the postoperative medication and is not supported by the results of large-scale studies. In the light of the considerable postoperative morbidity rate, it appears wise to indicate TE for PANDAS only in supervised clinical studies.
- Streptococcus pyogenes : Basic Biology to Clinical Manifestations: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) [BOOK]
- BOOKUniversity of Oklahoma Health Sciences Center: Oklahoma City (OK)
- The inclusion of a chapter on pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (or PANDAS) is essential to provide a history of the disease and provide current…
The inclusion of a chapter on pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (or PANDAS) is essential to provide a history of the disease and provide current information about its association with Streptococcus pyogenes (group A streptococci), tics, obsessive compulsive disorder (OCD) and its relationship to Sydenham chorea (SC), which is the neurologic manifestation of acute rheumatic fever. PANDAS has been misunderstood and confusing to doctors since its discovery, but the original group of the first 50 cases as described by Dr Susan Swedo (Swedo, et al., 1998) has a similarity to Sydenham chorea that distinguishes this initial group from tic and OCD cases. As this chapter will examine, the acute onset is an important feature of these disorders, as are their piano-playing choreiform movements, enuresis, night-time fears, separation anxiety, learning regression, and handwriting disabilities. The most current literature, which has been recently published in the Journal of Child and Adolescent Psychopharmacology (Murphy, et al., 2015b; Murphy, Parker-Athill, Lewin, Storch, & Mutch, 2015a; Toufexis, et al., 2015; Gerardi, Casadonte, Patel, & Murphy, 2015; Chang, et al., 2015), provides new insight into the clinical phenotype of PANDAS; namely, a subgroup of pediatric acute-onset neuropsychiatric syndrome (PANS), which has been proposed to have multiple etiologies, including those that are genetic and immunologic, and that present either with or without preceding infections, such as with Streptococcus pyogenes (Toufexis, et al., 2015). PANS is a subtype of obsessive compulsive disorder (OCD) that presents with an abrupt onset or exacerbation of neuropsychiatric symptoms (Murphy, et al., 2015b), including moderate or severe OCD. Elevated anti-streptococcal antibody titers tended to have higher OCD severity and the symptoms tended to lead to sudden and severe impairment, due to comorbidities, such as anxiety, behavioral regression, depression, and suicidality. Comorbid tics in PANS were associated with decline in school performance, visuomotor impairment, eating disorders, deterioration of handwriting skills, and lower quality of life, as compared to children without tics (Murphy, et al., 2015b). In addition, clinical evaluation of youth with PANS and PANDAS and recommendations for diagnosis were reported from the 2013 PANS conference held at Stanford University where a group of clinicians and researchers who were academicians with clinical and research interest in PANDAS and PANS (Chang, et al., 2015). PANDAS is clearly a subtype of PANS (Murphy, et al., 2015b; Murphy, Parker-Athill, Lewin, Storch, & Mutch, 2015a; Chang, et al., 2015) and not all PANS cases have an underlying streptococcal infection—but all PANDAS cases are associated with streptococcal infections, at least temporally. When these diseases appear, treatment with antibiotics can be successful, and a treatment trial of cefdinir by Murphy and colleagues indicated that therapy with cefdinir, a β lactam antibiotic, provided notable improvements in tic symptoms rated by the Yale Global Tic Severity Scale (YGTSS) and OCD symptoms rated by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). However, the differences within the groups as a whole were not significant. β-lactam antibiotics have been proposed to be neuroprotective above and beyond their antibiotic efficacy (Murphy, Parker-Athill, Lewin, Storch, & Mutch, 2015a). Anti-neuronal autoantibodies against the brain in SC and PANDAS react with brain antigens including dopamine receptors (Cox, et al., 2013; Brimberg, et al., 2012), lysoganglioside (Kirvan, Swedo, Heuser, & Cunningham, 2003; Kirvan, Swedo, Snider, & Cunningham, 2006a), and tubulin (Kirvan, Cox, Swedo, & Cunningham, 2007), as well as the activation of the calcium calmodulin-dependent protein kinase II (CaM KII) in human neuronal cells (Kirvan, Swedo, Heuser, & Cunningham, 2003). Human anti-brain antibodies expressed in Tg mice targeted dopaminergic neurons and signaled the dopamine D2 receptor (D2R) (Cox, et al., 2013). Evidence strongly suggests that human anti-brain autoantibodies induced by Streptococcus pyogenes infections target the dopamine receptors (Cox, et al., 2013; Brimberg, et al., 2012) and that animal models immunized with the S. pyogenes antigen develop obsessive behaviors and movement problems, along with antibodies that react with the dopamine receptors and signal the CaMKII, similar to antibodies found in humans with SC and PANDAS (Brimberg, et al., 2012; Lotan, et al., 2014a).
- Streptococcus pyogenes : Basic Biology to Clinical Manifestations: Adhesion and invasion of Streptococcus pyogenes into host cells and clinical relevance of intracellular streptococci [BOOK]
- BOOKUniversity of Oklahoma Health Sciences Center: Oklahoma City (OK)
- The heterogeneous genus of Streptococci plays an important role in human disease. Streptococci are estimated to cause 700 million human infections each year worldwide, with an estimated total of 500,…
The heterogeneous genus of Streptococci plays an important role in human disease. Streptococci are estimated to cause 700 million human infections each year worldwide, with an estimated total of 500,000 deaths (Carapetis, McDonald, & Wilson, 2005). Louis Pasteur recognized streptococci as one of the first microorganisms to cause contagious disease in 1879. For family physicians, Streptococcuspyogenes has generally been associated with a sore throat (strep throat) and less often associated with complications, like rheumatic fever or glomerulonephritis. Since the late 1980s, a resurgence of severe infections by S. pyogenes have been reported, which involve expanding and invasive soft tissue infections, as well as necrotizing fasciitis, and which are often accompanied by streptococcal toxic shock syndrome (STSS) (Reglinski & Sriskandan, 2014). In 1998, a sudden onset of neuropsychiatric illness, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) following pharyngitis, was described (Swedo, et al., 1998). During the last decade, it became clear that a related species, S. dysgalactiae subsp. equisimilis, can cause many of the same kinds of human infections with similar complications. Over the past 20 years, β-hemolytic species of streptococci were recognized as highly capable intracellular pathogens that are able to efficiently invade human cells in cell culture. (LaPenta, Rubens, Chi, & Cleary, 1994; Greco, et al., 1995; Rohde & Chhatwal, 2013). Evidence indicates that streptococci can survive and persist within human cells and remain impervious to antibiotic treatment and innate immune defenses. A well-established assumption is that bacterial pathogens must first attain intimate contact with host extracellular matrix proteins (ECM) on host cells in order to establish successful infections. That initial contact with ECM proteins or cells is accomplished by highly specific adhesins (Courtney, Hasty, & Dale, 2002; Jenkinson & Lamont, 1997; Nobbs, Lamont, & Jenkinson, 2009). Adhesins and other macromolecules that trigger the uptake of bacteria or invasion of the host cells are named invasins. One hallmark of streptococci is the expression of a highly variable and extensive repertoire of adhesins and invasins. Those proteins are differentially regulated and expressed in response to signals from the different environments within the human host (Nobbs, Lamont, & Jenkinson, 2009). Streptococci sometimes use mechanisms similar to those of other intracellular bacterial species and viruses to invade host cells. Due to their variable repertoire of adhesins and invasins, streptococci have evolved numerous strategies to be internalised and survive in host cells for their own benefit, namely escaping antibiotic treatment and the host immune system (Cunningham, 2000; Courtney, Hasty, & Dale, 2002; Nitsche-Schmitz, Rohde, & Chhatwal, 2007; Nobbs, Lamont, & Jenkinson, 2009; Rohde & Chhatwal, 2013; Talay, Gram-positive adhesins, 2005). This chapter will focus on the extensive repertoire of adhesins and invasins that are expressed by β-hemolytic streptococci and will examine their molecular interactions with host human host cells, as well as address the clinical and epidemiologic relevance of intracellular streptococci.
- Antineuronal antibodies in a heterogeneous group of youth and young adults with tics and obsessive-compulsive disorder. [Journal Article]
- JCJ Child Adolesc Psychopharmacol 2015; 25(1):76-85
- CONCLUSIONS: Our study suggested a significant correlation of streptococcal-associated tics and OCD with elevated anti-D1R and antilysoganglioside antineuronal antibodies in serum concomitant with higher activation of CaMKII in human neuronal cells. Youth and young adults with chronic tics and OCD may have underlying infectious/immunologic etiology.
- Secondary enuresis associated with chorea in a nigerian girl. [Case Reports]
- IJIndian J Psychol Med 2014; 36(3):324-5
- Enuresis is a distressing psycho-social disorder. It is often a neglected disorder, and its effect on the psychosocial development of a child is often overlooked, especially in those of low socio-eco…
Enuresis is a distressing psycho-social disorder. It is often a neglected disorder, and its effect on the psychosocial development of a child is often overlooked, especially in those of low socio-economic status. Its exact pathophysiology is not completely understood, but it has been related to the effect of dopamine in the basal ganglia. However, its association with pediatric autoimmune neuropsychiatric disorder associated with streptococci infection is well-established. But, the case of an 11-year-old Nigerian girl diagnosed with Sydenham's chorea and had secondary enuresis is reported.
- Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection. [Review]
- IRInt Rev Immunol 2014 Jul-Aug; 33(4):314-29
- The group A streptococcus, Streptococcus pyogenes, and its link to autoimmune sequelae, has acquired a new level of understanding. Studies support the hypothesis that molecular mimicry between the gr…
The group A streptococcus, Streptococcus pyogenes, and its link to autoimmune sequelae, has acquired a new level of understanding. Studies support the hypothesis that molecular mimicry between the group A streptococcus and heart or brain are important in directing immune responses in rheumatic fever. Rheumatic carditis, Sydenham chorea and a new group of behavioral disorders called pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections are reviewed with consideration of autoantibody and T cell responses and the role of molecular mimicry between the heart, brain and group A streptococcus as well as how immune responses contribute to pathogenic mechanisms in disease. In rheumatic carditis, studies have investigated human monoclonal autoantibodies and T cell clones for their crossreactivity and their mechanisms leading to valve damage in rheumatic heart disease. Although studies of human and animal sera from group A streptococcal diseases or immunization models have been crucial in providing clues to molecular mimicry and its role in the pathogenesis of rheumatic fever, study of human monoclonal autoantibodies have provided important insights into how antibodies against the valve may activate the valve endothelium and lead to T cell infiltration. Passive transfer of anti-streptococcal T cell lines in a rat model of rheumatic carditis illustrates effects of CD4+ T cells on the valve. Although Sydenham chorea has been known as the neurological manifestation of rheumatic fever for decades, the combination of autoimmunity and behavior is a relatively new concept linking brain, behavior and neuropsychiatric disorders with streptococcal infections. In Sydenham chorea, human mAbs and their expression in transgenic mice have linked autoimmunity to central dopamine pathways as well as dopamine receptors and dopaminergic neurons in basal ganglia. Taken together, the studies reviewed provide a basis for understanding streptococcal sequelae and how immune responses against group A streptococci influence autoimmunity and inflammatory responses in the heart and brain.
- Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: implications in human disease. [Journal Article]
- JIJ Immunol 2013 Dec 01; 191(11):5524-41
- How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic mani…
How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic manifestation of streptococcal-induced rheumatic fever. Previously, our novel SC-derived mAb 24.3.1 was found to recognize streptococcal and brain Ags. To investigate in vivo targets of human mAb 24.3.1, VH/VL genes were expressed in B cells of transgenic (Tg) mice as functional chimeric human VH 24.3.1-mouse C-region IgG1(a) autoantibody. Chimeric human-mouse IgG1(a) autoantibody colocalized with tyrosine hydroxylase in the basal ganglia within dopaminergic neurons in vivo in VH 24.3.1 Tg mice. Both human mAb 24.3.1 and IgG1(a) in Tg sera were found to react with human dopamine D2 receptor (D2R). Reactivity of chorea-derived mAb 24.3.1 or SC IgG with D2R was confirmed by dose-dependent inhibitory signaling of D2R as a potential consequence of targeting dopaminergic neurons, reaction with surface-exposed FLAG epitope-tagged D2R, and blocking of Ab reactivity by an extracellular D2R peptide. IgG from SC and a related subset of streptococcal-associated behavioral disorders called "pediatric autoimmune neuropsychiatric disorder associated with streptococci" (PANDAS) with small choreiform movements reacted in ELISA with D2R. Reaction with FLAG-tagged D2R distinguished SC from PANDAS, whereas sera from both SC and PANDAS induced inhibitory signaling of D2R on transfected cells comparably to dopamine. In this study, we define a mechanism by which the brain may be altered by Ab in movement and behavioral disorders.
New Search Next
- Autoimmune neurological disorders associated with group-A beta-hemolytic streptococcal infection. [Case Reports]
- BDBrain Dev 2013; 35(7):670-4
- Although central nervous system (CNS) disorders associated with group-A beta-hemolytic streptococcal (GABHS) infection occur only rarely, Sydenham's chorea is a well-recognized disease that can arise…
Although central nervous system (CNS) disorders associated with group-A beta-hemolytic streptococcal (GABHS) infection occur only rarely, Sydenham's chorea is a well-recognized disease that can arise following infection. Children may develop a tic, obsessive compulsive disorder (OCD), and extrapyramidal movement subsequent to GABHS infection. These disorders have been termed pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). Herein we report one case each of acute disseminated encephalomyelitis (ADEM), PANDAS and subacute encephalitis associated with GABHS infection. To evaluate the pathogenesis of the CNS disorders associated with GABHS infection, we measured levels of neurotransmitters, cytokines, anti-neuronal autoantibodies, and performed immunohistochemistry using patient sera to stain human brain sections. All three cases showed psychiatric behavioral disorders. Immunotherapy was effective, and homovanillic acid levels in the cerebrospinal fluid (CSF) were elevated at the acute stage in all three cases. In each case of ADEM and PANDAS, immunohistochemistry demonstrated neuronal impairment in the basal ganglia during the acute stage. Neuronal immunoreactivity was visualized in the cerebral cortex at the acute stage in the case of subacute encephalitis. There was no direct correlation between immunoreactivity of patient sera on the brain sections and positivity of anti-neuronal autoantibodies or CSF biomarkers. The results suggest that autoimmune responses may modulate neurotransmission, and the use of patient serum for immunohistochemistry is a sensitive screening method for the detection of anti-neuronal autoantibodies in CNS disorders associated with GABHS infection.