Answer:
PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with group A Streptococcus) is a complex syndrome associated with the immune response to streptococcal infection. The manifestations are complex behavior and functional changes including tic disorders, other increased neuromuscular activity such as fidgeting and hyperactivity, obsessive-compulsive behavior and other psychologic changes including anxiety, depression and emotional lability. There is controversy concerning the diagnosis as the syndrome is broad. There is overlap with other acute neuropsychiatric syndromes in children attributed to medications, viral infections and metabolic disorders. The relationship between group A streptococcal infection and the complex neuropsychiatric changes are based upon observations of individuals with prior streptococcal infection developing the manifestations, an increase in obsessive-compulsive behavior in children with Sydenhams chorea (an accepted complication of Group A streptococcal infection) and the complex immunologic effects of the response to group A streptococcal infection. The latter include evidence that immune response to the bacteria may lead to autoantibody recognizing the heart (rheumatic carditis) and/or the central nervous system (Syndenhams chorea). Typically the condition develops suddenly in children between 3 years of age and puberty. Most experts suspect the affected individual is predisposed to this condition but the infection exacerbates or triggers the development of the condition. Many of the affected children showed evidence of less severe manifestations prior the putative infection.
The immunologic connection with group A streptococcal infection is supported by evidence of neuronal antibodies in serum of affected children and possible improvement with immunologic therapy including systemic corticosteroids, plasmapheresis or other immunomodulators (1-3). However, there is no accepted therapy except for acute treatment of streptococcal infection if identified. Other studies have not confirmed the presence or predictive value of the neuronal autoantibodies further clouding the pathogenesis (4-5). The relationship with PANDAS like syndromes with other viruses such as measles is even more controversial.
My suggestion would be to ensure the child was investigated for group A streptococcal infection and appropriately treated. The value of delayed antistreptococcal therapy is unknown. I would consider prophylactic therapy for group A streptococcal disease, as is recommended for prior rheumatic fever, if streptococcal infection were confirmed at onset. I would not suggest any immunomodulator therapy unless the family wishes to go to a center with an interest in PANDAS. A resource for such research centers is here. Based upon the information provided, I would reassure the parents that the child is normally immunologically or pursue more in-depth evaluation of immunity if you deem necessary. I would also exclude, if appropriate, other causes of respiratory disease or recurrent infection, such as asthma, allergy or cystic fibrosis. I do not think the measles antibody titer nor the occurrence of the other infections is related to PANDAS. In my opinion there is no value in following the measles antibody titer or any other titer, and I would not modify the therapy based upon the measles antibody titer. The prognosis is not predictable and the child should be under the care of an experienced pediatric specialist who evaluates and treats the related behavioral disorders. If further information is needed I would again recommend consultation at a research center (see above).
1. Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome. Allen AJ, Leonard HL, Swedo SE J Am Acad Child Adolesc Psychiatry. 1995;34(3):307.
A review of clinical observations and literature reports leads to the hypothesis that, via a process analogous to Sydenham's chorea, infections with group A beta-hemolytic streptococci, among others, may trigger autoimmune responses that cause or exacerbate some cases of childhood-onset obsessive-compulsive disorder (OCD) or tic disorders (including Tourette's syndrome). If this hypothesis is correct, then immunological treatments should lead to decreased symptoms in some cases. Four cases with abrupt, severe onset or worsening of OCD or tics are presented from an open treatment study. All were boys aged 10 to 14 years. One had OCD, one had Tourette's syndrome, and two had both OCD and Tourette's syndrome. Clinically and on standardized rating scales, their symptoms were in the moderate to very severe range. Two had evidence of recent group A beta-hemolytic streptococci infections, and the others had histories of recent viral illnesses. Two were treated with plasmapheresis, one with intravenous immunoglobulin, and one with immunosuppressive doses of prednisone. All had a clinically significant response immediately after treatment. Diagnostic criteria are provided that describe these cases of pediatric, infection-triggered, autoimmune neuropsychiatric disorders (PITANDs). Suggestions are made regarding the evaluation and management of patients who may have this condition.
2. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, Swedo SE
Lancet. 1999;354(9185):1153.
Background: In children, exacerbations of tics and obsessive symptoms may occur after infection with group A beta-haemolytic streptococci. If post-streptococcal autoimmunity is the cause of the exacerbations, then children might respond to immunomodulatory treatments such as plasma exchange or intravenous immunoglobulin (IVIG). We studied whether plasma exchange or IVIG would be better than placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms.
Methods: Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome, were randomly assigned treatment with plasma exchange (five single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG). Symptom severity was rated at baseline, and at 1 month and 12 months after treatment by use of standard assessment scales for OCD, tics, anxiety, depression, and global function.
Findings: 30 children entered the study and 29 completed the trial. Ten received plasma exchange, nine IVIG, and ten placebo. At 1 month, the IVIG and plasma exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children's Yale-Brown obsessive compulsive scale score of 12 [45%]and 13 [58%], respectively), anxiety (2.1 [31%]and 3.0 [47%]improvement on National Institute of Mental Health anxiety scale), and overall functioning (2.9 [33%]and 2.8 [35%]improvement on National Institute of Mental Health global scale). Tic symptoms were also significantly improved by plasma exchange (mean change on Tourette syndrome unified rating scale of 49%). Treatment gains were maintained at 1 year, with 14 (82%) of 17 children "much" or "very much" improved over baseline (seven of eight for plasma exchange, seven of nine for IVIG).
Interpretation: Plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders. Further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies.
3. A putative poststreptococcal case of OCD with chronic tic disorder, not otherwise specified.Tucker DM, Leckman JF, Scahill L, Wilf GE, LaCamera R, Cardona L, Cohen P, Heidmann S, Goldstein J, Judge J, Snyder E, Bult A, Peterson BS, King R, Lombroso P. J Am Acad Child Adolesc Psychiatry. 1996;35(12):1684.
A 12-year-old girl presented with an atypical, recurrent, increasingly treatment-resistant case of obsessive-compulsive disorder and chronic tic disorder associated with profound separation anxiety, learning difficulty, and intermittent upper respiratory symptoms. In addition to detailed reviews of history and findings from many clinical caretakers from the prior 7 years, current pediatric, psychiatric, neuropsychological, neuroimaging, and clinical laboratory data were also available. Treatment options were considered from multiple perspectives: psychoanalytically oriented psychotherapy, conventional pharmacotherapy, family interventions, cognitive-behavioral therapy, and learning-supportive strategies. Psychological, neuropsychiatric, and neuroimmunological formulations of etiology were considered. Subsequent treatments included supportive psychotherapy, neuroleptic augmentation of selective serotonin reuptake inhibitors, prophylactic penicillin, and a course of six sessions of plasmapheresis over a 2-week period. The case raises questions for ongoing consideration that juxtapose dynamic, neuropsychiatric, and neuroimmunological perspectives.
4. Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls. Morris CM, Pardo-Villamizar C, Gause CD, Singer HS. J Neurol Sci. 2009;276(1-2):45.
PANDAS and some cases of Tourette syndrome (TS) have been proposed to be post-streptococcal movement disorders in which antibodies produced against group A beta-hemolytic streptococcus cross react against brain epitopes. Attempts to identify disease specific anti-striatal antibodies in the serum of affected patients have focused on the use of Western immunoblotting and ELISA methodologies. In this study, immunohistochemical techniques were used to identify serum anti-striatal antibody reactivity. In positive samples, double staining with anti-GFAP (glial) and anti-MAP2 (neuronal) was used to establish localization of the immunofluorescence. No significant differences in immunofluorescence or localization were identified in patients with PANDAS (n=30) and TS (n=30) as compared to controls (n=30). IF reactivity did not correlate with tic severity or elevated titers of antistreptococcal antibodies. Further comparisons showed no correlation between autoreactivity determined by immunofluorescence and the presence of previously measured immunoblot reactivity against human caudate or putative antigens (pyruvate kinase M1 and aldolase C). These results confirm an inability to distinguish patient populations by antibody measurements and raise further concerns about the presence of an autoimmune mechanism in PANDAS and TS.
5. Antibody binding to neuronal surface in Sydenham chorea, but not in PANDAS or Tourette syndrome Brilot F, Merheb V, Ding A, Murphy T, Dale RC. Neurology. 2011;76(17):1508. Epub 2011 Mar 16.
Objective: To test the hypothesis that Sydenham chorea (SC) immunoglobulin G (IgG) autoantibodies bind to specific neuronal surface proteins, whereas IgG from patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) or Tourette syndrome (TS) do not bind to neuronal surface proteins.
Methods: We used live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics. Using flow cytometry, we measured serum IgG cell surface binding in patients with SC (n = 11), PANDAS (n = 12), and TS (n = 11), and compared the findings to healthy controls (n = 11) and other neurologic controls (n = 11). In order to determine the specificity of binding to neuronal antigens, we also used a non-neuronal cell line, HEK 293.
Results: The mean IgG cell surface binding was significantly higher in the SC group compared to all other groups (p<0.001). By contrast, there was no difference between the PANDAS or TS groups and the controls. Using the non-neuronal HEK-293 cells, there was no significant difference in IgG cell surface binding between any groups.
Conclusions: Serum autoantibodies that bind to neuronal cell surface antigens are present in SC, but not in PANDAS or TS. These findings strengthen the hypothesis that SC is due to a pathogenic autoantibody, but weaken the autoantibody hypothesis in PANDAS and TS.
I hope this information is of help to you and your patient.
All my best.
Dennis K. Ledford, MD, FAAAAI