Immune system, autism and PANDAS/PANS
Pediatric Autoimmune Neuropsychiatric Disorders (PANDAS) And Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)
Prepared By Gail Szakacs, MD and Nancy O’Hara, MD
Author Contact information: Center for Integrative Health, LLC Nancy H. O'Hara, MD & Gail M. Szakacs, MD 3 Hollyhock Lane Wilton, CT 06897 Tel: 203-834-2813 Fax: 203-834-2831
Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal Infections, or PANDAS, is a common autoimmune disorder with far-reaching movement, behavioral, and cognitive consequences. Although we focus on the pediatric population as part of the PANDAS syndrome in this review, immune-mediated OCD/Tics/Neuropsychiatric Disorders can also affect adolescent and adult populations and should always be considered when specific signs and symptoms emerge.
As noted by Dr Sue Swedo at the NIH in the late 1990’s, PANDAS involves antibodies from a streptococcal infection reacting with brain tissue (specifically the basal ganglia) and triggers movement and behavioral problems. Rheumatic Fever is an older known disorder that illustrates this same disease process, in which antibodies from a streptococcal infection attack the heart valves, joints, and brain and result in heart disease, arthritis, and Sydenham’s Chorea. Although bacteria set the vicious cycle in motion, the real damage in this type of autoimmune disorder stems from the antibodies and the inappropriate immune response.
Although the exact mechanism of the autoimmune process involved with PANDAS is still under investigation, research published in The Journal of Neuroimmunology in 2006 by Kirvan, et al suggests the mechanism involves antibody-mediated cell-signaling post group A streptococcal infections. The antibodies produced in group A streptococcal infections are thought to penetrate the blood brain barrier (BBB) and activate a brain enzyme (CaM kinase II) with multiple functions that are negatively impacted in various neuropsychiatric disorders. The article notes that those with PANDAS have higher CaM kinase II activation than those with non-PANDAS OCD, tic, and ADHD groups not associated with streptococcal infection.
Although PANDAS is a clinical diagnosis, the traditional criteria for PANDAS include:
1. OCD and/or Tic Disorder
2. Pediatric onset of symptoms (age 3 to puberty) – sudden/dramatic onset
3. Episodic course of symptom severity (waxes and wanes)
4. Association with group A beta-hemolytic streptococcal infection (such as through a positive throat culture for strep or history of Scarlet Fever)
5. Association with neurologic abnormalities (such as motoric hyperactivity, choreiform movements, etc.)
Clinical experience reveals that traditional criteria for PANDAS do not capture the full scope and complexity of what is involved with the presentation, diagnosis, and treatment of this disorder. One must also consider the presence of other signs/ symptoms co-morbidities, frequent lack of known strep exposure/illness, specific lab abnormalities (or lack thereof), and response to treatment.
Other signs, symptoms, and comorbid diagnoses noted in children with PANDAS include irritability, personality changes, aggression, uncontrolled agitation, fear about bedtime regimen, fidgetiness, emotional lability, anxiety, enuresis, motoric symptoms (tics, handwriting changes, motoric hyperactivity, compulsive rituals), sensory defensiveness, impulsivity, depression, dysthymia, separation anxiety, anorexia, ADD, and ADHD.
Laboratory tools are limited and the traditional abnormalities of increased blood strep titers (ASO and DNAseB antibodies) and a positive throat culture are not always present. Therefore, normal levels of strep antibodies and negative cultures do not exclude the PANDAS diagnosis. Streptococcal bacteria found in gastrointestinal testing may provide a clue given other signs and symptoms consistent with PANDAS, but it is not enough to make a diagnosis. The emerging research noted above involving CaM kinase and anti-neuronal antibodies is promising and has important diagnostic and therapeutic implications. These newer tests are particularly helpful when blood ASO and DNAseB antibodies and other tests are negative in a child in whom PANDAS is suspected, however they are not yet commercially available.
As mentioned earlier, the real problem is thought to be the damage resulting from the inappropriate immune response to the bacterial infection. Damage from the antibodies recurs with each subsequent streptococcal exposure and PANDAS flare. Research studies have shown that antibodies alone are enough to cause the behavioral and movement problems noted in those with PANDAS. This is a crucial point, in that adequate PANDAS treatment requires comprehensive immune therapy, in addition to antibiotics. One is not enough without the other, and immune therapy is likely the more important of the two treatment arms.
Treatments to consider for PANDAS (one should discuss with primary doctor involved, but referral to an Immunologist experienced in PANDAS diagnosis and treatment is also recommended):
1. Antibiotics (used daily for treatment and sometimes less frequently for prophylaxis – zithromax, omnicef, penicillin, IM bicillin, clindamycin, etc)
2. Immune Modulation Therapy
a. Corticosteroids (short-term use of tapering dose – positive response often indicates the patient is more likely to respond positively to IVIG, but no response does not mean IVIG will be ineffective)
b. Intravenous immunoglobulin (IVIG) -- derived from human blood; pooled from many donors; can provide antibodies in those who are lacking them; can help to inactivate antigens and slow down an overactive immune system that is functioning inappropriately; case reports and studies show effectiveness
c. Plasmaphoresis – a type of plasma transfusion to remove antibodies; various case reports reveal positive results, but lack of long-term studies
d. Other natural anti-inflammatory and immune supporting therapies (curcumin, essential fatty acids, transfer factor/colostrum, probiotics, etc)
3. Natural antimicrobial therapies
a. Probiotics, including Saccharomyces Boulardii
c. Antimicrobial herbs (Berberine, etc)
4. Removal of adenoids and tonsils (no good studies on this; may even worsen signs and symptoms in some cases; but can still consider in certain cases where appropriate after referral to ENT Physician familiar with PANDAS).
5. Medications like SSRI’s (Prozac, Zoloft, etc) can often act as a “patch” for OCD or other symptoms, but should only be considered for short-term use in certain cases
PANDAS is a devastating autoimmune disorder in children that highlights another link between chronic and recurrent infection and neuropsychiatric and behavioral problems. Ongoing clinical experience and emerging research reveals the depth and scope of problems stemming from PANDAS is much more far-reaching than previously thought. While OCD and tics are still common, other issues like anxiety, bedtime fears, enuresis, aggression, and deficits in learning, attention, and social interaction are among the many manifestations that result from PANDAS and impair the daily functioning and cognitive progress for many children. Heightened clinical suspicion and more appropriate and comprehensive treatment with antibiotics and immune-modulating therapy will transform PANDAS from a devastating chronic illness with episodic flares into a treatable disorder.
PANDAS & PANS References:
Allen et al. Case Study: A New Infection-Triggered, Autoimmune Subtype of Pediatric OCD and Tourette's Syndrome, J Am Acad Child Adol Psych 1995, Vol. 34, Issue 3, Pages 307-311.
Bombaci et al. Protein Array Profiling of Tic Patient Sera Reveals a Broad Range and Enhanced Immune Response against Group A Streptococcus Antigens. PLoS One, 2009, 4(7): e6332.
Bradstreet et al. Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders, Med Hypoth. 2007;68(5):979-87. Epub 2006 Dec 5.
Cardona et al. Group A streptococcal infections and tic disorders in an Italian pediatric population. J Peds 2001.
Chmelik et al. Varied presentation of PANDAS: a case series. Clinical Pediatr. 2004, 43(4):379-82.
Cunningham, MW. Pathogenesis of Group A Streptococcal Infections. M Clin Microbiol, 2000, 13: 470–511.
Cunningham MW. Pathogenesis of group A streptococcal infections and their sequelae. Adv Exp Med Biol, 2008, 609: 29–42.
Cunningham MW, et al. Autoimmunity and behavior: Sydenham’s chorea and related disorders. J Neuroimmunology. 2008;203:185.
Ercan et al,.Mycoplasma pneumoniae infection and obsessive-compulsive disease: a case report. J Child Neurol, 2008; 23 (3):338-340.
Gabbay 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.
Galvin et al, J Clin Invest 2000.106: 217-224.
Hahn et la, Am Fam Phys 2005 May 15;71(10):1949-54
Hahn et al, Kelly’s Textbook of Rheumatology. 8th ed. Philadelphia, Pa: Saunders Elsevier; 2008: chap 74
Hoekstra PJ, et al. Association of common cold with exacerbations in pediatric but not adult patients with tic disorder: a prospective longitudinal study. J Child Adolesc Psychopharm. 2005; 15:285–292.
James et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004; 80: 1611-7.
Kawikova et al, Decreased number of regulatory T cells suggests impaired immune tolerance in children with Tourette’s syndrome. Biol Psychiatry. 2007; 61(3):273–8.
Kawikova et al. Children with Tourette’s syndrome may suffer IgA dysgammaglobulinemia: preliminary report. Biol Psychiatry. 2010; 67(7):679–83.
Kirvan et al. Antibody-mediated neuronal cell signaling in behavior and movement disorders. J Neuroimmunol. 2006;179:173–179.
Kirvan et al. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med 2003; 9: 914–920.
Kurlan R, et al. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: A prospective blinded cohort study. Pediatrics 2008; 121:1188–1197.
Kurlan R, et al. 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: 883–886.
Leckman et al. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: A prospective longitudinal study, J Am Acad Child Adolesc Psychiatry. 2011 February; 50(2): 108–118.e3.
Leslie et al. Neuropsychiatric disorders associated with streptococcal infection: A case-control study among privately insured children. J Am Acad Child Adolesc Psychiatry. 2008; 47(10):1166–72
Lewin et al. Neurocognitive functioning in youth with pediatric autoimmune neuropsychiatric disorders associated with streptococcus. J Neuropsychiatry Clin Neurosci. 2011 Fall;23(4):391-8.
Lit et al. A subgroup of Tourette’s patients over express specific natural killer cell genes in blood: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2007; 144B(7): 958–63.
Mell et al. Association between streptococcal infection and obsessive-compulsive disorder, Tourette’s syndrome, and tic disorder. , Pediatrics 2005; 116 (1): 56-60.
Murphy et al. Detecting pediatric autoimmune neuropsychiatric disorders asso- ciated with Streptococcus in children with obsessive-compulsive disorder and tics. Biol Psychiatry 2004; 55:61–68.
Murphy et al. Relationship of movements and behaviors to Group A Streptococcus infections in elementary school children. Biol Psychiatry 2007; 61:279–284.
Murphy et al. The immunobiology of Tourette’s disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: a way forward. J Child Adolesc Psychopharmacol. 2010; 20(4):317–31.
Murphy et al. Clinical Factors Associated with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, J Pediatr 2012;160:314-9.
Paluck et al. Prescribing practices and attitudes toward giving children antibiotics. Can Fam Physician 2001; 47:521–527.
Perimutter et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999; 354(9185):1153–8.
Perrin et al. Does group A beta-hemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children? Arch Pediatr Adolesc Med. 2004;158 (9):848–56.
Singer et al. Moving from PANDAS to CANS. J Pediatr 2012.
Snider LA, Sachdev V, MaCkaronis JE, St Peter M, Swedo SE (2004) Echocardiographic findings in the PANDAS subgroup. Pediatrics. 114: e748- 751.
Snider, LA et al. PANDAS: current status and directions for research. Mol Psychiatry, 2004. 9(10): p. 900-7.
Snider et al. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders. Biol Psychiatry.2005; 57 (7):788– 792
Swedo, S.E., et al., Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry, 1998. 155(2): p. 264-71.
Swedo, S.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(1): p. 110-2.
Swedo et al. The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. Pediatrics. 2004; 113: 907-911.
Swedo et al. From Research Subgroup to Clinical Syndrome: Modifying the PANDAS Criteria to Describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Ped Ther. 2012; 2 (2): 1-8.
Tait et al. The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease. , J Leuko Biol 2008