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2012-10-01 ACUTE SYMPTOM CHANGES: IS IT PANDAS? Sco5 M. Smith, P.A. Full PotenAal Wellness Center 485A Route 1 south, suite 320 Iselin, New Jersey 08830 (732) 726-‐1222 www.fullpotenAalwellnesscenter.com DISCLOSURES With all treatments and recommenda0ons, please consult with your child’s health care provider before implementa0on. Funding was received for a study on hyperbaric treatment in Au0sm from the Interna0onal Hyperbaric Associa0on. I have no financial rela0onships with manufacturers of hyperbaric chambers. The use of every treatment in Au0sm is “off-‐label” except for Risperidone. There are no current approved treatments for PANDAS or PANS. All treatments are “off-‐label” and evidence based. Professional CredenAals President, Full Poten0al Wellness Center www.fullpoten0alwellnesscenter.com Trea0ng children on the Au0sm Spectrum since 2003. Member of Medical & Scien0fic Advisory Board, P.A.N.D.A.S. Resource Network www.pandasresoursenetwork.com ACUTE SYMPTOM CHANGES: IS IT PANDAS? Contribu0ng author on several au0sm ar0cles and studies. Presenter at the Na0onal Au0sm Associa0on annual conference and local NAA chapters. Helpful Terminology PANDAS: Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infec0on PITAND: Pediatric Infec0on Triggered Autoimmune Neuropsychiatric Disorder PANS: Pediatric Acute-‐onset Neuropsychiatric Syndrome GABHS: Group A Beta Hemoly0c Strep IVIG: Inter Venous Immunoglobulin COMMON CAUSES OF ACUTE SYMPTOM CHANGES IN AUTISM THE USUAL SUSPECTS! Dysbiosis (yeast/bacteria) Hidden infec0ons (OM/sinusi0s) Cons0pa0on Seizures Pain: (GI inflamma0on/Dental issues…) Allergies 1 2012-10-01 New ConsideraAons For Acute Symptom Changes WHY PANDAS to PANS? A broader diagnos0c term like PANS helps Pediatric Acute-‐onset Neuropsychiatric be]er describe the acute onset of symptoms in the affected children PANS takes away the e0ologic criteria for diagnosis PANDAS remains a sub-‐set of PANS caused by a known pathogen, Group A Beta Hemoly0c Streptococcus (GABHS) PANS allows for more than one possible trigger Syndrome (PANS) Infec0on triggered (PITAND) GABHS (PANDAS) Lyme disease Mycoplasma pneumonia Non-‐Infec0on triggered Environmental factors Metabolic disorders PANS Diagnos0c Criteria PANDAS to PANS PANDAS AuAsm Science Digest, April 2012 Because the new diagnosis of PANS is so vast, this presenta0on will concentrate on the PANDAS sub-‐set 2 2012-10-01 PANDAS WHAT IS IT AND HOW DID WE GET HERE? PANDAS It is caused by an an0body that the body makes to fight strep It requires a breach in the blood-‐brain barrier (BBB) It is an immunologic condi0on with neurologic symptoms Eradica0ng the strep does not get rid of the an0bodies that the body has already made As with all autoimmune diseases, the goal is more likely management than cure PANDAS BRIEF REPORTS Identification of Children With Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections by a Marker Associated With Rheumatic Fever Susan E. Swedo, M.D., Henrietta L. Leonard, M.D., Barbara B. Mittleman, M.D., Albert J. Allen, M.D., Ph.D., Judith L. Rapoport, M.D., Sara P. Dow, Melissa E. Kanter, Floresta Chapman, and John Zabriskie, M.D. PANDAS Pediatric Auto-‐Immune Neuropsychiatric Disorder Associated with Streptococcus infec0on PANDAS The Journal of Immunology, Vol 151, Issue 5 2820-‐2828, Copyright © 1993 by American Association of Immunologists ARTICLES Epitopes of streptococcal M proteins that evoke antibodies that cross-‐ react with human brain MS Bronze and JB Dale Department of Veterans Affairs Medical Center, Memphis, TN. “Our data indicate that streptococcal M proteins contain brain-‐cross-‐reactive epitopes that could potentially be involved in the pathogenesis of Sydenham's chorea.” PANDAS a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection 1997; 154:110–112) K Yaddanapudi1,2, M Hornig1,2, R Serge1, J De Miranda1, A Baghban1, G Villar1 and W I Lipkin1 1Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA Correspondence: Dr M Hornig, Center for Infection and Immunity, Mailman School of Public Health,Columbia University, 722 W 168th Street, New York, NY 10032, USA. E-‐ mail:[email protected] 2These authors contributed equally to this work. Received 25 February 2009; Revised 11 June 2009; Accepted 15 June 2009; Published online 11 August 2009. Abstract 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 β-‐hemolytic streptococcus matrix (M) protein and cross-‐react with molecular targets complement C4 protein and α-‐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. Molecular Psychiatry (2010) 15, 712–726; doi:10.1038/mp.2009.77; published online 11 August 2009 Objective: The authors’ goal was to determine whether a trait marker of rheumatic fever susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychiatric disorders (obsessive-‐compulsive disorder and tic disorders) associated with streptococcal infections (PANDAS). Method: Blood samples obtained from 27 children with PANDAS, nine children with Sydenham’s chorea, and 24 healthy children were evaluated for D8/17 reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells. Results: The frequency of D8/17-‐positive individuals was significantly higher in both patient groups than it was among the healthy volunteers: 85% of the children with PANDAS and 89% of the children with Sydenham’s chorea, compared with 17% of the healthy children, were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient groups and was significantly higher in these groups than in the group of healthy children. Conclusions: These results suggest that there may be a subgroup of D8/17-‐positive children who present with clinical symptoms of obsessive-‐compulsive disorder and Tourette’s syndrome, rather than Sydenham’s chorea, but who have similar poststreptococcal autoimmunity. (Am J Psychiatry Molecular Psychiatry (2010) 15, 712–726; doi:10.1038/mp.2009.77; published online 11 August 2009 Passive transfer of streptococcus-‐induced antibodies reproduces behavioral disturbances in 3 2012-10-01 SIGNS AND SYMPTOMS PRIMARY MUST HAVE AN ACUTE CHANGE IN OCD OR A NEW ONSET TIC ____________________________________________________________________________ SECONDARY Choreiform Movements Emo0onal Lability Personality Changes Age Inappropriate Behaviors Separa0on Anxiety Opposi0onal Defiance Sensory Defensiveness ADHD/Fidge0ness/Poor Focus Major Depression Deteriora0on Of Handwri0ng Or Math Skills Urinary Frequency/Enuresis Anorexia/Fear Of Being Poisoned/Fear Of Choking PANDAS SIGNS AND SYMPTOMS PANDAS The ini0al acute OCD or TIC presenta0on has to be associated with confirmed strep infec0on or exposure. Posi0ve throat culture Physical exam findings Elevated Strep 0ters Exposure to friends or family members with confirmed strep PANDAS Because the symptoms overlap, and the course of au0sm can be so variable, the ini0al PANDAS exacerba0on is oben overlooked and treated as a worsening of au0s0c symptoms or treated as other common biomedical issues seen with au0sm. The longer PANDAS goes unrecognized and untreated, the more refractory it becomes. PANDAS TESTING TESTING FOR PANDAS AND ACUTE SYMPTOM CHANGES THERE IS NO DIAGNOSITIC TESTING FOR PANDAS 4 2012-10-01 PANDAS TESTING ACUTE SYMPTOM CHANGE TESTING ADDITIONAL TESTING PANDAS ASO/An0 DNase B Throat Culture Mycoplasma Serology Lyme Tes0ng K.U.B ***Cam Kinase ***Lymphocyte D8/17 Yale/Brown OCD Scale Yale/Brown TIC Scale Organic Acids (yeast/ bacteria) Stool tes0ng (dysbiosis/ inflamma0on) A good physical exam ASO 0ters Rise about 1 week aber infec0on or exposure Reach their peak at 2 to 3 weeks Without re-‐infec0on, usually normalizes by 6 months Does not usually rise with strep infec0on of the skin An0-‐DNase B Be]er test for strep infec0on of the skin Without new infec0on 0ters remain elevated for as long as 3 months A dental exam EEG PANDAS TESTING PANDAS TESTING A normal ASO and An0-‐DNase B 0ter does not rule out PANDAS A posi0ve ASO or An0-‐DNase B 0ter does not mean you have PANDAS! You would also need to have acute behavior changes consistent with PANDAS. PANDAS TESTING This study looked at 52 children with confirmed strep ASO 0ter was elevated in 27 of 52 (51.9%) An0-‐DNase B 0ter was elevated in 18 of 52 (34.6%) These 0ter levels are not posi0ve in all cases of strep! PANDAS TESTING CAM KINASE Cam Kinase is a valuable tool for PANDAS Great for helping with PANDAS evalua0on in kids with ASD where the ini0al exacerba0on may have been missed Unfortunately, this test was performed through a research study and the IRB was not extended 5 2012-10-01 PANDAS TESTING PANDAS TESTING PANDAS TESTING PANDAS TESTING PANDAS TESTING PANDAS TESTING LYMPHOCYTE D8/17 Unfortunately, not currently commercially available This is the an0body iden0fied in Sydenham’s Chorea and ini0ally in PANDAS 6 2012-10-01 PANDAS TESTING PANDAS TESTING YALE-‐BROWN OBCESSIVE COMPULSIVE SCALE (Y-‐BOCS) Simple ques0onnaire performed by provider Evaluates mul0ple subtypes of obsessions Evaluates mul0ple types of compulsions PANDAS TESTING PANDAS TESTING YALE GLOBAL TIC SEVERITY SCALE Reviews types and frequency of motor 0cs Reviews types and frequency of vocal 0cs PANDAS TESTING Motor Tic Symptom Checklist In the boxes on the left below, please check with a mark (x) the tics the patient 1) has EVER experienced 2) is CURRENTLY experiencing (during the past week) State AGE OF ONSET (in years) if patient has had that behavior. _______________________________________________________________ ADDITIONAL TESTING Phonic Tic Symptom Checklist In the boxes on the left below, please check with a mark (x) the tics the patient 1) has EVER experienced 2) is CURRENTLY experiencing (during the past week) State AGE OF ONSET (in years) if patient has had that behavior. For Acute Behavior Changes 7 2012-10-01 ADDITIONAL TESTING MYCOPLASMA TESTING ADDITIONAL TESTING LYME TESTING IgG and IgM 0ters Can exist with several co-‐infec0ons Can be tested by PCR Lyme does not cause PANDAS, but is a Mycoplasma can be a possible trigger for possible trigger for PANS (PITAND sub-‐type) PANS (PITAND sub-‐type) ADDITIONAL TESTING Psychiatr Clin North Am. 2002 Mar;25(1):1-‐16. Psychiatric presentations of non-‐HIV infectious diseases.Neurocysticercosis, Lyme disease, and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection. Schneider RK, Robinson MJ, Levenson JL. Source Departments of Psychiatry and Internal Medicine, Division of Consultation-‐Liaison Psychiatry, Medical College of Virginia, Campus of Virginia Commonwealth University, Richmond, Virginia, USA. [email protected] Abstract Infectious diseases can cause an array of symptoms, including psychiatric symptoms. Psychiatrists serving the medically ill need to be aware not only of classic infectious diseases (e.g., neurosyphilis and HIV), but also of less commonly discussed infectious diseases (e.g., NCC, PANDAS, and Lyme disease). These examples represent an internationally endemic disease (e.g., NCC), a probable immunogenetic disease (e.g., PANDAS), and a frequently overdiagnosed and overtreated disease (Lyme disease). ADDITIONAL TESTING ADDITIONAL TESTING K.U.B. Common X-‐Ray of the abdomen Stands for kidney/ureter/bladder Used to rule out cons0pa0on Cons0pa0on can present with acute behavioral and cogni0ve changes ADDITIONAL TESTING ORGANIC ACIDS (OAT/ONE/ORGANIX) Yeast/fungal dysbiosis Clostridia dysbiosis Addi0onal bacteria, Klebsiella 8 2012-10-01 ADDITIONAL TESTING ADDITIONAL TESTING PHYSICAL EXAM A good physical can rule out causes of acute behavior changes O00s media Sinus infec0on Abdominal disten0on Signs of allergy DENTAL EXAM Tooth pain can be a cause of acute behavior changes ADDITIONAL TESTING EEG Seizure ac0vity can cause acute behavioral changes Some seizure ac0vity is sub-‐clinical and classic physical signs of a seizure may not be present PANDAS PANDAS A CONTROVERSIAL DIAGNOSIS. PANDAS Unfortunately, as is the case with new diseases and condi0ons, there is much controversy about PANDAS . Some do not believe it exists. Most disagree on how to diagnose. Most disagree on treatment strategies. 9 2012-10-01 PANDAS PANDAS and AUTISM Common Symptoms Similar Pathologies Similar Treatment Success PANDAS and AUTISM SYMPTOMS PANDAS OCD Anxiety Rigidity Sleep abnormalities Odd/Choreiform movements Emotional lability Attention/focus CHANGES ARE ACUTE AUTISM Repetitive Behaviors Anxiety Rigidity Sleep abnormalities Odd movements Emotional lability Attention/focus PANDAS and AUTISM COMMON TREATMENTS An0bio0cs An0-‐inflammatories (non steroids) Medica0ons Dietary supplements Steroids IVIG CHANGES ARE SEMI-‐ ACUTE COMMON TREATMENTS L-‐Taurine COMMON TREATMENTS ANTIBIOTICS Mul0ple studies show improvement with a variety of an0bio0cs in au0sm Mainstay of treatment for PANDAS 10 2012-10-01 COMMON TREATMENT Increased urinary excretion of a 3-‐(3-‐hydroxyphenyl)-‐3-‐hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Shaw W. Source The Great Plains Laboratory, Inc., Lenexa, Kansas 66214, USA. [email protected] Abstract A compound identified as 3-‐(3-‐hydroxyphenyl)-‐3-‐hydroxypropionic acid (HPHPA) was found in higher concentrations in urine samples of children with autism compared to age and sex appropriate controls and in an adult with recurrent diarrhea due to Clostridium difficile infections. The highest value measured in urine samples was 7500 mmol/mol creatinine, a value 300 times the median normal adult value, in a patient with acute schizophrenia during an acute psychotic episode. The psychosis remitted after treatment with oral vancomycin with a concomitant marked decrease in HPHPA. The source of this compound appears to be multiple species of anaerobic bacteria of the Clostridium genus. The significance of this compound is that it is a probable metabolite of m-‐tyrosine (3-‐hydroxyphenylalanine), a tyrosine analog which depletes brain catecholamines and causes symptoms of autism (stereotypical behavior, hyperactivity, and hyper-‐reactivity) in experimental animals. COMMON TREATMENTS ANTI-‐INFLAMMATORIES Mul0ple medica0on choices Spironolactone Singular Motrin Mul0ple supplement choices Omega 3 fa]y acids Boswellia Curcumin Querce0n COMMON TREATMENTS COMMON TREATMENTS COMMON TREATMENTS COMMON TREATMENTS 11 2012-10-01 COMMON TREATMENTS COMMON TREATMENTS IVIG A human blood product Very expensive Not recognized as a treatment for au0sm Considered experimental by insurance companies for the treatment of au0sm and PANDAS Ongoing PANDAS IVIG study at NIH Au0sm is a disqualifying factor COMMON TREATMENTS COMMON TREATMENTS COMMON TREATMENT COMMON TREATMENT L-‐TAURINE An amino acid An inhibitory (calming) neurotransmi]er Helps make bile salts Is wasted in children with au0sm Helps dysregula0on of Cam Kinase 12 2012-10-01 COMMON TREATMENT PANDAS and AUTISM COMMON PATHOLOGY PANDAS Autoimmunity to basal ganglia Permeable BBB Dopamine excess COMMON PATHOLOGY AUTISM Autoimmunity to basal ganglia Permeable BBB Dopamine excess COMMON PATHOLOGY ANTIBODIES TO BASAL GANGLIA Brain structure with 3 areas Striatum (caudate and putamen) Pallidum Substan0a Nigra Controls movement Plays a role in mo0va0on Affected area in some OCD COMMON PATHOLOGY COMMON PATHOLOGY 13 2012-10-01 COMMON PATHOLOGY Oxford Journals Medicine QJM: An International Journal of Medicine Volume96, Issue3 Pp. 183-‐191. Autoimmunity and the basal ganglia: new insights into old diseases Abstract Sydenham's chorea (SC) occurs weeks or months after Group A streptococcal infection, and is characterized by involuntary, purposeless movements of the limbs, in addition to behavioural alteration. There is a body of evidence which suggests that SC is an immune-‐mediated brain disorder with regional localization to the basal ganglia. Recent reports have suggested that the spectrum of post-‐streptococcal CNS disease is broader than chorea alone, and includes other hyperkinetic movement disorders (tics, dystonia and myoclonus). In addition, there are high rates of behavioural sequelae, particularly emotional disorders such as obsessive-‐compulsive disorder, anxiety and depression. These findings have lead to the hypothesis that similar immune-‐mediated basal ganglia processes may be operating in common neuropsychiatric disease such as tic disorders, Tourette syndrome and obsessive-‐compulsive disorder. This review analyses the historical aspects of post-‐ streptococcal CNS disease, and the recent immunological studies which have addressed the hypothesis that common neuropsychiatric disorders may be secondary to basal ganglia autoimmunity. COMMON PATHOLOGY Permeability of blood-‐brain barrier COMMON PATHOLOGY COMMON PATHOLOGY Mol Psychiatry. 2010 Jul;15(7):712-‐26. Epub 2009 Aug 11. Passive transfer of streptococcus-‐induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disordersassociated with streptococcal infection . Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G, Lipkin WI. Source Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. Abstract 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 autoimmuneneuropsychiatric 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 thisneuropsychiatric 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 beta-‐ hemolytic streptococcus matrix (M) protein and cross-‐react with molecular targets complement C4 protein and alpha-‐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. COMMON PATHOLOGY PANDAS is an autoimmune disorder as stated in its defini0on. The an0bodies created for strep should not have access to the brain. The fact that they do demonstrates the blood-‐ brain barrier permeability and dysfunc0on. MY CHILD MAY HAVE PANDAS, NOW WHAT? 14 2012-10-01 PANDAS, NOW WHAT? Visit www.pandasresourcenetwork.com for support and informa0on. Make sure your provider is well versed in trea0ng PANDAS Avoid strep exposures. Become friendly with your school nurse; she may be able to no0fy you when there are kids out of school with strep Keep the GI tract as healthy as possible, healthy bacteria help regulate immune response and down regulate inflammatory cytokines PANDAS NOW WHAT? PANDAS NOW WHAT? Screen family members for current infec0ons or carrier state All three tests should be done (ASO/An0-‐DNase/ Throat culture) to look for acute infec0ons vs carrier states carrier does not get ill from strep carrier will not make strep an0bodies (if you have aso/ an0dnase+, you are not a carrier) tradi0onal an0bio0cs by themselves will not eradicate the carrier state Consider screening pets (dogs) PANDAS NOW WHAT? Avoid s0mulant medica0ons (Ritalin®/ Concerta®/Adderall®/Vyvanse®) Can worsen anxiety, OCD, and 0cs by raising dopamine Limit use of tradi0onal OCD medica0ons, as they are usually ineffec0ve SSRI TCA PANDAS NOW WHAT? PANDAS NOW WHAT? TONSILLECTOMY Some posi0ve case studies Risk of surgery and anesthesia Mixed success post surgery Tonsils are not the only possible strep infec0on site 15 2012-10-01 PANDAS NOW WHAT? PANDAS NOW WHAT? CONCLUSIONS CONCLUSIONS PANDAS and au0sm can occur together In pa0ents with au0sm, PANDAS should be considered whenever there is an acute change in behaviors or whenever there is a second regression In pa0ents with au0sm, PANDAS is oben ini0ally missed or explained as worsening of au0sm symptoms SPECIAL THANKS My great family My office staff and co-‐workers My paAents who keep asking tough quesAons and make me find the answers AUTISM CANADA There are several causes of acute changes in behavior Several condi0ons have symptoms that look like PANDAS Only strep can cause PANDAS, but with the diagnos0c transi0on to PANS, there are several other suspected triggers Sco5 M. Smith, P.A. FULL POTENTIAL WELLNESS CENTER 485A Route 1 south, suite 320 Iselin, New Jersey 08830 (732) 726-‐1222 www.fullpotenAalwellnesscenter.com 16
