PANS - A Detailed Study of the Patients, Their Symptoms, Biomarkers and Treatment Offered in a Scandinavian Cohort

Background: Obsessive-compulsive disorder (OCD) is considered one of the most debilitating of the psychiatric illnesses, yet much remains unclear regarding causes and cures. A diagnostic subgroup with acute onset of obsessive-compulsive symptoms (and sometimes tics or anorexia nervosa) possibly due to an autoimmune response, has been entitled Pediatric Acute onset Neuropsychiatric Syndrome (PANS). PANS is sometimes treated with immunomodulatory therapy or antibiotics, with a variable outcome. A diagnosis of PANS is supported by elevated levels of auto-antibodies and antibody-enzyme activity measured with the Cunningham panel, but the relationship between these biomarkers and the patients' symptoms remains unclear. A clinician rated symptom scale for PANS (the PANS scale) has been developed, but needs to be further evaluated regarding sensitivity and specificity.

Aims:

• To assess a Swedish cohort of patients diagnosed with PANS and compile their psychiatric health status, biomarkers, psychiatric symptoms, soft neurological signs and treatment outcomes in a systematic way
• To compare psychiatric health status, biomarkers and psychiatric, neurologic and motor symptoms in this PANS cohort with a control group of psychiatric patients and with healthy children.
• To evaluate the Cunningham panel as a diagnostic tool for PANS.
• To evaluate a clinician rated symptom scale (the PANS scale) as a diagnostic tool for PANS.

Method: Observational study Participants: Patients (n≈150) who have been tested with the Cunningham panel of PANS biomarkers in Sweden (or Swedish patients tested in Denmark) will be asked to participate.

Procedure: Assessment of current symptoms, psychiatric health, neurological and motor symptoms and possible biomarkers for PANS will be collected for all patients. Retrospective assessment through interview and medical records, including results from the first assessment with the Cunningham panel of PANS-biomarkers is made with all patients. 50 out of the total PANS cohort of 150 patients will be re-tested with the Cunningham panel. A control group consisting of psychiatric patients (n=60) and healthy children (n=25) will be examined with a similar test battery and signs and symptoms will be compared with the PANS group.

Significance:

Previous and current symptoms of PANS, levels of PANS biomarkers and treatment outcome will be investigated, thus knowledge regarding long-term outcome and evidence for the use of clinical assessment tools and biomarkers for diagnosing PANS will be gained.

Study Overview

• Status: Completed
• Conditions: PANDAS; Obsessive-compulsive Disorder; Obsessive-compulsive Disorder With Acute Onset; Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections; Pediatric Acute-onset Neuropsychiatric Syndrome (PANS); Childhood Acute Neuropsychiatric Symptoms (CANS)

Detailed Description

Data collected comprises:

Retrospective data

• Interview
• Medical records
• Five to Fifteen (FTF)
• Cunningham panel of PANS biomarkers result prior to inclusion (at time point 1)
• Change in Clinical Global Impression-Improvement (CGI-I) since the first assessment of the Cunningham panel

Current data

Current levels of Cunningham panel of PANS biomarkers

• Cunningham panel of PANS biomarkers at time point 2

Current neuropsychiatric status

• Psychiatric interview
• PANS symptom scale

Standardized assessment for children:

• Child behavior checklist (CBCL)
• The Autism spectrum Quotient: Children's version (AQ-Child)
• Brief Obsessive-Compulsive Scale (BOCS)
• Mini international Neuropsychiatric Interview - KID (M.I.N.I. KID)
• Five to Fifteen (FTF)

Standardized assessment for adults:

• Schizotypal Personality Disorder Questionnaire (SPQ)
• Liebowitz social anxiety scale (LSAS)
• The Autism spectrum Quotient (AQ)
• Adult ADHD Self-Report Scale (ASRS)
• Brown Attention-Deficit Disorder Scales (Brown ADD Scales)
• Quality of Life Inventory (QOLI)
• Brief obsessive-compulsive scale (BOCS)
• Mini international Neuropsychiatric Interview (M.I.N.I.)
• FTF retrospective data

Current soft neurological signs

• Alternating skips
• Romberg's balance test
• Diadochokinesia
• Involuntary finger movements

Current neuropsychological status

• Drawing exercises
• Writing exercises
• WAIS/WISC Block design
• WAIS/WISC Digit Span
• WAIS/WISC Letter Number Sequencing
• WAIS/WISC Digit Symbol Coding

Current biomarkers in blood/serum

• D8/17 antigen expression
• Human leukocyte antigen (HLA)
• C-reactive protein (CRP)
• T-cell activation
• Human proteome serum analysis

• Study Type: Observational
• Enrollment (Anticipated): 185

Contacts and Locations

Study Locations

• Sweden
  • Sverige
    • Stockholm, Sverige, Sweden, SE-112 81
      • Northern Stockholm psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Consecutive cases that have been assumed to have PANS and have been assessed with the Cunningham panel in Scandinavia.

Description

Inclusion Criteria the PANS-group:

• Scandinavian patients assessed with the Cunningham panel through Wieslab, Lund, Sweden or Statens Serum Institut (SSI), Copenhagen, Denmark.

Exclusion Criteria PANS-group:

• intellectual disability, non-Swedish speaking

Inclusion Criteria Psychiatric Controls:

• diagnosed with a psychiatric disorder
• age <40 years

Exclusion Criteria Psychiatric Controls:

• intellectual disability, non-Swedish speaking

Inclusion Criteria Healthy Controls:

• age and sex matched to the PANS-group

Exclusion Criteria Healthy controls:

• intellectual disability, non-Swedish speaking

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Other

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
PANS group; All current Swedish cases investigated with the Cunningham panel (approximately 150 individuals) will be invited to participate in the study. 50 of these will be re-assessed with the Cunningham panel.
Psychiatric controls; 60 individuals with psychiatric disorder (eg. ADHD, autism spectrum disorder, psychosis, major depression, obsessive-compulsive disorder) will be recruited.
Healthy controls; 25 age and sex matched children to the PANS group will be recruited.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Psychiatric health of individuals assessed with the Cunningham Panel of PANS-biomarkers	up to 4 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Sensitivity and Specificity of the Cuningham-Panel of PANS biomarkers as a diagnostic tool for PANS	up to 4 years

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: The Swedish Research Council

Publications and helpful links

General Publications

• Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, Swedo SE. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999 Oct 2;354(9185):1153-8. doi: 10.1016/S0140-6736(98)12297-3.
• Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998 Feb;155(2):264-71. doi: 10.1176/ajp.155.2.264. Erratum In: Am J Psychiatry 1998 Apr;155(4):578.
• Kirvan CA, Swedo SE, Heuser JS, Cunningham MW. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med. 2003 Jul;9(7):914-20. doi: 10.1038/nm892.
• Kirvan CA, Swedo SE, Snider LA, Cunningham MW. Antibody-mediated neuronal cell signaling in behavior and movement disorders. J Neuroimmunol. 2006 Oct;179(1-2):173-9. doi: 10.1016/j.jneuroim.2006.06.017. Epub 2006 Jul 27.
• Murphy TK, Sajid M, Soto O, Shapira N, Edge P, Yang M, Lewis MH, Goodman WK. Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics. Biol Psychiatry. 2004 Jan 1;55(1):61-8. doi: 10.1016/s0006-3223(03)00704-2.
• Bejerot S, Bruno K, Gerland G, Lindquist L, Nordin V, Pelling H, Humble MB. [Suspect PANDAS in children with acute neuropsychiatric symptoms. Infection behind the disease - long-term antibiotic therapy should be considered]. Lakartidningen. 2013 Oct 9-15;110(41):1803-6. No abstract available. Swedish.
• Bernstein GA, Victor AM, Pipal AJ, Williams KA. Comparison of clinical characteristics of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2010 Aug;20(4):333-40. doi: 10.1089/cap.2010.0034.
• Brimberg L, Benhar I, Mascaro-Blanco A, Alvarez K, Lotan D, Winter C, Klein J, Moses AE, Somnier FE, Leckman JF, Swedo SE, Cunningham MW, Joel D. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology. 2012 Aug;37(9):2076-87. doi: 10.1038/npp.2012.56. Epub 2012 Apr 25.
• Demiroren K, Yavuz H, Cam L, Oran B, Karaaslan S, Demiroren S. Sydenham's chorea: a clinical follow-up of 65 patients. J Child Neurol. 2007 May;22(5):550-4. doi: 10.1177/0883073807302614.
• Hachiya Y, Miyata R, Tanuma N, Hongou K, Tanaka K, Shimoda K, Kanda S, Hoshino A, Hanafusa Y, Kumada S, Kurihara E, Hayashi M. Autoimmune neurological disorders associated with group-A beta-hemolytic streptococcal infection. Brain Dev. 2013 Aug;35(7):670-4. doi: 10.1016/j.braindev.2012.10.003. Epub 2012 Nov 9.
• Kurlan R, Johnson D, Kaplan EL; Tourette Syndrome Study Group. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics. 2008 Jun;121(6):1188-97. doi: 10.1542/peds.2007-2657.
• Leckman JF, King RA, Gilbert DL, Coffey BJ, Singer HS, Dure LS 4th, Grantz H, Katsovich L, Lin H, Lombroso PJ, Kawikova I, Johnson DR, Kurlan RM, Kaplan EL. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry. 2011 Feb;50(2):108-118.e3. doi: 10.1016/j.jaac.2010.10.011. Epub 2010 Dec 31.
• Leonard HL, Swedo SE. Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Int J Neuropsychopharmacol. 2001 Jun;4(2):191-8. doi: 10.1017/S1461145701002371.
• Mabrouk AA, Eapen V. Challenges in the identification and treatment of PANDAS: a case series. J Trop Pediatr. 2009 Feb;55(1):46-8. doi: 10.1093/tropej/fmn039. Epub 2008 May 22.
• Morris-Berry CM, Pollard M, Gao S, Thompson C; Tourette Syndrome Study Group, Singer HS. Anti-streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome: single-point and longitudinal assessments. J Neuroimmunol. 2013 Nov 15;264(1-2):106-13. doi: 10.1016/j.jneuroim.2013.09.010. Epub 2013 Sep 18.
• Murphy TK, Goodman WK, Fudge MW, Williams RC Jr, Ayoub EM, Dalal M, Lewis MH, Zabriskie JB. B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette's syndrome? Am J Psychiatry. 1997 Mar;154(3):402-7. doi: 10.1176/ajp.154.3.402.
• Murphy TK, Kurlan R, Leckman J. The immunobiology of Tourette's disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: a way forward. J Child Adolesc Psychopharmacol. 2010 Aug;20(4):317-31. doi: 10.1089/cap.2010.0043.
• Nicholson TR, Ferdinando S, Krishnaiah RB, Anhoury S, Lennox BR, Mataix-Cols D, Cleare A, Veale DM, Drummond LM, Fineberg NA, Church AJ, Giovannoni G, Heyman I. Prevalence of anti-basal ganglia antibodies in adult obsessive-compulsive disorder: cross-sectional study. Br J Psychiatry. 2012 May;200(5):381-6. doi: 10.1192/bjp.bp.111.092007. Epub 2012 Jan 26.
• Singer HS, Gilbert DL, Wolf DS, Mink JW, Kurlan R. Moving from PANDAS to CANS. J Pediatr. 2012 May;160(5):725-31. doi: 10.1016/j.jpeds.2011.11.040. Epub 2011 Dec 22. No abstract available. Erratum In: J Pediatr. 2012 May;160(5):888.
• Swedo SE, Leonard HL, Mittleman BB, Allen AJ, Rapoport JL, Dow SP, Kanter ME, Chapman F, Zabriskie J. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry. 1997 Jan;154(1):110-2. doi: 10.1176/ajp.154.1.110.
• Tan J, Smith CH, Goldman RD. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Can Fam Physician. 2012 Sep;58(9):957-9.
• Vincenzi B, O'Toole J, Lask B. PANDAS and anorexia nervosa--a spotters' guide: suggestions for medical assessment. Eur Eat Disord Rev. 2010 Mar;18(2):116-23. doi: 10.1002/erv.977.
• Hesselmark E, Bejerot S. Patient Satisfaction and Treatments Offered to Swedish Patients with Suspected Pediatric Acute-Onset Neuropsychiatric Syndrome and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. J Child Adolesc Psychopharmacol. 2019 Oct;29(8):634-641. doi: 10.1089/cap.2018.0141. Epub 2019 Apr 19.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): June 30, 2017

Study Registration Dates

• First Submitted: June 17, 2014
• First Submitted That Met QC Criteria: July 11, 2014
• First Posted (Estimate): July 15, 2014

Study Record Updates

• Last Update Posted (Actual): October 22, 2020
• Last Update Submitted That Met QC Criteria: October 21, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Infections; Personality Disorders; Anxiety Disorders; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Disease; Compulsive Personality Disorder; Obsessive-Compulsive Disorder; Streptococcal Infections
• Other Study ID Numbers: 523-2011-3646_1