DISCLOSURE LOG FOI 24.25-0413 DOCUMENT 4

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Research Request — Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) & the Cunningham Panel Test

Diagnoses: ASD, OCD, ADHD and Pervasive Developmental Disorder

Applicant believes he has been misdiagnosed and has Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and is requesting Agency to fund neurology appointments with intent of obtaining diagnostic test (Cunningham Panel Test).

The following information is requested:

• The Cunningham Panel Test:
  • What it is?
  • Whether it is a valid diagnostic test?
  • Where/how someone can be tested?
  • What the test shows?
  • How this links to his current disabilities.
  • The link between neurology appointments and the Cunningham Test
  • Anything else that will be useful to know for the Tribunal.
• Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (‘PANDAS’)
  • What it is?
  • The validity of this as a diagnosis?
  • How this condition is treated?
  • How are you diagnosed with the condition?
  • The link (if any) between PANDAS and the Applicant’s disabilities.
  • Anything else that will be useful to know for the Tribunal.

What is the best practice for managing the Applicant’s current disabilities?

Date: 15/09/2020

Requester: Naomi redacted: s22(1)(a)(ii) - irrelevant (Senior Technical Advisor TAB/AAT)

Researcher: Jane redacted: s22(1)(a)(ii) - irrelevant (Research Team Leader)

Contents

Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) ……………………………………………………………………………………………………………………. 2

What it is? ……………………………………………………………………………………………………………………. 2

How are you diagnosed with the condition? ……………………………………………………………………. 3

The validity of this as a diagnosis? …………………………………………………………………………………. 4

How this condition is treated? ………………………………………………………………………………………… 4

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The link (if any) between PANDAS and the Applicant’s disabilities. …………………………………………… 5

The Cunningham Panel Test …………………………………………………………………………………………………….

What it is and what the test shows? ………………………………………………………………………………………

Results ……………………………………………………………………………………………………………………………

Whether it is a valid diagnostic test? ……………………………………………………………………………………..

Where/how someone can be tested? ……………………………………………………………………………………

How this links to his current disabilities. ………………………………………………………………………………..

The link between neurology appointments and the Cunningham Test ………………………………………

What is the best practice for managing the Applicant’s current disabilities? ………………………………….

Pervasive Developmental Disorder/Autism …………………………………………………………………………….

OCD …………………………………………………………………………………………………………………………………..

ADHD …………………………………………………………………………………………………………………………………

Please note:

The research and literature reviews collated by our TAB Research Team are not to be shared external to the Branch. These are for internal TAB use only and are intended to assist our advisors with their reasonable and necessary decision making.

Delegates have access to a wide variety of comprehensive guidance material. If Delegates require further information on access or planning matters they are to call the TAPS line for advice.

The Research Team are unable to ensure that the information listed below provides an accurate & up-to-date snapshot of these matters

Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)

What it is?

Paediatric autoimmune neuropsychiatric disorders associated with Streptococcus infections (PANDAS) is a neurological and psychiatric condition in which symptoms are brought on or worsened by a Streptococcal (strep) infection.

PANDAS is a subtype of obsessive-compulsive disorder (OCD) and/or tic disorders characterised by an abrupt, dramatic pattern of episodic or saw-tooth symptoms, with the initial episode occurring acutely or “overnight”. 1, 2 Over a period of 24 to 48 hours, parents of children with PANDAS report their child as experiencing OCD and/or tics, as well as cognitive decline and behavioural regression. A parent describing their child as “fa changed child” is not uncommon

The underlying cause of PANDAS is unclear, but studies suggest that a strep infection causes an abnormal immune response resulting in neuropsychiatric symptoms.

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PANDAS was first defined by Susan Swedo and her colleagues in 1998. 1 They described in detail 50 cases of this new clinical entity and established working criteria of PANDAS.

To meet the definition of PANDAS all 5 criteria must be met: 1, 2

1. Presence of obsessive-compulsive disorder (OCD) or a tic disorder, particularly multiple, complex or unusual tics

2. Pre-pubertal symptom onset

3. Acute symptom onset and episodic (relapsing-remitting) course

4. Temporal association between Group A streptococcal infection and symptom onset/exacerbations

5. Associated with neurological abnormalities, (particularly motor hyperactivity and Choreiform (repetitive and rapid, jerky, involuntary movement that appears to be well-coordinated) movements).

In Swedo’s first study a total of 144 periods of symptom exacerbations with a known relationship with streptococcal infections were reported. 1 The study also described some key clinical features of PANDAS that are not part of the diagnostic criteria, such as:

• Separation anxiety

• Deterioration in handwriting

• Choreiform movement (repetitive and rapid, jerky, involuntary movement that appears to be well-coordinated)

The first 50 patients also reported high rates of psychiatric comorbidity, including 66% reporting emotional lability and 54% reporting personality change. 1 The clinical criteria for PANDAS proposed in 1998 are still the ones in clinical use today.

How are you diagnosed with the condition?

Diagnosis is based on clinical data (diagnostic criteria) rather than diagnostic biomarkers. At the present time the clinical features of the illness are the only means of determining whether or not a child might have PANDAS (5 diagnostic criteria are listed above in ‘what is it’ section). 5, 7

A streptococcus serology, (ASOT and anti DNAseB) or throat swab may help confirm a recent Group A beta-haemolytic streptococci (GABHS) infection. If positive, the tests help confirm the involvement of Streptococcus and aid in the diagnosis of PANDAS. 5, 7

An elevated anti-streptococcal titer (such as an ASOT or an AntiDNAse-B) means the child has had a strep infection sometime within the past few months, and his/her body created antibodies to fight the streptococcus bacteria.

• This is a normal, healthy response and all healthy people create antibodies to fight infections

• Antibodies stay in the body for some time after the infection is gone, but the amount of time that the antibodies persist varies greatly between different individuals.

• Some children have “positive” antibody titers for many months after a single infection. This means that an elevated anti-streptococcal titer may have nothing to do with the present worsening symptoms, but instead indicates a long-since healed streptococcus infection.

• If an elevated Anti-streptococcal antibody titer correlates with episodes of sudden onset or exacerbation of symptoms, then it confirms the clinical diagnosis of PANDAS. 5, 7

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There are at this time no tests for PANDAS. The Cunningham protocol (a test for various antibodies) has been marketed as a test to support a diagnosis of PANS, but does not of itself diagnose PANS. 5, 7 The Cunningham panel will be covered further below.

The validity of this as a diagnosis?

PANDAS is now broadly accepted, however, validity of the PANDAS diagnosis has previously been the subject of controversy in the medical community due to: 3-5

1. Theories regarding the pathogenesis of PANDAS are still in debate (microbes have been proposed to induce autoantibodies that bind to brain proteins and affect behaviour)

2. Difficulty in showing the association of a new Group A Streptococcus (GAS) infection with a sudden exacerbation of tics or OCD

a. There are various studies which firmly deny the association between GAS and tics/OCD, however, there are considerably more that strongly support the association. 6

3. Diagnosis based on clinical data rather than diagnostic biomarkers

Arguments surrounding the validity may also arise from the rarity of the condition. The incidence and prevalence of PANDAS are not known, although it is rare. 7 In one prospective study, only 10 cases were identified among 30,000 throat cultures (1 in 3000) positive for group A streptococci (GAS). 7 Since then, the annual incidence has ranged between 0 per 10,000 cultures to 10 per 30,000 cultures, depending upon the strain of GAS and other factors. 7

How this condition is treated?

The literature on the treatment of PANDAS is diverse, and clinical consensus regarding optimal treatment strategy is lacking.

Cognitive behaviour therapy (CBT) including exposure and response prevention (ERP), and selective serotonin reuptake inhibitors (SSRIs) are the primary evidence-based therapies for OCD. 8 Approximately 50%–80% of patients with OCD respond to these treatments, 9 but a substantial proportion of patients subsequently experience lifelong treatment resistance. 9 Behavioural interventions, such as habit reversal training, and psychopharmacological treatment strategies are the recommended treatments for tic disorders. 10 In contrast to the recommended treatments, when an infectious or autoimmune aetiology is suspected, these treatments for OCD and tics may be insufficient.

A recent systematic review 11 has identified the following treatments for PANDAS:

• Antibiotics

• Intravenous immunoglobulin

• Therapeutic plasma exchange

• Tonsillectomy

• CBT

• Non-steroidal anti-inflammatory drugs (NSAIDs)

• Corticosteroids

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The link (if any) between PANDAS and the Applicant’s disabilities.

1. PANDAS is a sub-type of OCD

2. Attention deficit hyperactivity disorder (ADHD) symptoms and psychosis have been found to be more common in youth with PANDAS OCD than in peers with non-PANDAS OCD. 12, 13

The Cunningham Panel Test

What it is and what the test shows?

The below is taken directly from the Moleculera Labs (Oklahoma City, OK, USA) website which owns the Cunningham Panel test. Results are conducted using a patient’s blood sample.

The purpose of the Cunningham Panel™ is to provide laboratory results that assist physicians in diagnosing infection-induced autoimmune neuropsychiatric disorders (predominantly Paediatric Acute-Onset Neuropsychiatric Syndrome (PANS) or PANDAS). The panel measures the level of circulating antibodies directed against antigens concentrated in the brain, and measures the ability of these and other autoantibodies to increase the activity of an enzyme (CaMKII) that upregulates neurotransmitters in the brain.

The panel consists of five tests. Four of these tests provide results that are expressed as a titer, or final dilution, at which an endpoint reaction was observed on an Enzyme-Linked Immunosorbent Assay (ELISA) format. These tests measure circulating levels of autoantibodies directed against specific neuronal antigens, including: Dopamine D1 receptor (DRD1), Dopamine D2L receptor (DRD2L), Lysoganglioside GM1, and Tubulin. Autoimmune antibodies that bind to these targets may interfere or potentially lead to a blocking or stimulation of the function of these antigen. This, in turn, may trigger movement and neuropsychiatric disorders, along with OCD and abnormal neurologic behaviour

The 5th test, CaM Kinase II (CaMKII, Calcium-dependent Calmodulin Protein Kinase II) activation, produces a laboratory value (expressed as a numeric score) that reflects the percent above or below baseline CaMKII activity in a human neuronal cell line. CaMKII is a key enzyme that is involved in the upregulation of many neurotransmitters such as dopamine. CaMKII is also understood to increase the “plasticity” or sensitivity and responsiveness of neurologic receptors to neurotransmitters.

Results

The collective results of the panel of five tests provide a current assessment as to the autoimmune and anti-neuronal status of the patient at the time of the blood draw. Because it is a metabolic test, the laboratory values may vary over time, with treatment, and in conjunction with the presence and absence of symptoms.

At present, the Cunningham Panel does not include testing for infectious agents such as streptococcus or measure anti-streptococcal antibody titers. The goal is to assist physicians by determining if there are elevated anti-neuronal antibodies and neuronal cell activating antibodies circulating in the patient’s blood, rather than attempting to identify the infection associated with the autoimmune condition. In short, it cannot be used to diagnose PANDAS.

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Whether it is a valid diagnostic test?

Of concern is the fact that Moleculera Labs, (who markets and performs this test) is owned/co-founded by the person who developed the Cunningham Panel, Dr Madeline Cunningham.

The website lists various peer reviewed publications which they state confirms the validity and reliability of the test, however, there are several issues with this:

1. Creator of the test is an author on almost all publications

a. Few independent assessments of the test and only positive results listed b. Some of the publications listed on the website don’t even use the Cunningham Panel test in their experiments

2. Primary aim of studies isn’t to test the validity and reliability of the Cunningham Panel test. Most studies are showing an association between high test results and a particular neuropsychiatric condition

3. Most studies are investigating the Cunningham Panel in the diagnosis of Sydenham Chorea rather than PANDAS

a. Sydenham Chorea (SC) is a neurological disorder of childhood resulting from infection via Group A beta-haemolytic streptococcus (GABHS), the bacterium that causes rheumatic fever. SC is characterized by rapid, irregular, and aimless involuntary movements of the arms and legs, trunk, and facial muscles)

4. No large scale, high quality randomised controlled trials

In a 2017 study, 14 researchers evaluated the diagnostic accuracy of the 5 biomarkers used in the Cunningham Panel in 53 Swedish patients with PANS or PANDAS. Their results showed that the sensitivities of individual biomarkers in the Cunningham Panel ranged from 15 to 60 %, and specificities from 28 to 92 %. Positive predictive values ranged from 17 to 40 %, with negative predictive values from 44 to 74 %. A majority of the healthy controls (18/21) had pathological Cunningham Panel results, and test-retest reliability proved insufficient.

Note: As a rule, the sensitivity and specificity of a screening test should be above 80%.

External authors have critically analysed publications by the creator of the Cunningham Panel test and have concluded that “it is still unclear whether these biomarkers are sensitive and specific blood tests for PANS or PANDAS.” 15 Furthermore, no association has been shown between biomarker levels and symptom exacerbations in previous studies. 16-18

Where/how someone can be tested?

Patients can get a Cunningham Panel test through NutriPATH. This is an ‘Integrative Pathology Service’ that is privately owned and specialises in the area of functional health and wellbeing pathology testing. Patients are required to order a NutriPATH blood collection kit which they then take to a blood collection centre (e.g. Melbourne Pathology).

Website: http://nutripath.com.au/product/the-cunningham-profile-pandas-pans-test-code-3432/ Email: info@nutripath.com.au Phone: 1300 688 522 (within Australia) +61 3 9880 2900 (international)

The types of Healthcare practitioners listed on the NutriPATH website include:

• Osteopath

• Naturopath

• Nutritionist

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• Integrative GP

• Psychologist

How this links to his current disabilities.

The Cunningham Panel test is specifically designed to assist with the diagnosis of infection-induced autoimmune neuropsychiatric disorders. The participant has a diagnosis of OCD which PANDAS is associated with. Given there is insufficient evidence to show that the Cunningham Panel test is clinically useful or accurate it is not recommended.

The link between neurology appointments and the Cunningham Test

Unable to find any information which links neurology appointments to the Cunningham Panel test. The provider of the test in Australia doesn’t list neurologists as a healthcare provider that utilises their services.

Given that the condition is neuropsychiatric there would need to be input from a psychologist and/or psychiatrist, neurologist, neuropsychologist or general practitioner. Many of the treatments for the condition require medically prescribed medication.

What is the best practice for managing the Applicant’s current disabilities?

Pervasive Developmental Disorder/Autism

This is an extremely complex disorder with many evidence based treatment modalities. Treatments include a range of behavioural, psychosocial, educational, medical, and complementary approaches. The options vary by age and developmental status. 19

Chronic management is often required to maximize functional independence and quality of life by minimizing core deficits in social skills and communication, facilitating development and learning, promoting socialization, reducing maladaptive behaviours, and educating and supporting families. 19

OCD

As mentioned above, Cognitive behaviour therapy (CBT) including exposure and response prevention (ERP), and selective serotonin reuptake inhibitors (SSRIs) are the primary evidence-based therapies for OCD.

ADHD

Multimodal approach is recommended for treatment of ADHD. This may include medication, psychosocial management strategies and, where appropriate, educational interventions. 20

The National Institute for Health Care Excellence guideline recommends drug treatment as the first-line treatment for adults with ADHD with either moderate or severe levels of impairment. Methylphenidate is the first-line drug. 21

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References

1. Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, Dow S, Zamkoff J, Dubbert BK, Lougee L. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. American Journal of Psychiatry. 1998 Feb 1;155(2):264-71.
2. Swedo SE, Leckman JF, Rose NR. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatr Therapeut. 2012;2(2):113.
3. Kurlan R, Kaplan EL. 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 Apr 1;113(4):883-6.
4. Swedo SE, Leonard HL, Rapoport JL. The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. Pediatrics. 2004 Apr 1;113(4):907-11.
5. Murphy TK, Gerardi DM, Parker-Athill EC. The PANDAS Controversy: why (and how) is it still unsettled?. Current Developmental Disorders Reports. 2014 Dec 1;1(4):236-44.
6. Orefici G, Cardona F, Cox CJ, Cunningham MW. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). In Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet] 2016 Feb 10. University of Oklahoma Health Sciences Center.
7. Genetic and Rare Diseases Information Center (GARD). Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus infections. [Internet]. 2020 [cited 14 September 2020]. Available from: https://rarediseases.info.nih.gov/diseases/7312/pediatric-autoimmune-neuropsychiatric-disorders-associated-with-streptococcus-infections#ref 11819.
8. Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. Jama. 2004 Oct 27;292(16):1969.
9. Grant JE. Obsessive–compulsive disorder. New England Journal of Medicine. 2014 Aug 14;371(7):646-53.
10. Hollis C, Pennant M, Cuenca J, Glazebrook C, Kendall T, Whittington C, Stockton S, Larsson L, Bunton P, Dobson S, Groom M. Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis.
11. Sigra S, Hesselmark E, Bejerot S. Treatment of PANDAS and PANS: a systematic review. Neuroscience & Biobehavioral Reviews. 2018 Mar 1;86:51-65.
12. 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;20:333–40.
13. Murphy TK, Storch EA, Lewin AB, Edge PJ, Goodman WK. Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Pediatr. 2012;160:314–9. This publication adds to the literature by describing characteristics of youth with PANDAS OCD compared to non-PANDAS OCD.
14. Hesselmark E, Bejerot S. Biomarkers for diagnosis of pediatric acute neuropsychiatric syndrome (PANS)–Sensitivity and specificity of the Cunningham Panel. Journal of neuroimmunology. 2017 Nov 15;312:31-7.

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15. Vojdani A, Turnpaugh CC. Antibodies against Group A Streptococcus, dopamine receptors, and ganglioside GM1 cross-react with a variety of food antigens, potentially interfering with biomarkers for PANS and PANDAS. Biomarkers in Neuropsychiatry. 2020 Dec 1;3:100023.
16. Morris-Berry CM, Pollard M, Gao S, Thompson C, Singer HS, Tourette Syndrome Study Group. Anti-streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome: single-point and longitudinal assessments. Journal of Neuroimmunology. 2013 Nov 15;264(1-2):106-13.
17. Singer HS, Mascaro-Blanco A, Alvarez K, Morris-Berry C, Kawikova I, Ben-Pazi H, Thompson CB, Ali SF, Kaplan EL, Cunningham MW. Neuronal antibody biomarkers for Sydenham’s chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection. PloS one. 2015 Mar 20;10(3):e0120499.
18. Singer HS, Gause C, Morris C, Lopez P. Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Pediatrics. 2008 Jun 1;121(6):1198-205.
19. Subramanyam AA, Mukherjee A, Dave M, Chavda K. Clinical practice guidelines for autism spectrum disorders. Indian journal of psychiatry. 2019 Jan;61(Suppl 2):254.
20. Royal Australian and New Zealand College of Psychiatrists. Adult ADHD - practice guidelines. [Internet]. 2020 [cited 15 September 2020]. Available from: https://www.ranzcp.org/practice-education/guidelines-and-resources-for-practice/adult-adhd-practice-guidelines
21. National Institute for Clinical Excellence. Attention Deficit Hyperactivity Disorder: Diagnosis and Management of ADHD in Children, Young People and Adults. NICE Clinical Guidelines, No. 72. National Collaborating Centre for Mental Health (UK). British Psychological Society (UK), Leicester (UK). 2009.

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