Exam Clues in PANS and PANDAS - PowerPoint Presentation

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Exam Clues in PANS and PANDAS(and alternative diagnoses)

Theresa Willett, MD PhD

Assistant Professor, Pediatrics, Allergy ImmunologyMedical Co-Director, PANS/Immune Behavioral Health Clinic

Inflammatory Brain Disorders Virtual ConferenceMay 14, 2021

med.stanford.edu/pans

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Disclosures

I have no conflicts of interest to declare

Watermarked DermNetNZ images courtesy of CreativeCommons: https://creativecommons.org/licenses/by-

nc-nd/3.0/nz/legalcode

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Objectives

Recognize chorea and choreiform movementsIdentify skin findings for alternative diagnosis (rheumatic fever) and comorbidity (psoriasis)

Identify findings that indicate need for rheumatology evaluation Describe 3 alternative diagnoses to PANS/PANDAS

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PANDAS Diagnostic Criteria

Presence of OCD and/or a tic disorder

Pediatric onset: age 3yrs to puberty

Abrupt onset and episodic "sawtooth" pattern of severity Association with Group A Streptococcal infection.

Neurologic abnormalities, such as motoric hyperactivity: fidgeting, choreiform movements (on stressed postures but not present at rest), or tics during exacerbations.

(adapted from

Swedo

et al, Am J Psychiatry. 1998;155(2):264)

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PANS Diagnostic Criteria

I.

Abrupt, dramatic onset of obsessive-compulsive disorder OR severely restricted food intakeII. Concurrent presence of additional neuropsychiatric symptoms, (with similarly severe and acute onset), from

≥ 2 of the following categories: 1. Anxiety 2. Emotional lability and/or depression

3. Irritability, aggression, and/or severely oppositional behaviors4. Behavioral (developmental) regression 5. Deterioration in school performance (related to ADHD-like symptoms, memory deficits, cognitive changes)6. Sensory or motor abnormalities

7. Somatic signs and symptoms

III. Symptoms are

not better explained

by a known neurologic or medical disorder, such as Sydenham Chorea, lupus, psychological trauma.

(adapted from Chang et al, J Child

Adolesc

Psychopharmacol

. 2015)

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Strep

Motor issues

OCD/ Motor tics

Abrupt

Pediatric onset

PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC DISORDER

ASSOCIATED with STREPTOCOCCAL INFECTION

PANDAS

OCD/ARFID

Somatic:

Sleep problems, Urinary

Sensory/Motor

Regression

School issues

Mood / Irritability

Anxiety

Sawtooth

PANS

PEDIATRIC ACUTE-ONSET NEUROPSYCHIATRIC SYNDROME

Basal ganglia

injury can

release inhibitory circuits:

Movement

Mood/emotion

Behavior

Cognition

Procedural learning

Abrupt

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PANS/PANDAS

Part of Research/Diagnostic criteria

TicsChoreiform movements

Dysgraphia

Described in patients with PANS/PANDAS

Neurological “soft signs”

Dilated Pupils

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Inflammatory diseases with psychiatric symptoms

Primary CNS Vasculitis

Secondary

CNS Vasculitis

Autoimmune Encephalitis, Diffuse cerebritis

Lupus

Behcet’s

Sarcoidosis

Poly Arteritis Nodosa

Lupus

Limbic Encephalitis

(?) Hashimoto

’

s Encephalitis/SREAT

NMDA Receptor Ab Encephalitis

Sydenham

Chorea

Mycoplasma Basal Ganglia Encephalitis

Lupus, Antiphospholipid antibodies

PANDAS/PANS*

Basal Ganglia Encephalitis +/- Vasculitis

Non-inflammatory:

Wilson’s disease

Unknown mechanism

Psoriasis/Psoriatic arthritis

Spondyloarthritis

Inflammatory Bowel Disease

Sjogren’s, Scleroderma,

etc

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Exam: GENERAL

Ill vs well appearing

Age appropriateGroomingVitalsGrowth chartWeight gain/lossLinear growth velocity

TachycardiaHypertensionOrthostatic HR/BP changes* POTS (incr HR>30 bpm)Dehydration

Hypocaloric diet9

5 min

1 min

3 min

Orthostatic VS

* See Stewart et al 2018, Singer et al 2012

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HEENT

InfectionsAOM

Sinus drainageSinus pressurePharyngitis Tonsillitis Cervical lymph nodesThyroid enlargementThyroiditis

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HEENT

Dilated pupils

Uveitis RednessPhotosensitivityKayser–Fleischer ringWilson’s disease Nasal ulcers

Becet’s, SLE Oral ulcers/aphthae SLE, Behcet’s, IBD, Viral, CeliacMajor: >5mmMinor: <5mm

Herpetiform: pinpoint, clusters11

Uveitis

Major aphtha

Minor

aphthae

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CHEST

Lungs

Pneumonia Pleural rub Pneumonitis Consolidation, tachypnea

CardioMurmurMitral regurgitationHolosystolic blowingMitral thickening Mid-diast

low flow murmurAortic regurgutationDiastolic descrescendo

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Pericardial friction rub

Pericarditis

Prom S2

Pulm

HTN

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ABDOMEN / GENITOURINARY

Abd Tenderness

GeneralEpigastricRLQ Genital ulcers w scarsBehcet’s

Perianal ulcersIBD, Behcet’sPerianal skin tagsIBDPerianal erythema

Group A Strep13

Perianal Strep. rash

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SKIN and NAILS

Infection clues:

Scarlatiniform rashSplinter hemorrhagesImpetigoParonychiaDigital peelingErythema Marginatum (ARF)

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Erythema

marginatum

Splinter hem.

Peeling toes

Impetigo

Scarlatiniform

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SKIN and NAILS

Inflammatory clues:

DermatographismInflamed nailfoldsArthritis, SLE Erythema nodosuminfections, Behçet’s, IBD

Subcutaneous nodulesARFPathergy Behçet’s, IBDPseudofolliculitisBehçet’s

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SKIN and NAILS

Psoriasis

Nail pittingOnycholysisPlaques w scaleFissural erythemaErythrodermic type

Palmopustular

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SKIN and NAILS

Lupus specific

Malar rashNonspecificPhotosensitivityLivedo reticularisNon-scarring alopeciaNailfold abnormalities

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Malar

Livedo

Nailfold

hemorrhage

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Systemic Lupus

Erythematosis

Criteria: EULAR/ACR, SLICC Score components:Mucocutaneous lesionsSerositis

heart, lungSynovitis Neurologic*Seizure, PsychosisRenal Hematuria, proteinuriaLabs:

Anemia, thrombocytopenia, leukopeniaLow C3, C4ANA, phospholipids, dsDNA

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Discoid

Malar rash

Papular

erythema

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Behçet’s

Disease

Recurrent oral aphthaeScarring Genital ulcers Skin:pseudofolliculitis

AcneiformErythema nodosumEye:Ant/post uveitisRetinal vasculitisVascularVenus/arterial thrombosis

Arterial aneurism19

Neuro-

Behçets

Headache

CN palsies

Aseptic meningitis

Meningoencephalitis

Psychosis*

Cognitive dysfunction*

Criteria:

Koné-Paut

et al

Ann Rheum Di

s 2016

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MUSCULOSKELETAL

Joint tenderness, swelling, warmth

Entheseal tendernessSacroiliac tendernessFibromyalgia tenderness points

Key history points:Morning pain, stiffness

Slow moving in A.M.Pain after sitting “gelling”

Limping

20

Enthesitis

Related Arthritis

:

www.aboutkidshealth.ca

/

Article?contentid

=13&language=English

Dactylitis

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NEUROLOGICAL

“Soft Signs” – subtle, non-specific

Formal testing : PANESS scale, Cambridge Neurological InventorySlouched posture Tics: motor, verbalAbnormal glabellar reflex

Blink persists w >3 tapsMotor Overflow Involuntary movement with voluntary actionAge-appropriate <10yrsWeakness in hip flexors, neck flexorsGrip weakness

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NEUROLOGICAL

Motor

impersistence* Darting tongue“Jack in the box”Wormian tongue* Milkmaid grip* Spooning

Hyperextension MCP*Touchdown sign:Pronation and elbow flexion * Seen together these suggest Sydenham Chorea

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CHOREA

Chorea = dancing

May be present at restWorse w movementWorse with distraction, resists entrainmentDiscrete, brief, jerky movementsRandom, unpredictable, continuousInterfere w planned movement

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Athetosis

= smooth, writhing

Choreiform movements

“Chorea Minor”

Milder movements seen w extended pronated arms

Developmentally may be normal

May be seen w ADHD

See Mink and

Zinner

PIR

2010

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Sydenham Chorea

Most common secondary chorea in childhood

Onset subacute (hours to days)*weeks to months past Group A Strep infection

Behavioral changes:Impulsivity, aggressionOCDHistoryClumsiness Relapse +/- Strep

Incr risk with pregnancy, OCP

Exam:

Restless/fidgety

Spooning /hyperextension MCP

Touchdown sign on arm raise

Milkmaid’s grip

Darting Tongue

Dysarthria

Tendon reflex hang-up

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Revised Jones Criteria for ARF (2015)

Circulation 2015; 131:1806-1818.

As presented in UpToDate

"Acute rheumatic fever: Clinical manifestations and diagnosis"

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Acute Rheumatic Fever

Carditis

Pancarditis (pericardial, myocardial, and endocardial)PolyarthritisMigratory, asymmetricWarm, red, swollen, very painful*very responsive to NSAID

Erythema MarginatumFleeting, mobileIncreased w heatSubcutaneous nodules Rare but assoc w carditisPainless, firm, mobile 0.5-2cm

Knees/wrists/elbows, ext surface

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Group A Strep

Sites:

TonsillitisSinusitisSkin:Impetigo ErysipelasPerineal/perianal dermatitis

Complications:

Direct Infection

Exotoxins:

streptolysin, DNase, streptokinase,

Spe

, C5a peptidase

Scarlet Fever

Toxic Shock

Necrotizing Fasciitis

Puerperal sepsis

Immune:

Rheumatic Fever: joint, heart, brain

Post-Streptococcal

Glomerulonehphritis

OCD/PANDAS?

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Stanford PANS program:

med.stanford.edu/pans

PANS Research Consortium Treatment Recommendations 2017:JCAP Volume: 27 Issue 7: September 1, 2017

 Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I-–Psychiatric and Behavioral Interventions

. Thienemann et al. https://doi.org/10.1089/cap.2016.0145

Part II—Use of Immunomodulatory Therapies

.

Frankovich

et al.

https://doi.org/10.1089/cap.2016.0148

Part III—Treatment and Prevention of Infections

.

Cooperstock

et al.

https://doi.org/10.1089/cap.2016.0151

 

Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity

. Xu J et al. Am J Psychiatry. 2021 01 01;178(1):48-64.

Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging.

 Zheng J et al. JAMA

Netw

Open. 2020;3(5):e204063. doi:10.1001/jamanetworkopen.2020.4063

Familial Clustering of Immune-Mediated Diseases in Children with Abrupt-Onset Obsessive Compulsive Disorder.

Chan A et al. J Child

Adolesc

Psychopharmacol

. 2020 06;30(5):345-346.

Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity

. Silverman M et al. J Psychiatr

Res. 2019 03;110:93-102.

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Special Thank You

The Foundation for Children with Neuroimmune Disorders for supporting families and clinicians caring for children with PANS, PANDAS and other complex issues

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References : PANS, PANDAS, behavioral

Chang  K,

Frankovich  J, Cooperstock  M,  et al; PANS Collaborative Consortium.  Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference.  J Child

Adolesc Psychopharmacol. 2015;25(1):3-13. Asbahr FR, Negrão AB,

Gentil V, Zanetta DM, da Paz JA, Marques-Dias MJ, Kiss MH. Obsessive-compulsive and related symptoms in children and adolescents with rheumatic fever with and without chorea: a prospective 6-month study.  Am J Psychiatry. 1998;155(8):1122. Murphy, Tanya K. et al. Relationship of Movements and Behaviors to Group A Streptococcus Infections in Elementary School Children. 2007

Biological Psychiatry.

Volume 61, Issue 3, 279 - 284

Orlovska

S, et al. Association of Streptococcal Throat Infection With Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis in a Nationwide Study. JAMA Psychiatry. 2017;74(7):740–746.

doi:https

://

doi.org

/10.1001/jamapsychiatry.2017.0995

.Swedo  SE, Leonard  HL, Garvey  M,  et al.  Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. 

 Am J Psychiatry

. 1998;155(2):264-271.

Kayser

MS, Dalmau J. The emerging link between autoimmune disorders and neuropsychiatric disease. 

J Neuropsychiatry Clin

Neurosci

. 2011;23(1):90–97. doi:10.1176/jnp.23.1.jnp90

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References: Group A Strep, SC

Carapetis

JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685–94.* Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes

 : Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2016Dan JM et al. Recurrent group A Streptococcus tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant TFH cells. Science Translational Medicine  06 Feb 2019: Vol. 11, Issue 478, eaau3776. DOI: 10.1126/scitranslmed.aau3776 

Kaplan E. L., Chhatwal G. S., Rohde M. Reduced ability of penicillin to eradicate ingested group A streptococci from epithelial cells: clinical and pathogenetic implications. Clinical Infectious Diseases. 2006;43(11):1398–1406.Medina E, Rohde M, Chhatwal GS. Intracellular survival of Streptococcus pyogenes in polymorphonuclear cells results in increased bacterial virulence. Infect Immun. 2003;71(9):5376–5380. doi:10.1128/iai.71.9.5376-5380.2003

* Mink JW and 

Zinner

SH. Movement Disorders II: Chorea, Dystonia, Myoclonus, and Tremor.

Pediatrics in Review

 July 2010,  31 (7) 287-295

Olson D, Edmonson MB. Outcomes in children treated for perineal group A beta-hemolytic streptococcal dermatitis.

Pediatr

Infect Dis J. 2011 Nov;30(11):933-6.

Wierzbicki IH et al. Group A Streptococcal S Protein Utilizes Red Blood Cells as Immune Camouflage and Is a Critical Determinant for Immune Evasion. Cell Rep. 2019 Dec 3;29(10):2979-2989.e15.

doi

: 10.1016/j.celrep.2019.11.001.

*helpful review

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References SLE, ARF, Be

çet’s, POTS

2015 JONES CRITERIA: Gewitz MH et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association

. Circulation. 2015 May 19;131(20):1806-18. Chi AC, Neville BW, Krayer JW, Gonsalves WC. Oral manifestations of systemic disease. Am Fam Physician. 2010 Dec 1;82(11):1381-8. PMID: 21121523.

Chiewchengchol, D., Murphy, R., Edwards, S.W. et al. Mucocutaneous manifestations in juvenile-onset systemic lupus erythematosus: a review of literature. Pediatr Rheumatol 13, 1 (2015).Koné-Paut

I, et al; PEDBD group. Consensus classification criteria for

paediatric

Behçet's

disease from a prospective observational cohort: PEDBD. Ann Rheum Dis. 2016 Jun;75(6):958-64.

Levy DM,

Kamphuis

S. Systemic lupus erythematosus in children and adolescents. 

Pediatr Clin North Am. 2012;59(2):345-364. doi:10.1016/j.pcl.2012.03.007Singer W, Sletten DM, Opfer-Gehrking TL, Brands CK, Fischer PR, Low PA. Postural tachycardia in children and adolescents: what is abnormal?. J

Pediatr

. 2012;160(2):222-226. doi:10.1016/j.jpeds.2011.08.054

Stewart JM et al. Pediatric Disorders of Orthostatic Intolerance. Pediatrics. 2018 Jan;141(1):e20171673.

Tan CS, Hung LC (2017) Subcutaneous Nodules and Delayed Diagnosis in Acute Rheumatic Fever: A Case Report. Clin J Heart Dis 1(1): 1006.

Weiss, JE. Pediatric Systemic Lupus Erythematosus. Pediatrics in Review Feb 2012, 33 (2) 62-74

Yıldız

M, et al. Pediatric

Behçet's

disease - clinical aspects and current concepts [published online ahead of print, 2019 Sep 5]. 

Eur J

Rheumatol

. 2019;7(Suppl 1):1-10.

32

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Other helpful resources

DermNetNZ

: dermnetnz.org VisualDx (can be via UpToDate) has a wide variety of clinical images American Family Physician: www.aafp.org/journals/afp.html

Bite Sized Immunologywww.immunology.org/public-information/bitesized-immunology“BiteSized Immunology is a developing online resource designed to form a comprehensive guide to the immune system, yet approaching the topic via punchy, easy-to-digest, entries that outline major learning points.”

CDC page on Group A Strepwww.cdc.gov/groupastrep/diseases-hcp/index.html