Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives

Figures & data

Figure 1 Study selection flowchart. The flowchart shows the results of our review and process, in four steps: Identification: consisted of 765 articles, derived from a selection of a total of 1005 initial articles after deleting 240 duplicate reports; Screening: the articles were thoroughly examined: 269 were excluded and, subsequently, 496 records were screened; Eligibility: the number of full texts evaluated was 227 and 22 were excluded for the absence of eligibility criteria; Inclusion: 205 articles were identified as pertinent for inclusion in this review.

Box 1 PANS working criteria

(I) Abrupt dramatic onset of OCD or severely restricted food intake

(II) Concurrent presence of additional neuropsychiatric symptoms (with similarly severe and acute onset), from at least two of the following seven categories:

1. Anxiety

2. Emotional lability and/or depression

3. Irritability, aggression, and/or severely oppositional behaviors

4. Behavioral (developmental) regression

5. Deterioration in school performance (related to Attention Deficit/hyperactivity Disorder [ADHD]-like symptoms, memory deficits, and cognitive changes)

6. Sensory or motor abnormalities

7. Somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency

(III) Symptoms are not better explained by a known neurologic or medical disorder, such as Sydenham Chorea (SC).

Table 1 Laboratory-based Biomarkers

Laboratory Parameters	Tissue Tested	Significant Results	Totality of the Evidence	Studies
I. INFECTIVE
Antistreptolysin O antibody (ASO)	Serum	Positive in PANS/PANDAS (>250 IU)	***	Pavone et al (2004)^Citation167 [CCS]; Kurlan et al (2008)^Citation168 [OS]; Morris et al (2009)^Citation169 [OS]; Murphy et al (2012)^Citation34 [CSS]; Stagi et al (2014)^Citation170 [CCS]; Cox et al (2015)^Citation87 [OS]; Stagi et al (2018)^Citation171 [CSS]; Chain et al (2020)^Citation78 [CSS]; Murphy and Pichichero (2002)^Citation172 [OS]; Gamucci et al (2019)^Citation18 [OS]; Prato et al (2021)^Citation172 [SR].
Antistreptolysin O antibody (ASO)	Serum	Negative in PANS (<250 IU)	***	Luo et al (2004)^Citation173 [OS]; Bernstein et al (2010)^Citation174 [CCS]; Morris-Berry et al (2013)^Citation175 [OS]; Murphy et al (2013)^Citation176 [OS]; Gagliano et al (2020)^Citation10 [OS]; Gagliano et al (2021)^Citation118 [CSS]; Prato et al (2021)^Citation172 [SR].
Nasopharyngeal culture for Group A beta-hemolytic streptococcus (GABHS)	Throat	Positive in PANS/PANDAS	***	Murphy et al (2012)^Citation34 [CSS]; Swedo et al (1998)^Citation11 [CSS]; Lepri et al (2019)^Citation67 [CCS]; Leckman et al (2011)^Citation173 [CSS]; Orefici et al (2016)^Citation177 [SR]; Bryńska et al (2004)^Citation178 [SR], Gagliano et al (2020)^Citation10 [OS]; Gamucci et al (2019)^Citation18 [OS]; Calaprice et al (2017)^Citation13 [CCS].
Nasopharyngeal culture for other bacteria (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae Pseudomonas aeruginosa)	Throat	Positive in PANS	**	Gagliano et al (2020)^Citation10 [OS]; Prato et al (2021)^Citation172 [SR].
IgG and/or IgM Antibodies against different germs (AntiMycoplasma pneumoniae, Chlamydia pneumoniae, Epstein–Barr virus, Borrelia Burgdorferi, and Herpes Simplex Virus –HSV- Type 1)	Blood	Positive in PANS	***	Chang et al (2015)^Citation15 [GL]; Murphy et al (2014)^Citation179 [SR]; Hansen et al (2021)^Citation180 [SR]; Perrin et al (2004)^Citation181 [OS]; Lepri et al (2019)^Citation67 [CCS]; Gagliano et al (2020)^Citation10 [OS]; Murphy and Pichichero (2002)^Citation172[OS]; Esposito et al (2014)^Citation182 [SR]; Prato et al (2021)^Citation172 [SR].
	CSF	Negative in PANS	*	Gamucci et al (2019)^Citation18 [OS].
II. IMMUNE/AUTOIMMUNE
Thyroid tests
Antithyroid antibodies (Thyroid Stimulating Hormone Receptor Antibody [anti-TSH receptor] Anti-thyroid peroxidase [antiTPO], Thyroglobulin antibodies, TSH receptor antibodies [anti-TRAbs])	Blood Blood-serum Blood Blood Blood-serum	Positive in PANS/PANDAS	***	Stagi et al (2014)^Citation169 [CCS]; Frankovich et al (2015)^Citation2 [CCS]; Gromark et al (2019)^Citation7 [OS]; Gagliano et al (2020)^Citation10 [OS]; Gromark et al (2021)^Citation183 [OS]; Gamucci et al (2019)^Citation18 [OS]; Prato et al (2021)^Citation172 [SR].
Celiac tests
Anti-gliadin, Anti-endomysium, Anti-tissue-translglutaminase,	Serum Serum Serum	Positive in PANS	**	Stagi et al (2014)^Citation169 [CCS]; Frankovich et al (2015)^Citation2 [CCS]; Gromark et al (2019)^Citation7 [OS]; Gromark et al (2021)^Citation183 [OS].
Organ- and nonorgan-specific autoantibodies
Antinuclear antibodies (ANAs) anti-DNasi, anti-smooth muscle, anti-extractable nuclear antigens, anti-phospholipid, lupus-like anticoagulant, Anti-A carbohydrate (anti-ACHO) antibody	Serum	Positive in PANS/PANDAS	***	Chain et al (2020)^Citation78 [CSS]; Stagi et al (2014)^Citation169 [CCS]; Williams et al (2016)^Citation115 [RCT]; Gromark et al (2019)^Citation7 [OS]; Murphy et al (2012)^Citation34 [CSS]; Murphy et al (2013)^Citation176 [OS]; Gagliano et al (2020)^Citation10 [OS]; Lepri et al (2019)^Citation67 [CCS]; Gromark et al (2021)^Citation183 [OS]; Frankovich et al (2015)^Citation2 [CCS]; Gamucci et al (2019)^Citation18 [OS].
Antineural antibodies
Dopamine receptors D1 and D2 antibodies lysoganglioside-GM1 (lyso-GM1) antibodies calcium calmodulin dependent kinase II activity (CaMKII-activity) antibodies β-tubulin antibodies	Serum Serum	Elevated in PANS	***	Pavone et al (2004)^Citation167 [CCS]; Cox et al (2015)^Citation87 [OS]; Morris-Berry et al (2013)^Citation175 [OS]; Chain et al (2020)^Citation78 [CSS]; Stagi et al (2014)^Citation169 [CCS]; Kirvan et al (2006)^Citation46 [CCS]; Cunningham et al (2014)^Citation184 [SR]; Shimasaki et al (2020)^Citation79 [CSS]; Singer et al (2015)^Citation185,Citation186 [CCS]; Hesselmark et al (2017)^Citation82 [CCS]; Xu et al (2021)^Citation22 [CCS].
(CaMKII-activity) antibodies	CSF	Positive PANS/PANDAS	*	Kirvan et al (2006)^Citation46 [CCS]; Shimasaki et al (2020)^Citation79 [CSS].
Neuronal encephalitis spectrum antibodies	CSF	Negative in PANDAS Negative in PANS	* *	Chain et al (2020)^Citation78 [CSS]; Gamucci et al (2019)^Citation18 [OS].
III. INFLAMMATORY
Histone antibodies	Blood	Positive in PANS/PANDAS	*	Frankovich et al (2015)^Citation2 [CCS]; Chang et al (2015)^Citation15[GL]; Prato et al (2021)^Citation172 [SR].
Lymphocyte subset (T, B, natural killer [NK] cells)	Blood	Positive in PANS/PANDAS	*	Leckman et al (2011)^Citation173 [CSS]; Gilbert et al (2019)^Citation187 [SR].
D8/17-reactive cells	Blood	Positive in PANS/PANDAS	**	Swedo et al (1998)^Citation11 [CSS]; Luo et al (2004)^Citation173 [OS]; Sokol et al (2002)^Citation188 [CCS]; Prato et al (2021)^Citation172 [SR].
Erythrocyte sedimentation rate (ESR)	Blood	Increased in PANS/PANDAS	**	Frankovich et al (2015)^Citation2 [CCS]; Murphy et al (2012)^Citation34 [CSS]; Murphy et al (2013)^Citation176 [OS]; Gromark et al (2019)^Citation7 [OS]; Gromark et al (2021)^Citation183 [OS].
C-reactive protein (CRP)	Blood	Increased in PANS/PANDAS	***	Gagliano et al (2020)^Citation10 [OS]; Murphy et al (2012)^Citation34 [CSS], Murphy et al (2013)^Citation176 [OS]; Frankovich et al (2015)^Citation2 [CCS]; Gromark et al (2019)^Citation7 [OS]; Gromark et al (2021)^Citation183 [OS], Chang et al (2015)^Citation15 [GL], Gamucci et al (2019)^Citation18 [OS].
Neuron-specific Enolase (NSE)	Serum	Elevated in PANS	**	Gagliano et al (2021)^Citation118 [CSS];
Serum amyloid A (SAA)	Serum			Frankovich et al (2015)^Citation2 [CCS];
Complement activation	Blood			Stagi et al (2014)^Citation169 [CCS]; Prato et al (2021)^Citation172 [SR].
IgG, IgA, IgM
IL-1- β, IL1-ra, IL-2, IL-6, IL8, IL-10, IL-17A, TNF- α, IL-12, IL-12p70, CD-14, SGP130, IL-GR	Serum	Elevated in PANS	**	Frankovich et al (2015)^Citation2 [CCS]; Murphy et al (2012)^Citation34 [CSS]; Murphy et al (2013)^Citation176 [OS]; Gromark et al (2019)^Citation7 [OS]; Gromark et al (2021)^Citation183 [OS].
Granulocyte-macrophage colony-stimulating factor (GM-CSF) Cytokines	Serum CSF Serum	Elevated in PANS Normal in PANS Increased in PANS	* * *	Rodriguez et al (2017)^Citation189 [CCS]; Gamucci et al (2019)^Citation18 [OS]; Parker-Athill et al (2015);^Citation190 Rodriguez et al (2017)^Citation189 [CCS]
IV. GENERAL HEALTH PARAMETERS
Complete blood count (CBC)	Blood	Alterated in PANS/PANDAS	*	Leckman et al (2011)^Citation173 [CSS]; Stagi et al (2014)^Citation169 [CCS].
Ferritin	Serum	Reduced in PANS/PANDAS	**	Gromark et al (2019)^Citation7 [OS]; Gromark et al (2021)^Citation183[OS]; Chan et al (2021)^Citation191 [CSS]; Prato et al (2021)^Citation172 [SR].
Iron	Serum	Reduced in PANS/PANDAS	*	Chang et al (2015)^Citation15[GL]; Chan et al (2021)^Citation191 [CSS]; Prato et al (2021)^Citation172 [SR].
Vitamin D	Blood	Reduced in PANS/PANDAS	**	Celik et al (2016)^Citation192 [CCS]; Stagi et al (2018)^Citation170 [CSS]; Frankovich et al (2015)^Citation2 [CCS]; Gromark et al (2019)^Citation7 [OS]; Gromark et al (2021)^Citation183 [OS]; Prato et al (2021)^Citation172 [SR].
TSH, fT3 and fT4	Blood	Increased in PANS/PANDAS, reduced in PANS/PANDAS	**	Stagi et al (2014)^Citation169 [CCS]; Gagliano et al (2020)^Citation10 [OS]; Gromark et al (2019)^Citation7 [OS]; Gromark et al (2021)^Citation183 [OS]; Prato et al (2021)^Citation172 [SR].

Notes: The table shows an overview of PANS versus PANDAS and of PANS-associated putative biomarkers stratified on the basis of the totality of the evidence through a Likert scale from 1 to 3 (referring to the number of the supporting studies available – see the abbreviation explanation). The study design is also stated (see abbreviation). *Between 1 and 3 studies; **between 4 and 6 studies; ***= or > 7 studies.

Abbreviations: MA, meta-analysis; SR, systematic review; RCT, randomized controlled trial; OS, prospective or retrospective observational study; CCS, case-control study; CSS, cross-sectional study; CR and CS, case reports and case series; GL, guidelines.

Table 2 Main behavioral/neuropsychological evaluation instruments

Test	Test Description/Function
PANSS	Pediatric Acute Neuropsychiatric Symptom Scale (PANSS), (Version: June 6, 2012), a parent version form to assess common PANDAS/PANS symptoms, developed based on clinical experience, Swedo S, Kovacevic M, Latimer B and Leckman J, with the help of Pohlman D, Moore K and many other parents (see https://aspire.care). The structure of the scale provides sub-scores for each symptom included in the PANS criteria and a total score ranging between 0 and 50 points. The impairment in self-esteem, family life, social acceptance, and school or job functioning, is also estimated.
CY-BOCS	Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS), a semi-structured interview measuring obsessive-compulsive symptom severity in children and adolescents^Citation193
YGTSS	Yale Global Tic Severity Scale score (YGTSS), a common semi-structured interview, followed by a questionnaire, documenting the intensity, complexity and frequency of motor and phonic tics; the total score is a measure of overall tic severity.^Citation194
PARS	Pediatric anxiety Rating Scale (PARS), a clinician-rated instrument for assessing the severity of anxiety symptoms associated with anxiety disorders (social phobia, separation anxiety disorder, and generalized anxiety disorder) in children.^Citation195
C-GAS	Children’s Global Assessment Scale (C-GAS), a useful measure of general functioning, aimed at children and young people aged 6–17 years old, as a complement to syndrome-specific scales (derived from an adaptation of the Global Assessment Scale for adults).^Citation196
USCRS	UFMG (Universidad Federal de Minas Gerais) Sydenham’s Chorea (SC) Rating Scale (USCRS), an instrument designed to provide a quantitative description of the performances and activities of daily living, behavioral abnormalities, and motor function of subjects with SC. The administration of the scale supports the neurological examination.^Citation197
Wechsler scales: WPPSI-III/ WISC-IV/ WAIS-IV	The most widely used measure of general cognitive ability and intellectual functioning of children and adults: WPPSI-III (Wechsler Preschool and Primary Scale of Intelligence- III), WISC-IV (Wechsler Intelligence Scale for Children - IV), WAIS-IV (Wechsler Adult Intelligence Scale- IV). For children over four, the IQ score is made up of the following indices: Verbal Comprehension, Visual Spatial Fluid Reasoning, Working Memory, Processing Speed.^Citation198–201

Notes: See: for PANS scale and C-GAS;^32,135 for YGTSS and CY-BOCS;^19,32 for USCRS²⁰² and;²⁰³ for Wechsler scales,¹⁸ and⁸³.

Table 3 Immunomodulatory/anti-inflammatory and antimicrobial treatment options

Active treatment		Dosage and Schedule	Totality of the Evidence	Studies and Study Designs
Immunomodulatory and anti-inflammatory
Prednisone	Oral	1–2mg/kg day, pulse (max dose 60–120 mg) for short duration (4–5 days)	*	Frankovich et al (2017)^Citation33 [GL]
		Alternatively 1–2 mg/kg, once daily, or divided twice daily, maximum 60–120 mg daily) for 5–10 days; then taper for 4–8 weeks.		Brown et al (2017)^Citation126[OS]
Dexamethasone	Oral	20 mg/m^2 divided twice daily for 3 days	*	Frankovich et al (2017)^Citation33 [GL]
		Monthly oral pulses for 3 months (each pulse being 10 (–15) mg/m2 daily in two doses on three consecutive days)		Pfeiffer et al (2020)^Citation122[GL]
Methylprednisolone	Intravenous	30mg/kg/dose/day from one to three consecutive daily pulses (maximum 1000 mg/dose/24 hours)	*	Frankovich et al (2017)^Citation33 [GL]
Ibuprofen	Oral	10 mg/kg/dose, three times a day, maximum dose: 600 mg/dose	*	Brown et al (2017)^Citation126 [OS] Spartz et al (2017)^Citation131 [OS]
		10–15 mg/kg/dose, three times a day, maximum 500 mg/dose (4–12 weeks)		Pfeiffer et al (2020)^Citation122 [GL]
Naproxen	Oral	10 mg/kg/dose, two times a day, maximum dose: 500 mg/dose	*	Brown et al, (2017)^Citation126[OS]; Spartz et al (2017)^Citation131[OS]
		10–20 mg/kg/day split in two doses, max 500 mg twice a day (4–12 weeks)		Pfeiffer et al (2020)^Citation122 [GL]
Sulindac	Oral	2–4 mg/kg/day in two divided doses, maximum: 6 mg/kg/day, maximum dose 400 mg/day)	*	Brown et al (2017)^Citation126[OS]; Spartz et al (2017)^Citation131 [OS];
Celecoxib	Oral	50–100 mg, two times a day	*	Spartz et al (2017)^Citation131 [OS]
		100 mg twice daily for 12 weeks		Westwell-Roper et al^Citation132 (2022) [RCT]
IVIG (Intravenous Immunoglobulin)	Intravenous	Induction dose: 1.5–2 g/kg (maximum dose 70 g); second and subsequent dosing: 1–2 g/kg; intervals of 4–6-week between the doses	**	Frankovich et al (2017)^Citation33 [GL]
		(Octagam 5%) 1 g/kg of body weight every 21 days (+/– 3 days) for a total of six infusions (cycles) over a period of 18 weeks		Melamed et al (2021)^Citation204 [OS]
		6-week trial of IVIG (1 g/kg/day on 2 consecutive days), followed by a 12–24 weeks optional open-label treatment for non-responders.		Williams et al (2016)^Citation115 [OS]
		2 g/kg monthly for three months		Hajjari eu al. (2022)^Citation136 [OS]
		Boost 2 g/kg over 2 days and thereafter every month (1 g/kg over two consecutive days) for 3–6 months		Pfeiffer et al (2020)^Citation122 [GL]
Plasma exchange (plasmapheresis)	Blood plasma	5 single volume exchanges for 2 weeks	*	Perlmutter et al (1999)^Citation205 [RCT]
		1.5 volume therapeutic exchanges for 3–5 days (3–4 runs)		Latimer et al (2015)^Citation138 [OS]
Rituximab	Intravenous	750 mg/m^2 (maximum dose 1000 mg) in 2 doses separated by 2 weeks	*	Frankovich et al (2017)^Citation33 [GL]
Mycophenolate Mofetil (MMF)	Oral	600 mg/m^2/dose twice daily (max dose 1500 mg/dose)	*	Frankovich et al (2017)^Citation33 [GL]
Antimicrobial treatment
Azithromycin	Oral	10 mg/kg up to 500 mg per day; 4 weeks treatment in acute phase; daily administration or 3 times weekly in chronic treatment	**	Blankenship et al (2020)^Citation145 [CR] Murphy et al (2017)^Citation144 [RCT] Snider et al (2005)^Citation143 [PD] Rea et al (2021)^Citation19 [OS]
Penicillin	Oral	Penicillin V-K 250 mg two times a day for 30 days	*	Snider et al (2005)^Citation143 [PD]
	Oral/intramuscular	Amoxicillin/clavulanic acid for 10–21 days at diagnosis followed by prophylaxis with benzathine benzylpenicillin (600,000–1,200,000) every 21 days, for at least 5 years		Lepri et al (2019)^Citation67 [OS]
	Oral/intramuscular	Cycles of oral amoxicillin-clavulanic acid followed by intramuscular benzylpenicillin, amdinocillin every 21 days		Rea et al (2021)^Citation19 [OS]
Cefdinir	Oral	g 14 mg/kg per day in two daily doses (max 600 mg)	*	Murphy et al (2015)^Citation32 [RCT]
Different antimicrobial treatments according to the regional guidelines for suspected ongoing bacterial infections	Oral	Dosage not stated (following regional guidelines for suspected ongoing bacterial infections), maximum treatment duration of 14 days		Pfeiffer et al (2020)^Citation122 [GL]

Notes: The table shows an overview of the available studies on immunomodulatory/anti-inflammatory and antimicrobial treatment stratified on the basis of the totality of the evidence (by a Likert scale from 1 to 3 referring to the number of the supporting studies available; see the abbreviation). The study design is also stated (see the abbreviation). *Between 1 and 3 studies; **between 4 and 6 studies; ***, = or > 7 studies.

Abbreviations: MA, meta-analysis; SR, systematic review; RCT, randomized controlled trial; OS, prospective or retrospective observational study; CCS, case-control study; CSS, cross-sectional study; CR and CS, case reports and case series; GL, guidelines; PD, case report with (parallel design).

Figure 2 Treatment work-up.

Notes: (a and b) the immunomodulatory/anti-inflammatory treatments and the psychological treatments should be guaranteed to all patients; (c) the antimicrobial treatments should be administered if an infective condition is active or if prophylaxis of recurrent infections is needed; (d) psychoactive medications may be adopted when a patient does not respond satisfactorily to immunotherapy or during the acute phases with the purpose of reducing symptoms.

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